2024-03-28T23:22:29Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/86832019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Böse, Jens
Gruber, Achim D
Helming, Laura
Schiebe, Stefanie
Wegener, Ivonne
Hafner, Martin
Beales, Marianne
Köntgen, Frank
Lengeling, Andreas
2007-02-21T08:21:20Z
2004
2007-02-21T08:21:20Z
2004
Journal of Biology 2004 3(4):15
1478-5854
1475-4924
15345036
10.1186/jbiol10
http://hdl.handle.net/10033/8683
549712
Background Phagocytosis of apoptotic cells is fundamental to animal development, immune function and cellular homeostasis. The phosphatidylserine receptor (Ptdsr) on phagocytes has been implicated in the recognition and engulfment of apoptotic cells and in anti-inflammatory signaling. To determine the biological function of the phosphatidylserine receptor in vivo, we inactivated the Ptdsr gene in the mouse. Results Ablation of Ptdsr function in mice causes perinatal lethality, growth retardation and a delay in terminal differentiation of the kidney, intestine, liver and lungs during embryogenesis. Moreover, eye development can be severely disturbed, ranging from defects in retinal differentiation to complete unilateral or bilateral absence of eyes. Ptdsr -/- mice with anophthalmia develop novel lesions, with induction of ectopic retinal-pigmented epithelium in nasal cavities. A comprehensive investigation of apoptotic cell clearance in vivo and in vitro demonstrated that engulfment of apoptotic cells was normal in Ptdsr knockout mice, but Ptdsr-deficient macrophages were impaired in pro- and anti-inflammatory cytokine signaling after stimulation with apoptotic cells or with lipopolysaccharide. Conclusion Ptdsr is essential for the development and differentiation of multiple organs during embryogenesis but not for apoptotic cell removal. Ptdsr may thus have a novel, unexpected developmental function as an important differentiation-promoting gene. Moreover, Ptdsr is not required for apoptotic cell clearance by macrophages but seems to be necessary for the regulation of macrophage cytokine responses. These results clearly contradict the current view that the phosphatidylserine receptor primarily functions in apoptotic cell clearance.
en_US
BioMed Central
http://jbiol.com/content/3/4/15
http://creativecommons.org/licenses/by/2.0
Copyright © 2004 Böse et al., licensee BioMed Central Ltd.
The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal
YES2018-06-13T02:27:08ZBackground
Phagocytosis of apoptotic cells is fundamental to animal development, immune function and cellular homeostasis. The phosphatidylserine receptor (Ptdsr) on phagocytes has been implicated in the recognition and engulfment of apoptotic cells and in anti-inflammatory signaling. To determine the biological function of the phosphatidylserine receptor in vivo, we inactivated the Ptdsr gene in the mouse.
Results
Ablation of Ptdsr function in mice causes perinatal lethality, growth retardation and a delay in terminal differentiation of the kidney, intestine, liver and lungs during embryogenesis. Moreover, eye development can be severely disturbed, ranging from defects in retinal differentiation to complete unilateral or bilateral absence of eyes. Ptdsr -/- mice with anophthalmia develop novel lesions, with induction of ectopic retinal-pigmented epithelium in nasal cavities. A comprehensive investigation of apoptotic cell clearance in vivo and in vitro demonstrated that engulfment of apoptotic cells was normal in Ptdsr knockout mice, but Ptdsr-deficient macrophages were impaired in pro- and anti-inflammatory cytokine signaling after stimulation with apoptotic cells or with lipopolysaccharide.
Conclusion
Ptdsr is essential for the development and differentiation of multiple organs during embryogenesis but not for apoptotic cell removal. Ptdsr may thus have a novel, unexpected developmental function as an important differentiation-promoting gene. Moreover, Ptdsr is not required for apoptotic cell clearance by macrophages but seems to be necessary for the regulation of macrophage cytokine responses. These results clearly contradict the current view that the phosphatidylserine receptor primarily functions in apoptotic cell clearance.oai:repository.helmholtz-hzi.de:10033/86842019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Schneider, Jürgen E
Böse, Jens
Bamforth, Simon D
Gruber, Achim D
Broadbent, Carol
Clarke, Kieran
Neubauer, Stefan
Lengeling, Andreas
Bhattacharya, Shoumo
2007-02-21T08:21:50Z
2004-12-22
2007-02-21T08:21:50Z
2004-12-22
BMC Developmental Biology 2004 4:16
1471-213X
15615595
10.1186/1471-213X-4-16
http://hdl.handle.net/10033/8684
545075
Background Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo. Results We developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development. Conclusions Our novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases.
en_US
BioMed Central
http://www.biomedcentral.com/1471-213X/4/16
http://creativecommons.org/licenses/by/2.0
Copyright © 2004 Schneider et al; licensee BioMed Central Ltd.
Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique
YES2018-06-12T22:51:34ZBackground
Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo.
Results
We developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development.
Conclusions
Our novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases.oai:repository.helmholtz-hzi.de:10033/159562019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Mahieu, Tina
Park, Jin Mo
Revets, Hilde
Pasche, Bastian
Lengeling, Andreas
Staelens, Jan
Wullaert, Andy
Vanlaere, Ineke
Hochepied, Tino
van Roy, Frans
Karin, Michael
Libert, Claude
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
2008-01-11T10:24:09Z
2008-01-11T10:24:09Z
2006-02-14
The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production. 2006, 103 (7):2292-7 Proc. Natl. Acad. Sci. U.S.A.
0027-8424
16455798
10.1073/pnas.0510874103
http://hdl.handle.net/10033/15956
Proceedings of the National Academy of Sciences of the United States of America
Although activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta, although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.
en
Adaptor Proteins, Signal Transducing
Animals
Bone Marrow Cells
Disease Susceptibility
Down-Regulation
Feedback, Biochemical
Female
Interferon-beta
Leishmaniasis, Cutaneous
Lipopolysaccharides
Listeria Infections
Listeria monocytogenes
Macrophages
Male
Membrane Proteins
Mice
Mice, Inbred Strains
Myeloid Differentiation Factor 88
Receptor, Interferon alpha-beta
Receptors, Interferon
The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production.
Article2018-06-13T07:45:53ZAlthough activation of Toll-like receptor 4 (TLR4)-positive cells is essential for eliminating Gram-negative bacteria, overactivation of these cells by the TLR4 ligand LPS initiates a systemic inflammatory reaction and shock. Here we demonstrate that SPRET/Ei mice, derived from Mus spretus, exhibit a dominant resistance against LPS-induced lethality. This resistance is mediated by bone marrow-derived cells. Macrophages from these mice exhibit normal signaling and gene expression responses that depend on the myeloid differentiation factor 88 adaptor protein, but they are impaired in IFN-beta production. The defect appears to be specific for IFN-beta, although the SPRET/Ei IFN-beta promoter is normal. In vivo IFN-beta induction by LPS or influenza virus is very low in SPRET/Ei mice, but IFN-beta-treatment restores the sensitivity to LPS, and IFN type 1 receptor-deficient mice are also resistant to LPS. Because of the defective induction of IFN-beta, these mice are completely resistant to Listeria monocytogenes and highly sensitive to Leishmania major infection. Stimulation of SPRET/Ei macrophages leads to rapid down-regulation of IFN type 1 receptor mRNA expression, which is reflected in poor induction of IFN-beta-dependent genes. This finding indicates that the resistance of SPRET/Ei mice to LPS is due to disruption of a positive-feedback loop that amplifies IFN-beta production. In contrast to TLR4-deficient mice, SPRET/Ei mice resist both LPS and sepsis induced with Klebsiella pneumoniae.oai:repository.helmholtz-hzi.de:10033/422532019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Hahn, Phillip
Böse, Jens
Edler, Stefanie
Lengeling, Andreas
Research Group Infection Genetics, Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research, D-31824 Braunschweig, Germany. Phillip.Hahn@helmholtz-hzi.de
2008-12-11T14:47:36Z
2008-12-11T14:47:36Z
2008
Genomic structure and expression of Jmjd6 and evolutionary analysis in the context of related JmjC domain containing proteins. 2008, 9:293 BMC Genomics
1471-2164
18564434
10.1186/1471-2164-9-293
http://hdl.handle.net/10033/42253
BMC genomics
BACKGROUND: The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function. RESULTS: We describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded beta-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups. CONCLUSION: We give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.
en
http://www.biomedcentral.com/1471-2164/9/293
Amino Acid Sequence
Animals
Chromosome Mapping
Computational Biology
Conserved Sequence
Databases, Nucleic Acid
Databases, Protein
Evolution, Molecular
Expressed Sequence Tags
Gene Expression
Genomics
Humans
Likelihood Functions
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Molecular
Phylogeny
Promoter Regions (Genetics)
Protein Isoforms
Protein Structure, Secondary
Receptors, Cell Surface
Sequence Alignment
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Species Specificity
Genomic structure and expression of Jmjd6 and evolutionary analysis in the context of related JmjC domain containing proteins.
Article2018-06-12T22:14:25ZBACKGROUND: The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function. RESULTS: We describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded beta-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups. CONCLUSION: We give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.oai:repository.helmholtz-hzi.de:10033/705532019-08-30T11:36:04Zcom_10033_620626col_10033_620627
Srivastava, Barkha
Błazejewska, Paulina
Hessmann, Manuela
Bruder, Dunja
Geffers, Robert
Mauel, Susanne
Gruber, Achim D
Schughart, Klaus
Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Braunschweig, Germany.
2009-06-16T11:45:54Z
2009-06-16T11:45:54Z
2009
Host genetic background strongly influences the response to influenza a virus infections. 2009, 4 (3):e4857 PLoS ONE
1932-6203
19293935
10.1371/journal.pone.0004857
http://hdl.handle.net/10033/70553
PloS one
The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD(50) to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses.
en
Host genetic background strongly influences the response to influenza a virus infections.
Article2018-06-13T19:45:08ZThe genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD(50) to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses.oai:repository.helmholtz-hzi.de:10033/784932019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Webby, Celia J
Wolf, Alexander
Gromak, Natalia
Dreger, Mathias
Kramer, Holger
Kessler, Benedikt
Nielsen, Michael L
Schmitz, Corinna
Butler, Danica S
Yates, John R
Delahunty, Claire M
Hahn, Phillip
Lengeling, Andreas
Mann, Matthias
Proudfoot, Nicholas J
Schofield, Christopher J
Böttger, Angelika
Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
2009-08-25T13:11:27Z
2009-08-25T13:11:27Z
2009-07-03
Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. 2009, 325 (5936):90-3 Science
1095-9203
19574390
10.1126/science.1175865
http://hdl.handle.net/10033/78493
Science (New York, N.Y.)
The finding that the metazoan hypoxic response is regulated by oxygen-dependent posttranslational hydroxylations, which regulate the activity and lifetime of hypoxia-inducible factor (HIF), has raised the question of whether other hydroxylases are involved in the regulation of gene expression. We reveal that the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit (U2AF65) undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe(II) and 2-oxoglutarate-dependent dioxygenase Jumonji domain-6 protein (Jmjd6). Jmjd6 is a nuclear protein that has an important role in vertebrate development and is a human homolog of the HIF asparaginyl-hydroxylase. Jmjd6 is shown to change alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for Jmjd6 in the regulation of RNA splicing.
en
Alternative Splicing
Amino Acid Sequence
Biocatalysis
Cell Line
Chromatography, Liquid
Hela Cells
Humans
Hydroxylation
Lysine
Molecular Sequence Data
Nuclear Proteins
Protein Processing, Post-Translational
RNA, Small Interfering
Receptors, Cell Surface
Recombinant Proteins
Ribonucleoproteins
Tandem Mass Spectrometry
Tropomyosin
Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing.
Article2018-06-13T02:44:07ZThe finding that the metazoan hypoxic response is regulated by oxygen-dependent posttranslational hydroxylations, which regulate the activity and lifetime of hypoxia-inducible factor (HIF), has raised the question of whether other hydroxylases are involved in the regulation of gene expression. We reveal that the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit (U2AF65) undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe(II) and 2-oxoglutarate-dependent dioxygenase Jumonji domain-6 protein (Jmjd6). Jmjd6 is a nuclear protein that has an important role in vertebrate development and is a human homolog of the HIF asparaginyl-hydroxylase. Jmjd6 is shown to change alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for Jmjd6 in the regulation of RNA splicing.oai:repository.helmholtz-hzi.de:10033/962752019-08-30T11:29:17Zcom_10033_620626col_10033_620627
Alberts, Rudi
Srivastava, Barkha
Wu, Haiya
Viegas, Nuno
Geffers, Robert
Klawonn, Frank
Novoselova, Natalia
do Valle, Tania Zaverucha
Panthier, Jean-Jacques
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2010-04-12T09:25:07Z
2010-04-12T09:25:07Z
2010-04
Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection. 2010, 12 (4):309-18 Microbes Infect.
1769-714X
20114087
10.1016/j.micinf.2010.01.008
http://hdl.handle.net/10033/96275
Microbes and infection / Institut Pasteur
Inbred mouse strains exhibit differences in susceptibility to influenza A infections. However, the molecular mechanisms underlying these differences are unknown. Therefore, we infected a highly susceptible mouse strain (DBA/2J) and a resistant strain (C57BL/6J) with influenza A H1N1 (PR8) and performed genome-wide expression analysis. We found genes expressed in lung epithelium that were specifically down-regulated in DBA/2J mice, whereas a cluster of genes on chromosome 3 was only down-regulated in C57BL/6J. In both mouse strains, chemokines, cytokines and interferon-response genes were up-regulated, indicating that the main innate immune defense pathways were activated. However, many immune response genes were up-regulated in DBA/2J much stronger than in C57BL/6J, and several immune response genes were exclusively regulated in DBA/2J. Thus, susceptible DBA/2J mice showed a hyper-inflammatory response. This response is similar to infections with highly pathogenic influenza virus and may serve as a paradigm for a hyper-inflammatory host response to influenza A virus.
en
Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection.
Article2018-06-13T15:58:38ZInbred mouse strains exhibit differences in susceptibility to influenza A infections. However, the molecular mechanisms underlying these differences are unknown. Therefore, we infected a highly susceptible mouse strain (DBA/2J) and a resistant strain (C57BL/6J) with influenza A H1N1 (PR8) and performed genome-wide expression analysis. We found genes expressed in lung epithelium that were specifically down-regulated in DBA/2J mice, whereas a cluster of genes on chromosome 3 was only down-regulated in C57BL/6J. In both mouse strains, chemokines, cytokines and interferon-response genes were up-regulated, indicating that the main innate immune defense pathways were activated. However, many immune response genes were up-regulated in DBA/2J much stronger than in C57BL/6J, and several immune response genes were exclusively regulated in DBA/2J. Thus, susceptible DBA/2J mice showed a hyper-inflammatory response. This response is similar to infections with highly pathogenic influenza virus and may serve as a paradigm for a hyper-inflammatory host response to influenza A virus.oai:repository.helmholtz-hzi.de:10033/966582019-08-30T11:28:23Zcom_10033_620626col_10033_620627
Gruenberger, Michael
Alberts, Rudi
Smedley, Damian
Swertz, Morris
Schofield, Paul
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Inhoffenstr, 7, D-38124 Braunschweig, Germany. kls@helmholtz-hzi.de.
2010-04-16T11:52:58Z
2010-04-16T11:52:58Z
2010
Towards the integration of mouse databases - definition and implementation of solutions to two use-cases in mouse functional genomics. 2010, 3 (1):16notBMC Res Notes
1756-0500
20205870
10.1186/1756-0500-3-16
http://hdl.handle.net/10033/96658
BMC research notes
ABSTRACT: BACKGROUND: The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases. RESULTS: We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, "MUSIG-Gen" starts from a list of gene names and collects a wide range of data types from several distributed databases in a "shopping cart"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, "MUSIG-Phen", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes. CONCLUSION: The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists.
ENG
null
Towards the integration of mouse databases - definition and implementation of solutions to two use-cases in mouse functional genomics.
Article2018-06-13T16:58:19ZABSTRACT: BACKGROUND: The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases. RESULTS: We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, "MUSIG-Gen" starts from a list of gene names and collects a wide range of data types from several distributed databases in a "shopping cart"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, "MUSIG-Phen", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes. CONCLUSION: The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists.oai:repository.helmholtz-hzi.de:10033/1076352019-08-30T11:28:51Zcom_10033_620626col_10033_620627
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany, klaus.schughart@helmholtz-hzi.de.
2010-07-14T14:43:32Z
2010-07-14T14:43:32Z
2010-07-11
SYSGENET: a meeting report from a new European network for systems genetics. 2010:notMamm Genome
1432-1777
20623354
10.1007/s00335-010-9273-7
http://hdl.handle.net/10033/107635
Mammalian genome : official journal of the International Mammalian Genome Society
The first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers working in the field of systems genetics using mouse genetic reference populations (GRP) participated in the meeting and exchanged their results, phenotyping approaches, and data analysis tools for studying systems genetics. In addition, the future of GRP resources and phenotyping in Europe was discussed.
ENG
null
SYSGENET: a meeting report from a new European network for systems genetics.
Article2018-06-13T00:27:38ZThe first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers working in the field of systems genetics using mouse genetic reference populations (GRP) participated in the meeting and exchanged their results, phenotyping approaches, and data analysis tools for studying systems genetics. In addition, the future of GRP resources and phenotyping in Europe was discussed.oai:repository.helmholtz-hzi.de:10033/1171452019-08-30T11:30:32Zcom_10033_620626col_10033_620627
Hahn, Phillip
Wegener, Ivonne
Burrells, Alison
Böse, Jens
Wolf, Alexander
Erck, Christian
Butler, Danica
Schofield, Christopher J
Böttger, Angelika
Lengeling, Andreas
Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2010-12-03T15:03:16Z
2010-12-03T15:03:16Z
2010
Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation. 2010, 5 (10):e13769 PLoS ONE
1932-6203
21060799
10.1371/journal.pone.0013769
http://hdl.handle.net/10033/117145
PloS one
BACKGROUND: Methylation of residues in histone tails is part of a network that regulates gene expression. JmjC domain containing proteins catalyze the oxidative removal of methyl groups on histone lysine residues. Here, we report studies to test the involvement of Jumonji domain-containing protein 6 (Jmjd6) in histone lysine demethylation. Jmjd6 has recently been shown to hydroxylate RNA splicing factors and is known to be essential for the differentiation of multiple tissues and cells during embryogenesis. However, there have been conflicting reports as to whether Jmjd6 is a histone-modifying enzyme. METHODOLOGY/PRINCIPAL FINDINGS: Immunolocalization studies reveal that Jmjd6 is distributed throughout the nucleoplasm outside of regions containing heterochromatic DNA, with occasional localization in nucleoli. During mitosis, Jmjd6 is excluded from the nucleus and reappears in the telophase of the cell cycle. Western blot analyses confirmed that Jmjd6 forms homo-multimers of different molecular weights in the nucleus and cytoplasm. A comparison of mono-, di-, and tri-methylation states of H3K4, H3K9, H3K27, H3K36, and H4K20 histone residues in wildtype and Jmjd6-knockout cells indicate that Jmjd6 is not involved in the demethylation of these histone lysine residues. This is further supported by overexpression of enzymatically active and inactive forms of Jmjd6 and subsequent analysis of histone methylation patterns by immunocytochemistry and western blot analysis. Finally, treatment of cells with RNase A and DNase I indicate that Jmjd6 may preferentially associate with RNA/RNA complexes and less likely with chromatin. CONCLUSIONS/SIGNIFICANCE: Taken together, our results provide further evidence that Jmjd6 is unlikely to be involved in histone lysine demethylation. We confirmed that Jmjd6 forms multimers and showed that nuclear localization of the protein involves association with a nucleic acid matrix.
en
Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation.
Article2018-06-13T01:32:28ZBACKGROUND: Methylation of residues in histone tails is part of a network that regulates gene expression. JmjC domain containing proteins catalyze the oxidative removal of methyl groups on histone lysine residues. Here, we report studies to test the involvement of Jumonji domain-containing protein 6 (Jmjd6) in histone lysine demethylation. Jmjd6 has recently been shown to hydroxylate RNA splicing factors and is known to be essential for the differentiation of multiple tissues and cells during embryogenesis. However, there have been conflicting reports as to whether Jmjd6 is a histone-modifying enzyme. METHODOLOGY/PRINCIPAL FINDINGS: Immunolocalization studies reveal that Jmjd6 is distributed throughout the nucleoplasm outside of regions containing heterochromatic DNA, with occasional localization in nucleoli. During mitosis, Jmjd6 is excluded from the nucleus and reappears in the telophase of the cell cycle. Western blot analyses confirmed that Jmjd6 forms homo-multimers of different molecular weights in the nucleus and cytoplasm. A comparison of mono-, di-, and tri-methylation states of H3K4, H3K9, H3K27, H3K36, and H4K20 histone residues in wildtype and Jmjd6-knockout cells indicate that Jmjd6 is not involved in the demethylation of these histone lysine residues. This is further supported by overexpression of enzymatically active and inactive forms of Jmjd6 and subsequent analysis of histone methylation patterns by immunocytochemistry and western blot analysis. Finally, treatment of cells with RNase A and DNase I indicate that Jmjd6 may preferentially associate with RNA/RNA complexes and less likely with chromatin. CONCLUSIONS/SIGNIFICANCE: Taken together, our results provide further evidence that Jmjd6 is unlikely to be involved in histone lysine demethylation. We confirmed that Jmjd6 forms multimers and showed that nuclear localization of the protein involves association with a nucleic acid matrix.oai:repository.helmholtz-hzi.de:10033/1232912019-08-30T11:25:11Zcom_10033_620626col_10033_620627
Michaelson, Jacob J
Alberts, Rudi
Schughart, Klaus
Beyer, Andreas
Cellular Networks and Systems Biology, Biotechnology Center - TU Dresden, Dresden, Germany.
2011-03-02T11:51:15Z
2011-03-02T11:51:15Z
2010
Data-driven assessment of eQTL mapping methods. 2010, 11:502 BMC Genomics
1471-2164
20849587
10.1186/1471-2164-11-502
http://hdl.handle.net/10033/123291
BMC genomics
The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.
en
Animals
Bias (Epidemiology)
Chromosome Mapping
Computer Simulation
Databases, Genetic
Gene Expression Regulation
Hematopoietic Stem Cells
Hippocampus
Lung
Mice
Models, Genetic
Mutation
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Quantitative Trait, Heritable
Sample Size
T-Lymphocytes, Regulatory
Data-driven assessment of eQTL mapping methods.
Article2018-06-13T02:30:37ZThe analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.oai:repository.helmholtz-hzi.de:10033/1234862019-08-30T11:28:51Zcom_10033_620626col_10033_620627
Bucher, Kirsten
Dietz, Klaus
Lackner, Peter
Pasche, Bastian
Fendel, Rolf
Mordmüller, Benjamin
Ben-Smith, Anne
Hoffmann, Wolfgang H
Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
2011-03-03T15:22:40Z
2011-03-03T15:22:40Z
2011-01
Schistosoma co-infection protects against brain pathology but does not prevent severe disease and death in a murine model of cerebral malaria. 2011, 41 (1):21-31 Int. J. Parasitol.
1879-0135
20708623
10.1016/j.ijpara.2010.06.008
http://hdl.handle.net/10033/123486
International journal for parasitology
Co-infections of helminths and malaria parasites are common in human populations in most endemic areas. It has been suggested that concomitant helminth infections inhibit the control of malaria parasitemia but down-modulate severe malarial disease. We tested this hypothesis using a murine co-infection model of schistosomiasis and cerebral malaria. C57BL/6 mice were infected with Schistosoma mansoni and 8-9 weeks later, when Schistosoma infection was patent, mice were co-infected with Plasmodium berghei ANKA strain. We found that a concomitant Schistosoma infection increased parasitemia at the beginning of the P. berghei infection. It did not protect against P. berghei-induced weight loss and hypothermia, and P. berghei-mono-infected as well as S. mansoni-P. berghei-co-infected animals showed a high case fatality between days 6 and 8 of malarial infection. However, co-infection significantly reduced P. berghei-induced brain pathology. Over 40% of the S. mansoni-P. berghei-co-infected animals that died during this period were completely protected against haemorrhaging, plugging of blood vessels and infiltration, indicating that mortality in these animals was not related to cerebral disease. Schistosoma mansoni-P. berghei-co-infected mice had elevated plasma concentrations of IL-5 and IL-13 and on day 6 lower levels of IFN-γ, IL-10, monocyte chemoattractant protein-1 (MCP-1) and monokine induced by IFN-γ (MIG) than P. berghei-mono-infected mice. We conclude that in P. berghei infections, disease and early death are caused by distinct pathogenic mechanisms, which develop in parallel and are differentially influenced by the immune response to S. mansoni. This might explain why, in co-infected mice, death could be induced in the absence of brain pathology.
en
Schistosoma co-infection protects against brain pathology but does not prevent severe disease and death in a murine model of cerebral malaria.
Article2018-06-12T22:03:29ZCo-infections of helminths and malaria parasites are common in human populations in most endemic areas. It has been suggested that concomitant helminth infections inhibit the control of malaria parasitemia but down-modulate severe malarial disease. We tested this hypothesis using a murine co-infection model of schistosomiasis and cerebral malaria. C57BL/6 mice were infected with Schistosoma mansoni and 8-9 weeks later, when Schistosoma infection was patent, mice were co-infected with Plasmodium berghei ANKA strain. We found that a concomitant Schistosoma infection increased parasitemia at the beginning of the P. berghei infection. It did not protect against P. berghei-induced weight loss and hypothermia, and P. berghei-mono-infected as well as S. mansoni-P. berghei-co-infected animals showed a high case fatality between days 6 and 8 of malarial infection. However, co-infection significantly reduced P. berghei-induced brain pathology. Over 40% of the S. mansoni-P. berghei-co-infected animals that died during this period were completely protected against haemorrhaging, plugging of blood vessels and infiltration, indicating that mortality in these animals was not related to cerebral disease. Schistosoma mansoni-P. berghei-co-infected mice had elevated plasma concentrations of IL-5 and IL-13 and on day 6 lower levels of IFN-γ, IL-10, monocyte chemoattractant protein-1 (MCP-1) and monokine induced by IFN-γ (MIG) than P. berghei-mono-infected mice. We conclude that in P. berghei infections, disease and early death are caused by distinct pathogenic mechanisms, which develop in parallel and are differentially influenced by the immune response to S. mansoni. This might explain why, in co-infected mice, death could be induced in the absence of brain pathology.oai:repository.helmholtz-hzi.de:10033/1238462019-08-30T11:25:43Zcom_10033_620626col_10033_620627
Slansky, Elisabeth
Li, Jialiang
Häupl, Thomas
Morawietz, Lars
Krenn, Veit
Pessler, Frank
Medical Faculty 'Carl Gustav Carus', Technical University of Dresden, Germany.
2011-03-08T09:06:05Z
2011-03-08T09:06:05Z
2010-09
Quantitative determination of the diagnostic accuracy of the synovitis score and its components. 2010, 57 (3):436-43 Histopathology
1365-2559
20840673
10.1111/j.1365-2559.2010.03641.x
http://hdl.handle.net/10033/123846
Histopathology
To assess the diagnostic accuracy of a three-component synovitis score and to determine the relative contribution of each of its components to its overall discriminatory power.
en
Arthritis, Rheumatoid
Cell Proliferation
Humans
Osteoarthritis
ROC Curve
Synovial Membrane
Synovitis
Quantitative determination of the diagnostic accuracy of the synovitis score and its components.
Article2011-09-15T00:00:00ZTo assess the diagnostic accuracy of a three-component synovitis score and to determine the relative contribution of each of its components to its overall discriminatory power.oai:repository.helmholtz-hzi.de:10033/1297792019-08-30T11:31:23Zcom_10033_620626col_10033_620627
Durzyńska, Julia
Błazejewska, Paulina
Szydłowski, Jarosław
Goździcka-Józefiak, Anna
Department of Molecular Virology, Faculty of Biology, University of A. Mickiewicz, Poznan, Poznan. juliadur@amu.edu.pl
2011-05-19T10:59:48Z
2011-05-19T10:59:48Z
2010-08
Detection of anti-HPV11-L1 antibodies in immune sera from patients suffering from recurrent respiratory papillomatosis using ELISA. 2010, 23 (4):415-23 Viral Immunol.
1557-8976
20712486
10.1089/vim.2010.0014
http://hdl.handle.net/10033/129779
Viral immunology
Infection with human papillomaviruses (mostly HPV6 and HPV11) may lead to recurrent respiratory papillomatosis (RRP), a chronic disease affecting 2-4/100,000 people. Papillomas have to be removed surgically so patients can breathe normally. Papillomas often grow back and some patients are subjected to a number of operations. In general, asymptomatic HPV-positive people have low levels of antiviral antibodies in their sera, as the human humoral response is weak due to HPV's biology. In patients suffering from RRP who have undergone multiple surgeries, a blood-epithelium barrier breach stimulates the production of anti-HPV antibodies. Our study's aim was to produce HisTag-HPV11-L1 major capsid protein in E. coli cells, and to purify it. We also sought to detect anti-HPV11-L1 antibodies in antisera obtained from RRP patients using ELISA. Clinical samples were collected from 47 patients with RRP (antisera and papillomas), and from 32 controls (sera and oral swabs), from the Wielkopolska region of Poland. Antisera and control sera were used to coat microplates, HisTag-HPV11-L1 antigen was applied, and antibody-antigen complexes were detected by anti-HisTag monoclonal antibody in an ELISA assay. Simultaneously, total cellular DNA was extracted from papillomas and oral squamous cells obtained from controls. All DNA samples were screened for HPV DNA using MY-PCR. All patients were HPV-positive (30% for HPV6 and 70% for HPV11). Statistically significant correlations were found between the amount of anti-HPV11-L1 antibodies in the sera of RRP patients and the number of surgical procedures they underwent. Although HPV virus-like particles are most often used for anti-HPV antibody detection, the ELISA method presented herein is another viable option for use in RRP patients.
en
Antibodies, Viral
Antibody Specificity
Antigens, Viral
Capsid Proteins
Child
Child, Preschool
Enzyme-Linked Immunosorbent Assay
Human papillomavirus 11
Human papillomavirus 6
Humans
Immune Sera
Oncogene Proteins, Viral
Papillomavirus Infections
Poland
Recombinant Proteins
Recurrence
Respiratory Tract Infections
Detection of anti-HPV11-L1 antibodies in immune sera from patients suffering from recurrent respiratory papillomatosis using ELISA.
Article2018-06-13T00:04:48ZInfection with human papillomaviruses (mostly HPV6 and HPV11) may lead to recurrent respiratory papillomatosis (RRP), a chronic disease affecting 2-4/100,000 people. Papillomas have to be removed surgically so patients can breathe normally. Papillomas often grow back and some patients are subjected to a number of operations. In general, asymptomatic HPV-positive people have low levels of antiviral antibodies in their sera, as the human humoral response is weak due to HPV's biology. In patients suffering from RRP who have undergone multiple surgeries, a blood-epithelium barrier breach stimulates the production of anti-HPV antibodies. Our study's aim was to produce HisTag-HPV11-L1 major capsid protein in E. coli cells, and to purify it. We also sought to detect anti-HPV11-L1 antibodies in antisera obtained from RRP patients using ELISA. Clinical samples were collected from 47 patients with RRP (antisera and papillomas), and from 32 controls (sera and oral swabs), from the Wielkopolska region of Poland. Antisera and control sera were used to coat microplates, HisTag-HPV11-L1 antigen was applied, and antibody-antigen complexes were detected by anti-HisTag monoclonal antibody in an ELISA assay. Simultaneously, total cellular DNA was extracted from papillomas and oral squamous cells obtained from controls. All DNA samples were screened for HPV DNA using MY-PCR. All patients were HPV-positive (30% for HPV6 and 70% for HPV11). Statistically significant correlations were found between the amount of anti-HPV11-L1 antibodies in the sera of RRP patients and the number of surgical procedures they underwent. Although HPV virus-like particles are most often used for anti-HPV antibody detection, the ELISA method presented herein is another viable option for use in RRP patients.oai:repository.helmholtz-hzi.de:10033/1329862019-08-30T11:32:17Zcom_10033_620626col_10033_620627
do Valle, Tânia Zaverucha
Billecocq, Agnès
Guillemot, Laurent
Alberts, Rudi
Gommet, Céline
Geffers, Robert
Calabrese, Kátia
Schughart, Klaus
Bouloy, Michèle
Montagutelli, Xavier
Panthier, Jean-Jacques
Unité Génétique Fonctionnelle de la Souris, Institut Pasteur, Paris, France.
2011-06-10T14:15:40Z
2011-06-10T14:15:40Z
2010-11-15
A new mouse model reveals a critical role for host innate immunity in resistance to Rift Valley fever. 2010, 185 (10):6146-56 J. Immunol.
1550-6606
20937849
10.4049/jimmunol.1000949
http://hdl.handle.net/10033/132986
Journal of immunology (Baltimore, Md. : 1950)
Rift Valley fever (RVF) is an arthropod-borne viral disease repeatedly reported in many African countries and, more recently, in Saudi Arabia and Yemen. RVF virus (RVFV) primarily infects domesticated ruminants, resulting in miscarriage in pregnant females and death for newborns and young animals. It also has the ability to infect humans, causing a feverish syndrome, meningoencephalitis, or hemorrhagic fever. The various outcomes of RVFV infection in animals and humans argue for the existence of host genetic determinants controlling the disease. We investigated the susceptibility of inbred mouse strains to infection with the virulent RVFV ZH548 strain. Compared with classical BALB/cByJ mice, wild-derived Mus m. musculus MBT/Pas mice exhibited earlier and greater viremia and died sooner, a result in sharp contrast with their resistance to infection with West Nile virus and influenza A. Infection of mouse embryonic fibroblasts (MEFs) from MBT/Pas mice with RVFV also resulted in higher viral production. Microarray and quantitative RT-PCR experiments showed that BALB/cByJ MEFs displayed a significant activation of the type I IFN pathway. In contrast, MBT/Pas MEFs elicited a delayed and partial type I IFN response to RVFV infection. RNA interference-mediated inhibition of genes that were not induced by RVFV in MBT/Pas MEFs increased viral production in BALB/cByJ MEFs, thus demonstrating their functional importance in limiting viral replication. We conclude that the failure of MBT/Pas murine strain to induce, in due course, a complete innate immune response is instrumental in the selective susceptibility to RVF.
en
Animals
Disease Models, Animal
Fibroblasts
Gene Expression Profiling
Genetic Predisposition to Disease
Immunity, Innate
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Rift Valley Fever
A new mouse model reveals a critical role for host innate immunity in resistance to Rift Valley fever.
Article2018-06-13T07:42:17ZRift Valley fever (RVF) is an arthropod-borne viral disease repeatedly reported in many African countries and, more recently, in Saudi Arabia and Yemen. RVF virus (RVFV) primarily infects domesticated ruminants, resulting in miscarriage in pregnant females and death for newborns and young animals. It also has the ability to infect humans, causing a feverish syndrome, meningoencephalitis, or hemorrhagic fever. The various outcomes of RVFV infection in animals and humans argue for the existence of host genetic determinants controlling the disease. We investigated the susceptibility of inbred mouse strains to infection with the virulent RVFV ZH548 strain. Compared with classical BALB/cByJ mice, wild-derived Mus m. musculus MBT/Pas mice exhibited earlier and greater viremia and died sooner, a result in sharp contrast with their resistance to infection with West Nile virus and influenza A. Infection of mouse embryonic fibroblasts (MEFs) from MBT/Pas mice with RVFV also resulted in higher viral production. Microarray and quantitative RT-PCR experiments showed that BALB/cByJ MEFs displayed a significant activation of the type I IFN pathway. In contrast, MBT/Pas MEFs elicited a delayed and partial type I IFN response to RVFV infection. RNA interference-mediated inhibition of genes that were not induced by RVFV in MBT/Pas MEFs increased viral production in BALB/cByJ MEFs, thus demonstrating their functional importance in limiting viral replication. We conclude that the failure of MBT/Pas murine strain to induce, in due course, a complete innate immune response is instrumental in the selective susceptibility to RVF.oai:repository.helmholtz-hzi.de:10033/1341792019-08-30T11:31:49Zcom_10033_620626col_10033_620627
Swertz, Morris A
Velde, K Joeri van der
Tesson, Bruno M
Scheltema, Richard A
Arends, Danny
Vera, Gonzalo
Alberts, Rudi
Dijkstra, Martijn
Schofield, Paul
Schughart, Klaus
Hancock, John M
Smedley, Damian
Wolstencroft, Katy
Goble, Carole
de Brock, Engbert O
Jones, Andrew R
Parkinson, Helen E
Jansen, Ritsert C
Genomics Coordination Center, Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. m.a.swertz@rug.nl
2011-06-22T12:36:49Z
2011-06-22T12:36:49Z
2010
XGAP: a uniform and extensible data model and software platform for genotype and phenotype experiments. 2010, 11 (3):R27 Genome Biol.
1465-6914
20214801
10.1186/gb-2010-11-3-r27
http://hdl.handle.net/10033/134179
Genome biology
We present an extensible software model for the genotype and phenotype community, XGAP. Readers can download a standard XGAP (http://www.xgap.org) or auto-generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans.
en
Animals
Genetic Association Studies
Genomics
Humans
Mice
Models, Genetic
Quantitative Trait Loci
Software
XGAP: a uniform and extensible data model and software platform for genotype and phenotype experiments.
Article2018-06-13T01:33:31ZWe present an extensible software model for the genotype and phenotype community, XGAP. Readers can download a standard XGAP (http://www.xgap.org) or auto-generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans.oai:repository.helmholtz-hzi.de:10033/1361352019-08-30T11:31:49Zcom_10033_620626col_10033_620627
Holz, Andreas
Kollmus, Heike
Ryge, Jesper
Niederkofler, Vera
Dias, Jose
Ericson, Johan
Stoeckli, Esther T
Kiehn, Ole
Arnold, Hans-Henning
Cell and Molecular Biology, University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany.
2011-07-15T14:21:44Z
2011-07-15T14:21:44Z
2010-12
The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance. 2010, 137 (24):4249-60 Development
1477-9129
21068056
10.1242/dev.053819
http://hdl.handle.net/10033/136135
Development (Cambridge, England)
The transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling. The present report shows that in mice lacking both Nkx2 proteins, the presumptive progenitor cells in the p3 domain of the neural tube convert to motor neurons (MN) and never acquire the fate of V3 interneurons. This result supports the concept that Nkx2 transcription factors are required to establish V3 progenitor cells by repressing the early MN lineage-specific program, including genes like Olig2. Nkx2.2 and Nkx2.9 proteins also perform an additional, hitherto unknown, function in the development of non-neuronal floor plate cells. Here, we demonstrate that loss of both Nkx2 genes results in an anatomically smaller and functionally impaired floor plate causing severe defects in axonal pathfinding of commissural neurons. Defective floor plates were also seen in Nkx2.2(+/-);Nkx2.9(-/-) compound mutants and even in single Nkx2.9(-/-) mutants, suggesting that floor plate development is sensitive to dose and/or timing of Nkx2 expression. Interestingly, adult Nkx2.2(+/-);Nkx2.9(-/-) compound-mutant mice exhibit abnormal locomotion, including a permanent or intermittent hopping gait. Drug-induced locomotor-like activity in spinal cords of mutant neonates is also affected, demonstrating increased variability of left-right and flexor-extensor coordination. Our data argue that the Nkx2.2 and Nkx2.9 transcription factors contribute crucially to the formation of neuronal networks that function as central pattern generators for locomotor activity in the spinal cord. As both factors affect floor plate development, control of commissural axon trajectories might be the underlying mechanism.
en
Animals
Body Patterning
Embryo, Mammalian
Homeodomain Proteins
Immunohistochemistry
In Situ Hybridization
Mice
Mice, Mutant Strains
Neural Tube
Spinal Cord
Stem Cells
Transcription Factors
The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance.
Article2018-06-13T17:07:55ZThe transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling. The present report shows that in mice lacking both Nkx2 proteins, the presumptive progenitor cells in the p3 domain of the neural tube convert to motor neurons (MN) and never acquire the fate of V3 interneurons. This result supports the concept that Nkx2 transcription factors are required to establish V3 progenitor cells by repressing the early MN lineage-specific program, including genes like Olig2. Nkx2.2 and Nkx2.9 proteins also perform an additional, hitherto unknown, function in the development of non-neuronal floor plate cells. Here, we demonstrate that loss of both Nkx2 genes results in an anatomically smaller and functionally impaired floor plate causing severe defects in axonal pathfinding of commissural neurons. Defective floor plates were also seen in Nkx2.2(+/-);Nkx2.9(-/-) compound mutants and even in single Nkx2.9(-/-) mutants, suggesting that floor plate development is sensitive to dose and/or timing of Nkx2 expression. Interestingly, adult Nkx2.2(+/-);Nkx2.9(-/-) compound-mutant mice exhibit abnormal locomotion, including a permanent or intermittent hopping gait. Drug-induced locomotor-like activity in spinal cords of mutant neonates is also affected, demonstrating increased variability of left-right and flexor-extensor coordination. Our data argue that the Nkx2.2 and Nkx2.9 transcription factors contribute crucially to the formation of neuronal networks that function as central pattern generators for locomotor activity in the spinal cord. As both factors affect floor plate development, control of commissural axon trajectories might be the underlying mechanism.oai:repository.helmholtz-hzi.de:10033/2154702019-08-30T11:31:23Zcom_10033_620626col_10033_620627
Kas, Martien J
Kahn, René S
Collier, David A
Waddington, John L
Ekelund, Jesper
Porteous, David J
Schughart, Klaus
Hovatta, Iiris
Department of Neuroscience and Pharmacology, University Medical Center Utrecht, 3584CG Utrecht, The Netherlands. m.j.h.kas@umcutrecht.nl
2012-03-13T08:57:16Z
2012-03-13T08:57:16Z
2011-09-28
Translational neuroscience of Schizophrenia: seeking a meeting of minds between mouse and man. 2011, 3 (102):102mr3 Sci Transl Med
1946-6242
21957171
10.1126/scitranslmed.3002917
http://hdl.handle.net/10033/215470
Science translational medicine
Understanding the etiology of developmental brain disorders such as schizophrenia is critical for achieving advances in treatment and requires new research strategies that control for individual variation in genetic background, environmental challenges, and expression of phenotype. SYSGENET, a European systems genetics network for the study of complex genetic human diseases with mouse genetic reference populations, brought together in Helsinki a cross-disciplinary group of clinical and basic scientists and mouse geneticists to debate, formulate, and prioritize a strategy for future research based on mouse models. The main conclusions of this meeting are summarized here.
en
Archived with thanks to Science translational medicine
Translational neuroscience of Schizophrenia: seeking a meeting of minds between mouse and man.
Article2018-06-13T00:26:11ZUnderstanding the etiology of developmental brain disorders such as schizophrenia is critical for achieving advances in treatment and requires new research strategies that control for individual variation in genetic background, environmental challenges, and expression of phenotype. SYSGENET, a European systems genetics network for the study of complex genetic human diseases with mouse genetic reference populations, brought together in Helsinki a cross-disciplinary group of clinical and basic scientists and mouse geneticists to debate, formulate, and prioritize a strategy for future research based on mouse models. The main conclusions of this meeting are summarized here.oai:repository.helmholtz-hzi.de:10033/2183312019-08-30T11:34:48Zcom_10033_620626col_10033_620627
Durrant, Caroline
Swertz, Morris A
Alberts, Rudi
Arends, Danny
Möller, Steffen
Mott, Richard
Prins, Pjotr
van der Velde, K Joeri
Jansen, Ritsert C
Schughart, Klaus
University of Oxford.
2012-04-12T14:22:09Z
2012-04-12T14:22:09Z
2012-03
Bioinformatics tools and database resources for systems genetics analysis in mice--a short review and an evaluation of future needs. 2012, 13 (2):135-42 Brief. Bioinformatics
1477-4054
22396485
10.1093/bib/bbr026
http://hdl.handle.net/10033/218331
Briefings in bioinformatics
During a meeting of the SYSGENET working group 'Bioinformatics', currently available software tools and databases for systems genetics in mice were reviewed and the needs for future developments discussed. The group evaluated interoperability and performed initial feasibility studies. To aid future compatibility of software and exchange of already developed software modules, a strong recommendation was made by the group to integrate HAPPY and R/qtl analysis toolboxes, GeneNetwork and XGAP database platforms, and TIQS and xQTL processing platforms. R should be used as the principal computer language for QTL data analysis in all platforms and a 'cloud' should be used for software dissemination to the community. Furthermore, the working group recommended that all data models and software source code should be made visible in public repositories to allow a coordinated effort on the use of common data structures and file formats.
en
Archived with thanks to Briefings in bioinformatics
Bioinformatics tools and database resources for systems genetics analysis in mice--a short review and an evaluation of future needs.
Article2018-06-12T17:58:31ZDuring a meeting of the SYSGENET working group 'Bioinformatics', currently available software tools and databases for systems genetics in mice were reviewed and the needs for future developments discussed. The group evaluated interoperability and performed initial feasibility studies. To aid future compatibility of software and exchange of already developed software modules, a strong recommendation was made by the group to integrate HAPPY and R/qtl analysis toolboxes, GeneNetwork and XGAP database platforms, and TIQS and xQTL processing platforms. R should be used as the principal computer language for QTL data analysis in all platforms and a 'cloud' should be used for software dissemination to the community. Furthermore, the working group recommended that all data models and software source code should be made visible in public repositories to allow a coordinated effort on the use of common data structures and file formats.oai:repository.helmholtz-hzi.de:10033/2394742019-08-30T11:37:23Zcom_10033_620626col_10033_620627
Anderson, Iain
Held, Brittany
Lapidus, Alla
Nolan, Matt
Lucas, Susan
Tice, Hope
Del Rio, Tijana Glavina
Cheng, Jan-Fang
Han, Cliff
Tapia, Roxanne
Goodwin, Lynne A
Pitluck, Sam
Liolios, Konstantinos
Mavromatis, Konstantinos
Pagani, Ioanna
Ivanova, Natalia
Mikhailova, Natalia
Pati, Amrita
Chen, Amy
Palaniappan, Krishna
Land, Miriam
Brambilla, Evelyne-Marie
Rohde, Manfred
Spring, Stefan
Göker, Markus
Detter, John C
Woyke, Tanja
Bristow, James
Eisen, Jonathan A
Markowitz, Victor
Hugenholtz, Philip
Klenk, Hans-Peter
Kyrpides, Nikos C
2012-08-22T13:30:14Z
2012-08-22T13:30:14Z
2012-05-25
Genome sequence of the homoacetogenic bacterium Holophaga foetida type strain (TMBS4(T)). 2012, 6 (2):174-84 Stand Genomic Sci
1944-3277
22768361
10.4056/sigs.2746047
http://hdl.handle.net/10033/239474
Standards in genomic sciences
Holophaga foetida Liesack et al. 1995 is a member of the phylum Acidobacteria and is of interest for its ability to anaerobically degrade aromatic compounds and for its production of volatile sulfur compounds through a unique pathway. The genome of H. foetida strain TMBS4(T) is the first to be sequenced for a representative of the class Holophagae. Here we describe the features of this organism, together with the complete genome sequence (improved high quality draft), and annotation. The 4,127,237 bp long chromosome with its 3,615 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
en
Archived with thanks to Standards in genomic sciences
Genome sequence of the homoacetogenic bacterium Holophaga foetida type strain (TMBS4(T)).
Article2018-06-13T01:22:02ZHolophaga foetida Liesack et al. 1995 is a member of the phylum Acidobacteria and is of interest for its ability to anaerobically degrade aromatic compounds and for its production of volatile sulfur compounds through a unique pathway. The genome of H. foetida strain TMBS4(T) is the first to be sequenced for a representative of the class Holophagae. Here we describe the features of this organism, together with the complete genome sequence (improved high quality draft), and annotation. The 4,127,237 bp long chromosome with its 3,615 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.oai:repository.helmholtz-hzi.de:10033/2359712019-08-30T11:37:44Zcom_10033_620626col_10033_620627
Alberts, Rudi
Lu, Lu
Williams, Robert W
Schughart, Klaus
Department of Infection Genetics, University of Veterinary Medicine Hannover, Inhoffenstr, Braunschweig, Germany.
2012-07-27T12:11:15Z
2012-07-27T12:11:15Z
2011
Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures. 2011, 12:61 Respir. Res.
1465-993X
21535883
10.1186/1465-9921-12-61
http://hdl.handle.net/10033/235971
Respiratory research
The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.
en
Archived with thanks to Respiratory research
Animals
B-Lymphocytes
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease
Heredity
Lod Score
Lung
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred DBA
Oligonucleotide Array Sequence Analysis
Phenotype
Quantitative Trait, Heritable
RNA, Messenger
Species Specificity
T-Lymphocytes
Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures.
Article2018-06-13T03:46:41ZThe lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.oai:repository.helmholtz-hzi.de:10033/2370712019-08-22T12:38:21Zcom_10033_620626col_10033_620627
2012-08-02T13:57:39Z
2012-08-02T13:57:39Z
2012-02
The genome architecture of the Collaborative Cross mouse genetic reference population. 2012, 190 (2):389-401 Genetics
1943-2631
22345608
10.1534/genetics.111.132639
http://hdl.handle.net/10033/237071
Genetics
The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.
en
Archived with thanks to Genetics
Animals
Breeding
Crosses, Genetic
Extinction, Biological
Female
Founder Effect
Genome
Genotype
Linkage Disequilibrium
Male
Mice
Mice, Inbred Strains
Reproduction
The genome architecture of the Collaborative Cross mouse genetic reference population.
Article2018-06-13T21:27:39ZThe Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.oai:repository.helmholtz-hzi.de:10033/2451912019-08-30T11:27:46Zcom_10033_620626com_10033_6832col_10033_620627col_10033_6833
Wilke, Sonja
Krausze, Joern
Büssow, Konrad
Department of Molecular Structural Biology, Helmholtz Centre for Infection Research, Inhoffenstr, 7, 38124 Braunschweig, Germany. konrad@buessow.com.
2012-09-20T09:22:54Z
2012-09-20T09:22:54Z
2012
Crystal structure of the conserved domain of the DC lysosomal associated membrane protein: implications for the lysosomal glycocalyx. 2012, 10:62 BMC Biol.
1741-7007
22809326
10.1186/1741-7007-10-62
http://hdl.handle.net/10033/245191
BMC biology
ABSTRACT:
en
Archived with thanks to BMC biology
Crystal structure of the conserved domain of the DC lysosomal associated membrane protein: implications for the lysosomal glycocalyx.
Article2018-06-12T17:46:13ZABSTRACT:oai:repository.helmholtz-hzi.de:10033/2552402019-08-30T11:28:51Zcom_10033_620626col_10033_620627
Akmatov, Manas K
Gatzemeier, Anja
Schughart, Klaus
Pessler, Frank
Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2012-12-11T13:06:39Z
2012-12-11T13:06:39Z
2012
Equivalence of self- and staff-collected nasal swabs for the detection of viral respiratory pathogens. 2012, 7 (11):e48508 PLoS ONE
1932-6203
23155387
10.1371/journal.pone.0048508
http://hdl.handle.net/10033/255240
PloS one
The need for the timely collection of diagnostic biosamples during symptomatic episodes represents a major obstacle to large-scale studies on acute respiratory infection (ARI) epidemiology. This may be circumvented by having the participants collect their own nasal swabs. We compared self- and staff-collected swabs in terms of swabbing quality and detection of viral respiratory pathogens.
en
Archived with thanks to PloS one
Equivalence of self- and staff-collected nasal swabs for the detection of viral respiratory pathogens.
Article2018-06-12T17:33:46ZThe need for the timely collection of diagnostic biosamples during symptomatic episodes represents a major obstacle to large-scale studies on acute respiratory infection (ARI) epidemiology. This may be circumvented by having the participants collect their own nasal swabs. We compared self- and staff-collected swabs in terms of swabbing quality and detection of viral respiratory pathogens.oai:repository.helmholtz-hzi.de:10033/2554632019-08-30T11:31:49Zcom_10033_620626col_10033_620627
He, Feng
Chen, Hairong
Probst-Kepper, Michael
Geffers, Robert
Eifes, Serge
Del Sol, Antonio
Schughart, Klaus
Zeng, An-Ping
Balling, Rudi
1] Department of Infection Genetics, Helmholtz Centre for Infection Research (HZI), University of Veterinary Medicine Hannover, Braunschweig, Germany [2] Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
2012-12-12T10:43:05Z
2012-12-12T10:43:05Z
2012-11-20
PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells. 2012, 8:624 Mol. Syst. Biol.
1744-4292
23169000
10.1038/msb.2012.56
http://hdl.handle.net/10033/255463
Molecular systems biology
Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function.
en
Archived with thanks to Molecular systems biology
PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.
Article2018-06-13T09:23:54ZHuman FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function.oai:repository.helmholtz-hzi.de:10033/2789392019-08-30T11:37:24Zcom_10033_620626col_10033_620627
Nedelko, Tatiana
Kollmus, Heike
Klawonn, Frank
Spijker, Sabine
Lu, Lu
Heßman, Manuela
Alberts, Rudi
Williams, Robert W
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, 38124, Braunschweig, Germany.
2013-04-04T13:30:16Z
2013-04-04T13:30:16Z
2012
Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner. 2012, 13:411 BMC Genomics
1471-2164
22905720
10.1186/1471-2164-13-411
http://hdl.handle.net/10033/278939
BMC genomics
There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.
en
Archived with thanks to BMC genomics
Alleles
Animals
Body Weight
Chromosome Mapping
Disease Resistance
Host-Pathogen Interactions
Influenza A Virus, H1N1 Subtype
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Orthomyxoviridae Infections
Quantitative Trait Loci
Time Factors
Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner.
Article2018-06-13T09:07:20ZThere is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.oai:repository.helmholtz-hzi.de:10033/2885792019-08-30T11:37:44Zcom_10033_620626col_10033_620627
Dengler, Leonie
May, Mathias
Wilk, Esther
Bahgat, Mahmoud M
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2013-05-07T08:54:54Z
2013-05-07T08:54:54Z
2012
Immunization with live virus vaccine protects highly susceptible DBA/2J mice from lethal influenza A H1N1 infection. 2012, 9:212 Virol. J.
1743-422X
22992381
10.1186/1743-422X-9-212
http://hdl.handle.net/10033/288579
Virology journal
The mouse represents an important model system to study the host response to influenza A infections and to evaluate new prevention or treatment strategies. We and others reported that the susceptibility to influenza A virus infections strongly varies among different inbred mouse strains. In particular, DBA/2J mice are highly susceptible to several influenza A subtypes, including human isolates and exhibit severe symptoms after infection with clinical isolates.
en
Archived with thanks to Virology journal
Animals
Antibodies, Viral
Antibody Specificity
Disease Models, Animal
Humans
Immunoglobulin G
Influenza A Virus, H1N1 Subtype
Influenza Vaccines
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Orthomyxoviridae Infections
Vaccines, Attenuated
Immunization with live virus vaccine protects highly susceptible DBA/2J mice from lethal influenza A H1N1 infection.
Article2018-06-12T21:36:13ZThe mouse represents an important model system to study the host response to influenza A infections and to evaluate new prevention or treatment strategies. We and others reported that the susceptibility to influenza A virus infections strongly varies among different inbred mouse strains. In particular, DBA/2J mice are highly susceptible to several influenza A subtypes, including human isolates and exhibit severe symptoms after infection with clinical isolates.oai:repository.helmholtz-hzi.de:10033/3048372019-08-30T11:34:19Zcom_10033_620626col_10033_620627
Dimitrakopoulou, Konstantina
Vrahatis, Aristidis G.
Wilk, Esther
Tsakalidis, Athanasios K.
Bezerianos, Anastasios
2013-10-31T10:11:58Z
2013-10-31T10:11:58Z
2013-10-31
OLYMPUS: An automated hybrid clustering method in time series gene expression. Case study: Host response after Influenza A (H1N1) infection 2013, 111 (3):650 Computer Methods and Programs in Biomedicine
1692607
10.1016/j.cmpb.2013.05.025
http://hdl.handle.net/10033/304837
Computer Methods and Programs in Biomedicine
http://linkinghub.elsevier.com/retrieve/pii/S016926071300182X
Archived with thanks to Computer Methods and Programs in Biomedicine
OLYMPUS: An automated hybrid clustering method in time series gene expression. Case study: Host response after Influenza A (H1N1) infection
Article2018-06-12T18:00:44Zoai:repository.helmholtz-hzi.de:10033/3052592019-08-30T11:25:43Zcom_10033_620626col_10033_620627
Lasch, Peter
Neuschl, Christina
Millrose, Marion K
Alberts, Rudi
Schughart, Klaus
Naumann, Dieter
Brockmann, Gudrun A
Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115, Berlin, Germany.
2013-11-12T15:31:52Z
2013-11-12T15:31:52Z
2013
ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains. 2013, 14:386 BMC Genomics
1471-2164
23758785
10.1186/1471-2164-14-386
http://hdl.handle.net/10033/305259
BMC genomics
Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues.
en
Archived with thanks to BMC genomics
Animals
DNA, Recombinant
Diet, High-Fat
Genomics
Inbreeding
Male
Mice
Phenotype
Quantitative Trait Loci
Spectroscopy, Fourier Transform Infrared
ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains.
Article2018-06-13T14:06:52ZObesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues.oai:repository.helmholtz-hzi.de:10033/3056352019-08-30T11:33:02Zcom_10033_620626col_10033_620627
Leist, Sarah
Kollmus, Heike
Pilzner, Carolin
Schughart, Klaus
Infektionsgenetic, Hemholtz Zentrum für Infektionsforschung, Inhoffenstr. 7, 38125Braunschweig
2013-11-21T15:47:24Z
2013-11-21T15:47:24Z
2013-11-21
Eine innovative Mauspopulation als genetisches Modell für den Menschen 2013, 19 (5):502 BIOspektrum
0947-0867
1868-6249
10.1007/s12268-013-0346-5
http://hdl.handle.net/10033/305635
BIOspektrum
http://link.springer.com/10.1007/s12268-013-0346-5
Archived with thanks to BIOspektrum
Eine innovative Mauspopulation als genetisches Modell für den Menschen
Article2014-09-15T00:00:00Zoai:repository.helmholtz-hzi.de:10033/3066412019-08-30T11:33:01Zcom_10033_620626col_10033_620627
Hatesuer, Bastian
Bertram, Stephanie
Mehnert, Nora
Bahgat, Mahmoud M.
Nelson, Peter S.
Pöhlman, Stefan
Schughart, Klaus
Basler, Christopher F.
Infectiongenetics, Helmholtz Centre for Infection research, Inhoffenstr. 7, D38124 Braunschweig, Germany
2013-12-10T09:38:55Z
2013-12-10T09:38:55Z
2013-12-10
Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice 2013, 9 (12):e1003774 PLoS Pathogens
1553-7374
10.1371/journal.ppat.1003774
http://hdl.handle.net/10033/306641
PLoS Pathogens
http://dx.plos.org/10.1371/journal.ppat.1003774
Archived with thanks to PLoS Pathogens
Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice
Article2018-06-13T20:01:41Zoai:repository.helmholtz-hzi.de:10033/3222302019-08-30T11:36:05Zcom_10033_620626col_10033_620627
Hall, Rabea A
Liebe, Roman
Hochrath, Katrin
Kazakov, Andrey
Alberts, Rudi
Laufs, Ulrich
Böhm, Michael
Fischer, Hans-Peter
Williams, Robert W
Schughart, Klaus
Weber, Susanne N
Lammert, Frank
2014-06-24T12:58:19Z
2014-06-24T12:58:19Z
2014
Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population. 2014, 9 (2):e89279 PLoS ONE
1932-6203
24586654
10.1371/journal.pone.0089279
http://hdl.handle.net/10033/322230
PloS one
The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.
en
Archived with thanks to PloS one
Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.
Article2018-06-13T07:25:12ZThe progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.oai:repository.helmholtz-hzi.de:10033/3323512019-08-30T11:36:05Zcom_10033_620626col_10033_620627
Dengler, Leonie
Kühn, Nora
Shin, Dai-Lun
Hatesuer, Bastian
Schughart, Klaus
Wilk, Esther
2014-10-09T08:55:44Z
2014-10-09T08:55:44Z
2014
Cellular changes in blood indicate severe respiratory disease during influenza infections in mice. 2014, 9 (7):e103149 PLoS ONE
1932-6203
25058639
10.1371/journal.pone.0103149
http://hdl.handle.net/10033/332351
PloS one
Influenza A infection is a serious threat to human and animal health. Many of the biological mechanisms of the host-pathogen-interactions are still not well understood and reliable biomarkers indicating the course of the disease are missing. The mouse is a valuable model system enabling us to study the local inflammatory host response and the influence on blood parameters under controlled circumstances. Here, we compared the lung and peripheral changes after PR8 (H1N1) influenza A virus infection in C57BL/6J and DBA/2J mice using virus variants of different pathogenicity resulting in non-lethal and lethal disease. We monitored hematological and immunological parameters revealing that the granulocyte to lymphocyte ratio in the blood represents an early indicator of severe disease progression already two days after influenza A infection in mice. These findings might be relevant to optimize early diagnostic options of severe influenza disease and to monitor successful therapeutic treatment in humans.
en
Archived with thanks to PloS one
Cellular changes in blood indicate severe respiratory disease during influenza infections in mice.
Article2018-06-12T23:30:56ZInfluenza A infection is a serious threat to human and animal health. Many of the biological mechanisms of the host-pathogen-interactions are still not well understood and reliable biomarkers indicating the course of the disease are missing. The mouse is a valuable model system enabling us to study the local inflammatory host response and the influence on blood parameters under controlled circumstances. Here, we compared the lung and peripheral changes after PR8 (H1N1) influenza A virus infection in C57BL/6J and DBA/2J mice using virus variants of different pathogenicity resulting in non-lethal and lethal disease. We monitored hematological and immunological parameters revealing that the granulocyte to lymphocyte ratio in the blood represents an early indicator of severe disease progression already two days after influenza A infection in mice. These findings might be relevant to optimize early diagnostic options of severe influenza disease and to monitor successful therapeutic treatment in humans.oai:repository.helmholtz-hzi.de:10033/3326452019-08-30T11:34:48Zcom_10033_620626col_10033_620627
Regus-Leidig, Hanna
Fuchs, Michaela
Löhner, Martina
Leist, Sarah R
Leal-Ortiz, Sergio
Chiodo, Vince A
Hauswirth, William W
Garner, Craig C
Brandstätter, Johann H
2014-10-10T09:40:19Z
2014-10-10T09:40:19Z
2014
In vivo knockdown of Piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses. 2014, 8:259 Front Cell Neurosci
1662-5102
25232303
10.3389/fncel.2014.00259
http://hdl.handle.net/10033/332645
Frontiers in cellular neuroscience
Piccolo is the largest known cytomatrix protein at active zones of chemical synapses. A growing number of studies on conventional chemical synapses assign Piccolo a role in the recruitment and integration of molecules relevant for both endo- and exocytosis of synaptic vesicles, the dynamic assembly of presynaptic F-actin, as well as the proteostasis of presynaptic proteins, yet a direct function in the structural organization of the active zone has not been uncovered in part due to the expression of multiple alternatively spliced isoforms. We recently identified Piccolino, a Piccolo splice variant specifically expressed in sensory ribbon synapses of the eye and ear. Here we down regulated Piccolino in vivo via an adeno-associated virus-based RNA interference approach and explored the impact on the presynaptic structure of mouse photoreceptor ribbon synapses. Detailed immunocytochemical light and electron microscopical analysis of Piccolino knockdown in photoreceptors revealed a hitherto undescribed photoreceptor ribbon synaptic phenotype with striking morphological changes of synaptic ribbon ultrastructure.
en
Archived with thanks to Frontiers in cellular neuroscience
In vivo knockdown of Piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses.
Article2018-06-13T15:14:15ZPiccolo is the largest known cytomatrix protein at active zones of chemical synapses. A growing number of studies on conventional chemical synapses assign Piccolo a role in the recruitment and integration of molecules relevant for both endo- and exocytosis of synaptic vesicles, the dynamic assembly of presynaptic F-actin, as well as the proteostasis of presynaptic proteins, yet a direct function in the structural organization of the active zone has not been uncovered in part due to the expression of multiple alternatively spliced isoforms. We recently identified Piccolino, a Piccolo splice variant specifically expressed in sensory ribbon synapses of the eye and ear. Here we down regulated Piccolino in vivo via an adeno-associated virus-based RNA interference approach and explored the impact on the presynaptic structure of mouse photoreceptor ribbon synapses. Detailed immunocytochemical light and electron microscopical analysis of Piccolino knockdown in photoreceptors revealed a hitherto undescribed photoreceptor ribbon synaptic phenotype with striking morphological changes of synaptic ribbon ultrastructure.oai:repository.helmholtz-hzi.de:10033/6209952019-08-30T11:33:30Zcom_10033_620626col_10033_620627
Dimitrakopoulou, Konstantina
Tsimpouris, Charalampos
Papadopoulos, George
Pommerenke, Claudia
Wilk, Esther
Sgarbas, Kyriakos N
Schughart, Klaus
Bezerianos, Anastasios
2017-07-05T13:45:15Z
2017-07-05T13:45:15Z
2011-10-21
2015-09-04T08:23:21Z
Journal of Clinical Bioinformatics. 2011 Oct 21;1(1):27
http://dx.doi.org/10.1186/2043-9113-1-27
http://hdl.handle.net/10033/620995
Abstract Background The immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli. Results We applied the Time Varying Dynamic Bayesian Network (TV-DBN) method for reconstructing the gene regulatory interactions based on time series gene expression data for the mouse C57BL/6J inbred strain after infection with influenza A H1N1 (PR8) virus. Initially, 3500 differentially expressed genes were clustered with the use of k-means algorithm. Next, the successive in time GRNs were built over the expression profiles of cluster centroids. Finally, the identified GRNs were examined with several topological metrics and available protein-protein and protein-DNA interaction data, transcription factor and KEGG pathway data. Conclusions Our results elucidate the potential of TV-DBN approach in providing valuable insights into the temporal rewiring of the lung transcriptome in response to H1N1 virus.
Dynamic gene network reconstruction from gene expression data in mice after influenza A (H1N1) infection
Journal Article
en
Dimitrakopoulou et al; licensee BioMed Central Ltd.2018-06-13T19:48:56ZAbstract
Background
The immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli.
Results
We applied the Time Varying Dynamic Bayesian Network (TV-DBN) method for reconstructing the gene regulatory interactions based on time series gene expression data for the mouse C57BL/6J inbred strain after infection with influenza A H1N1 (PR8) virus. Initially, 3500 differentially expressed genes were clustered with the use of k-means algorithm. Next, the successive in time GRNs were built over the expression profiles of cluster centroids. Finally, the identified GRNs were examined with several topological metrics and available protein-protein and protein-DNA interaction data, transcription factor and KEGG pathway data.
Conclusions
Our results elucidate the potential of TV-DBN approach in providing valuable insights into the temporal rewiring of the lung transcriptome in response to H1N1 virus.oai:repository.helmholtz-hzi.de:10033/6209502018-06-12T23:18:20Zcom_10033_620626col_10033_620627
Wilk, Esther
Pandey, Ashutosh K
Leist, Sarah R
Hatesuer, Bastian
Preusse, Matthias
Pommerenke, Claudia
Wang, Junxi
Schughart, Klaus
2017-06-15T09:02:14Z
2017-06-15T09:02:14Z
2015-09-02
2015-09-04T08:24:20Z
BMC Genomics. 2015 Sep 02;16(1):655
http://dx.doi.org/10.1186/s12864-015-1867-8
http://hdl.handle.net/10033/620950
Abstract Background The host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection. Results We performed a detailed expression analysis to identify (i) correlations between changes in expression of host and virus genes, (ii) host genes involved in viral replication, and (iii) genes showing differential expression between two mouse strains that strongly differ in resistance to influenza infections. These genes may be key players involved in regulating the differences in pathogenesis and host defense mechanisms after influenza A infections. Expression levels of influenza segments correlated well with the viral load and may thus be used as surrogates for conventional viral load measurements. Furthermore, we investigated the functional role of two genes, Reg3g and Irf7, in knock-out mice and found that deletion of the Irf7 gene renders the host highly susceptible to H1N1 infection. Conclusions Using RNAseq analysis we identified novel genes important for viral replication or the host defense. This study adds further important knowledge to host-pathogen-interactions and suggests additional candidates that are crucial for host susceptibility or survival during influenza A infections.
RNAseq expression analysis of resistant and susceptible mice after influenza A virus infection identifies novel genes associated with virus replication and important for host resistance to infection
Journal Article
en
Wilk et al.
PMID didn't resolve!2018-06-12T23:18:20ZAbstract
Background
The host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection.
Results
We performed a detailed expression analysis to identify (i) correlations between changes in expression of host and virus genes, (ii) host genes involved in viral replication, and (iii) genes showing differential expression between two mouse strains that strongly differ in resistance to influenza infections. These genes may be key players involved in regulating the differences in pathogenesis and host defense mechanisms after influenza A infections. Expression levels of influenza segments correlated well with the viral load and may thus be used as surrogates for conventional viral load measurements. Furthermore, we investigated the functional role of two genes, Reg3g and Irf7, in knock-out mice and found that deletion of the Irf7 gene renders the host highly susceptible to H1N1 infection.
Conclusions
Using RNAseq analysis we identified novel genes important for viral replication or the host defense. This study adds further important knowledge to host-pathogen-interactions and suggests additional candidates that are crucial for host susceptibility or survival during influenza A infections.oai:repository.helmholtz-hzi.de:10033/6208912019-08-30T11:24:31Zcom_10033_620626col_10033_620627
Bergmann, Silke
Rohde, Manfred
Schughart, Klaus
Lengeling, Andreas
2017-04-07T08:46:45Z
2017-04-07T08:46:45Z
2013-07-15
2015-09-04T08:25:07Z
Gut Pathogens. 2013 Jul 15;5(1):19
http://dx.doi.org/10.1186/1757-4749-5-19
http://hdl.handle.net/10033/620891
Abstract Background In vivo bioluminescence imaging (BLI) is a powerful method for the analysis of host-pathogen interactions in small animal models. The commercially available bioluminescent Listeria monocytogenes strain Xen32 is commonly used to analyse immune functions in knockout mice and pathomechanisms of listeriosis. Findings To analyse and image listerial dissemination after oral infection we have generated a murinised Xen32 strain (Xen32-mur) which expresses a previously described mouse-adapted internalin A. This strain was used alongside the Xen32 wild type strain and the bioluminescent L. monocytogenes strains EGDe-lux and murinised EGDe-mur-lux to characterise bacterial dissemination in orally inoculated BALB/cJ mice. After four days of infection, Xen32 and Xen32-mur infected mice displayed consistently higher rates of bioluminescence compared to EGDe-lux and EGDe-mur-lux infected animals. However, surprisingly both Xen32 strains showed attenuated virulence in orally infected BALB/c mice that correlated with lower bacterial burden in internal organs at day 5 post infection, smaller losses in body weights and increased survival compared to EGDe-lux or EGDe-mur-lux inoculated animals. The Xen32 strain was made bioluminescent by integration of a lux-kan transposon cassette into the listerial flaA locus. We show here that this integration results in Xen32 in a flaA frameshift mutation which makes this strain flagella deficient. Conclusions The bioluminescent L. monocytogenes strain Xen32 is deficient in flagella expression and highly attenuated in orally infected BALB/c mice. As this listerial strain has been used in many BLI studies of murine listeriosis, it is important that the scientific community is aware of its reduced virulence in vivo.
The bioluminescent Listeria monocytogenes strain Xen32 is defective in flagella expression and highly attenuated in orally infected BALB/cJ mice
en
Bergmann et al.; licensee BioMed Central Ltd.2018-06-12T16:54:08ZAbstract
Background
In vivo bioluminescence imaging (BLI) is a powerful method for the analysis of host-pathogen interactions in small animal models. The commercially available bioluminescent Listeria monocytogenes strain Xen32 is commonly used to analyse immune functions in knockout mice and pathomechanisms of listeriosis.
Findings
To analyse and image listerial dissemination after oral infection we have generated a murinised Xen32 strain (Xen32-mur) which expresses a previously described mouse-adapted internalin A. This strain was used alongside the Xen32 wild type strain and the bioluminescent L. monocytogenes strains EGDe-lux and murinised EGDe-mur-lux to characterise bacterial dissemination in orally inoculated BALB/cJ mice. After four days of infection, Xen32 and Xen32-mur infected mice displayed consistently higher rates of bioluminescence compared to EGDe-lux and EGDe-mur-lux infected animals. However, surprisingly both Xen32 strains showed attenuated virulence in orally infected BALB/c mice that correlated with lower bacterial burden in internal organs at day 5 post infection, smaller losses in body weights and increased survival compared to EGDe-lux or EGDe-mur-lux inoculated animals. The Xen32 strain was made bioluminescent by integration of a lux-kan transposon cassette into the listerial flaA locus. We show here that this integration results in Xen32 in a flaA frameshift mutation which makes this strain flagella deficient.
Conclusions
The bioluminescent L. monocytogenes strain Xen32 is deficient in flagella expression and highly attenuated in orally infected BALB/c mice. As this listerial strain has been used in many BLI studies of murine listeriosis, it is important that the scientific community is aware of its reduced virulence in vivo.oai:repository.helmholtz-hzi.de:10033/6208832019-08-30T11:31:23Zcom_10033_620626col_10033_620627
Alberts, Rudi
Chen, Hairong
Pommerenke, Claudia
Smit, August B
Spijker, Sabine
Williams, Robert W
Geffers, Robert
Bruder, Dunja
Schughart, Klaus
2017-04-04T08:02:05Z
2017-04-04T08:02:05Z
2011-12-19
2015-09-04T08:25:33Z
BMC Genomics. 2011 Dec 19;12(1):610
http://dx.doi.org/10.1186/1471-2164-12-610
http://hdl.handle.net/10033/620883
Abstract Background Regulatory T cells (Tregs) play an essential role in the control of the immune response. Treg cells represent important targets for therapeutic interventions of the immune system. Therefore, it will be very important to understand in more detail which genes are specifically activated in Treg cells versus T helper (Th) cells, and which gene regulatory circuits may be involved in specifying and maintaining Treg cell homeostasis. Results We isolated Treg and Th cells from a genetically diverse family of 31 BXD type recombinant inbred strains and the fully inbred parental strains of this family--C57BL/6J and DBA/2J. Subsequently genome-wide gene expression studies were performed from the isolated Treg and Th cells. A comparative analysis of the transcriptomes of these cell populations allowed us to identify many novel differentially expressed genes. Analysis of cis- and trans-expression Quantitative Trait Loci (eQTLs) highlighted common and unique regulatory mechanisms that are active in the two cell types. Trans-eQTL regions were found for the Treg functional genes Nrp1, Stat3 and Ikzf4. Analyses of the respective QTL intervals suggested several candidate genes that may be involved in regulating these genes in Treg cells. Similarly, possible candidate genes were found which may regulate the expression of F2rl1, Ctla4, Klrb1f. In addition, we identified a focused group of candidate genes that may be important for the maintenance of self-tolerance and the prevention of allergy. Conclusions Variation of expression across the strains allowed us to find many novel gene-interaction networks in both T cell subsets. In addition, these two data sets enabled us to identify many differentially expressed genes and to nominate candidate genes that may have important functions for the maintenance of self-tolerance and the prevention of allergy.
Expression QTL mapping in regulatory and helper T cells from the BXD family of strains reveals novel cell-specific genes, gene-gene interactions and candidate genes for auto-immune disease
Journal Article
en
Alberts et al; licensee BioMed Central Ltd.2018-06-12T23:55:45ZAbstract
Background
Regulatory T cells (Tregs) play an essential role in the control of the immune response. Treg cells represent important targets for therapeutic interventions of the immune system. Therefore, it will be very important to understand in more detail which genes are specifically activated in Treg cells versus T helper (Th) cells, and which gene regulatory circuits may be involved in specifying and maintaining Treg cell homeostasis.
Results
We isolated Treg and Th cells from a genetically diverse family of 31 BXD type recombinant inbred strains and the fully inbred parental strains of this family--C57BL/6J and DBA/2J. Subsequently genome-wide gene expression studies were performed from the isolated Treg and Th cells. A comparative analysis of the transcriptomes of these cell populations allowed us to identify many novel differentially expressed genes. Analysis of cis- and trans-expression Quantitative Trait Loci (eQTLs) highlighted common and unique regulatory mechanisms that are active in the two cell types. Trans-eQTL regions were found for the Treg functional genes Nrp1, Stat3 and Ikzf4. Analyses of the respective QTL intervals suggested several candidate genes that may be involved in regulating these genes in Treg cells. Similarly, possible candidate genes were found which may regulate the expression of F2rl1, Ctla4, Klrb1f. In addition, we identified a focused group of candidate genes that may be important for the maintenance of self-tolerance and the prevention of allergy.
Conclusions
Variation of expression across the strains allowed us to find many novel gene-interaction networks in both T cell subsets. In addition, these two data sets enabled us to identify many differentially expressed genes and to nominate candidate genes that may have important functions for the maintenance of self-tolerance and the prevention of allergy.oai:repository.helmholtz-hzi.de:10033/6208432019-08-30T11:32:16Zcom_10033_620626col_10033_620627
Wu, Haiya
Haist, Verena
Baumgärtner, Wolfgang
Schughart, Klaus
Helmholtz Centre for infection research, Ihoffenstr. 7, 38124 Braunschweig, Germany.
2017-03-06T11:35:28Z
2017-03-06T11:35:28Z
2010-07-28
2015-09-04T08:26:33Z
Virology Journal. 2010 Jul 28;7(1):172
http://dx.doi.org/10.1186/1743-422X-7-172
http://hdl.handle.net/10033/620843
Abstract The importance of the adaptive immune response for secondary influenza infections and protection from a lethal challenge after vaccination has been well documented. However, some controversy still exists concerning the specific involvement of B and T cells during a primary infection. Here, we have followed the survival, weight loss, viral load and lung pathology in Rag2 -/- knock-out mice after infection with influenza A virus (H1N1). Infected wild type mice initially lost weight early after infection but then cleared the virus and recovered. Rag2 -/- mice, however, showed similar weight loss kinetics in the early stages after infection but weight loss continued post infection and culminated in death. In contrast to wild type mice, Rag2 -/- mice were not able to clear the virus, despite an increased inflammatory response. Furthermore, they did not recruit virus-specific lymphocytes into the lung in the later stages after infection and exhibited sustained pulmonary lesions.
Sustained viral load and late death in Rag2-/- mice after influenza A virus infection
Article
en
Wu et al.2018-06-13T19:40:12ZAbstract
The importance of the adaptive immune response for secondary influenza infections and protection from a lethal challenge after vaccination has been well documented. However, some controversy still exists concerning the specific involvement of B and T cells during a primary infection. Here, we have followed the survival, weight loss, viral load and lung pathology in Rag2
-/-
knock-out mice after infection with influenza A virus (H1N1). Infected wild type mice initially lost weight early after infection but then cleared the virus and recovered. Rag2
-/-
mice, however, showed similar weight loss kinetics in the early stages after infection but weight loss continued post infection and culminated in death. In contrast to wild type mice, Rag2
-/-
mice were not able to clear the virus, despite an increased inflammatory response. Furthermore, they did not recruit virus-specific lymphocytes into the lung in the later stages after infection and exhibited sustained pulmonary lesions.oai:repository.helmholtz-hzi.de:10033/6207872019-08-30T11:37:44Zcom_10033_620626col_10033_620627
Alberts, Rudi
Schughart, Klaus
2017-01-27T11:47:43Z
2017-01-27T11:47:43Z
2010-10-15
2015-09-04T08:26:10Z
BMC Bioinformatics. 2010 Oct 15;11(1):516
http://dx.doi.org/10.1186/1471-2105-11-516
http://hdl.handle.net/10033/620787
Abstract Background Quantitative trait locus (QTL) mapping identifies genomic regions that likely contain genes regulating a quantitative trait. However, QTL regions may encompass tens to hundreds of genes. To find the most promising candidate genes that regulate the trait, the biologist typically collects information from multiple resources about the genes in the QTL interval. This process is very laborious and time consuming. Results QTLminer is a bioinformatics tool that automatically performs QTL region analysis. It is available in GeneNetwork and it integrates information such as gene annotation, gene expression and sequence polymorphisms for all the genes within a given genomic interval. Conclusions QTLminer substantially speeds up discovery of the most promising candidate genes within a QTL region.
QTLminer: identifying genes regulating quantitative traits
Journal Article
en
Alberts and Schughart.2018-06-12T23:41:08ZAbstract
Background
Quantitative trait locus (QTL) mapping identifies genomic regions that likely contain genes regulating a quantitative trait. However, QTL regions may encompass tens to hundreds of genes. To find the most promising candidate genes that regulate the trait, the biologist typically collects information from multiple resources about the genes in the QTL interval. This process is very laborious and time consuming.
Results
QTLminer is a bioinformatics tool that automatically performs QTL region analysis. It is available in GeneNetwork and it integrates information such as gene annotation, gene expression and sequence polymorphisms for all the genes within a given genomic interval.
Conclusions
QTLminer substantially speeds up discovery of the most promising candidate genes within a QTL region.oai:repository.helmholtz-hzi.de:10033/6207802018-06-13T02:27:56Zcom_10033_620626col_10033_620627
Preusse, Matthias
Schughart, Klaus
Wilk, Esther
Klawonn, Frank
Pessler, Frank
2017-01-27T11:29:29Z
2017-01-27T11:29:29Z
2015-06-06
2015-09-04T08:27:33Z
BMC Research Notes. 2015 Jun 06;8(1):225
http://dx.doi.org/10.1186/s13104-015-1195-8
http://hdl.handle.net/10033/620780
Abstract Background Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters. Methods DBA/2J and C57BL/6J mice (n = 5–8 per observation) were evaluated in a time course experiment of IAV infection, focusing on early time points. After anesthesia with ketamine/xylazine, a suspension of 2 × 103 focus forming units of the mouse-adapted IAV strain A/Puerto Rico/8/1934 (H1N1) in 20 µl sterile PBS, or 20 µl sterile PBS only (“mock treatment”), were instilled intranasally. Weight loss was assessed daily, and eight common hematological parameters and viral hemagglutinin (HA) mRNA expression were determined after 6, 12, 18, 24, 48 and 120 h. Results Hematological differences between the strains were apparent even in untreated mice. Infection-dependent changes, in particular increased granulocyte and decreased lymphocyte counts, were first detectable after 18 h in DBA/2J, were fully manifest in both strains at 48 h, and were usually more pronounced in the DBA/2J mice. In this strain, relative granulocyte and lymphocyte counts and the granulocyte/lymphocyte ratio correlated with viral HA mRNA expression and weight loss. In C57BL/6J, hematological parameters did not correlate with weight loss, but HA mRNA expression correlated weakly with total leukocyte counts, granulocyte/lymphocyte ratio, relative and absolute granulocyte counts, and relative lymphocyte counts. Significant changes due to mock treatment were mild and were detected only in C57BL/6J. Conclusion This study underscores the value of hematological parameters in monitoring disease evolution in the early phase of IAV infection, and likely other pathogens. The hematological response to infection may differ significantly among inbred mouse strains.
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains
Journal Article
en
Preusse et al.2018-06-13T02:27:56ZAbstract
Background
Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters.
Methods
DBA/2J and C57BL/6J mice (n = 5–8 per observation) were evaluated in a time course experiment of IAV infection, focusing on early time points. After anesthesia with ketamine/xylazine, a suspension of 2 × 103 focus forming units of the mouse-adapted IAV strain A/Puerto Rico/8/1934 (H1N1) in 20 µl sterile PBS, or 20 µl sterile PBS only (“mock treatment”), were instilled intranasally. Weight loss was assessed daily, and eight common hematological parameters and viral hemagglutinin (HA) mRNA expression were determined after 6, 12, 18, 24, 48 and 120 h.
Results
Hematological differences between the strains were apparent even in untreated mice. Infection-dependent changes, in particular increased granulocyte and decreased lymphocyte counts, were first detectable after 18 h in DBA/2J, were fully manifest in both strains at 48 h, and were usually more pronounced in the DBA/2J mice. In this strain, relative granulocyte and lymphocyte counts and the granulocyte/lymphocyte ratio correlated with viral HA mRNA expression and weight loss. In C57BL/6J, hematological parameters did not correlate with weight loss, but HA mRNA expression correlated weakly with total leukocyte counts, granulocyte/lymphocyte ratio, relative and absolute granulocyte counts, and relative lymphocyte counts. Significant changes due to mock treatment were mild and were detected only in C57BL/6J.
Conclusion
This study underscores the value of hematological parameters in monitoring disease evolution in the early phase of IAV infection, and likely other pathogens. The hematological response to infection may differ significantly among inbred mouse strains.oai:repository.helmholtz-hzi.de:10033/6207752019-08-30T11:32:16Zcom_10033_620626col_10033_620627
Dogan, Ayca
Lasch, Peter
Neuschl, Christina
Millrose, Marion K
Alberts, Rudi
Schughart, Klaus
Naumann, Dieter
Brockmann, Gudrun A
2017-01-27T10:29:08Z
2017-01-27T10:29:08Z
2013-06-10
2015-09-04T08:27:57Z
BMC Genomics. 2013 Jun 10;14(1):386
http://dx.doi.org/10.1186/1471-2164-14-386
http://hdl.handle.net/10033/620775
Abstract Background Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues. Results Mice from 29 BXD recombinant inbred mouse strains were put on high fat diet and gross-compositional changes in adipose, liver and muscle tissues were measured by ATR-FTIR spectroscopy. The analysis of genotype-phenotype correlations revealed significant quantitative trait loci (QTL) on chromosome 12 for the content of fat and collagen, collagen integrity, and the lipid to protein ratio in adipose tissue and on chromosome 17 for lipid to protein ratio in liver. Using gene expression and sequence information, we suggest Rsad2 (viperin) and Colec11 (collectin-11) on chromosome 12 as potential quantitative trait candidate genes. Rsad2 may act as a modulator of lipid droplet contents and lipid biosynthesis; Colec11 might play a role in apoptopic cell clearance and maintenance of adipose tissue. An increased level of Rsad2 transcripts in adipose tissue of DBA/2J compared to C57BL/6J mice suggests a cis-acting genetic variant leading to differential gene activation. Conclusion The results demonstrate that the analytical method of ATR-FTIR spectroscopy effectively contributed to decompose the macromolecular composition of tissues that accumulate fat and to link this information with genetic determinants. The candidate genes in the QTL regions may contribute to obesity-related diseases in humans, in particular if the results can be verified in a bigger BXD cohort.
ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains
Journal Article
en
Dogan et al.; licensee BioMed Central Ltd.2018-06-13T00:54:56ZAbstract
Background
Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues.
Results
Mice from 29 BXD recombinant inbred mouse strains were put on high fat diet and gross-compositional changes in adipose, liver and muscle tissues were measured by ATR-FTIR spectroscopy. The analysis of genotype-phenotype correlations revealed significant quantitative trait loci (QTL) on chromosome 12 for the content of fat and collagen, collagen integrity, and the lipid to protein ratio in adipose tissue and on chromosome 17 for lipid to protein ratio in liver. Using gene expression and sequence information, we suggest Rsad2 (viperin) and Colec11 (collectin-11) on chromosome 12 as potential quantitative trait candidate genes. Rsad2 may act as a modulator of lipid droplet contents and lipid biosynthesis; Colec11 might play a role in apoptopic cell clearance and maintenance of adipose tissue. An increased level of Rsad2 transcripts in adipose tissue of DBA/2J compared to C57BL/6J mice suggests a cis-acting genetic variant leading to differential gene activation.
Conclusion
The results demonstrate that the analytical method of ATR-FTIR spectroscopy effectively contributed to decompose the macromolecular composition of tissues that accumulate fat and to link this information with genetic determinants. The candidate genes in the QTL regions may contribute to obesity-related diseases in humans, in particular if the results can be verified in a bigger BXD cohort.oai:repository.helmholtz-hzi.de:10033/6207642018-06-12T23:26:52Zcom_10033_620626col_10033_620627
Bahgat, Mahmoud M
Błazejewska, Paulina
Schughart, Klaus
2017-01-27T09:23:22Z
2017-01-27T09:23:22Z
2011-01-20
2015-09-04T08:28:33Z
Virology Journal. 2011 Jan 20;8(1):27
http://dx.doi.org/10.1186/1743-422X-8-27
http://hdl.handle.net/10033/620764
Abstract Background Host serine proteases are essential for the influenza virus life cycle because the viral haemagglutinin is synthesized as a precursor which requires proteolytic maturation. Therefore, we studied the activity and expression of serine proteases in lungs from mice infected with influenza and evaluated the effect of serine protease inhibitors on virus replication both in cell culture and in infected mice. Results Two different inbred mouse strains were investigated: DBA/2J as a highly susceptible and C57Bl/6J as a more resistant strain to influenza virus infection. The serine proteases from lung homogenates of mice exhibited pH optima of 10.00. Using the substrate Bz-Val-Gly-Arg-p-nitroanilide or in zymograms, the intensities of proteolysis increased in homogenates from both mouse strains with time post infection (p.i.) with the mouse-adapted influenza virus A/Puerto Rico/8/34 (H1N1; PR8). In zymograms at day 7 p.i., proteolytic bands were stronger and numerous in lung homogenates from DBA/2J than C57Bl/6J mice. Real-time PCR results confirmed differential expression of several lung proteases before and after infecting mice with the H1N1 virus. The most strongly up-regulated proteases were Gzma, Tmprss4, Elane, Ctrl, Gzmc and Gzmb. Pretreatment of mouse and human lung cell lines with the serine protease inhibitors AEBSF or pAB or a cocktail of both prior to infection with the H1N1 or the A/Seal/Massachusetts/1/80 (H7N7; SC35M) virus resulted in a decrease in virus replication. Pretreatment of C57Bl/6J mice with either AEBSF or a cocktail of AEBSF and pAB prior to infection with the H1N1 virus significantly reduced weight loss and led to a faster recovery of treated versus untreated mice while pAB alone exerted a very poor effect. After infection with the H7N7 virus, the most significant reduction of weight loss was obtained upon pretreatment with either the protease inhibitor cocktail or pAB. Furthermore, pretreatment of C57BL/6J mice with AEBSF prior to infection resulted in a significant reduction in the levels of both the H1N1 and H7N7 nucleoproteins in mice lungs and also a significant reduction in the levels of the HA transcript in the lungs of the H1N1- but not the H7N7-infected mice. Conclusion Multiple serine protease activities might be implicated in mediating influenza infection. Blocking influenza A virus infection in cultured lung epithelia and in mice by the used serine protease inhibitors may provide an alternative approach for treatment of influenza infection.
Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection
Journal Article
en
Bahgat et al; licensee BioMed Central Ltd.2018-06-12T23:26:52ZAbstract
Background
Host serine proteases are essential for the influenza virus life cycle because the viral haemagglutinin is synthesized as a precursor which requires proteolytic maturation. Therefore, we studied the activity and expression of serine proteases in lungs from mice infected with influenza and evaluated the effect of serine protease inhibitors on virus replication both in cell culture and in infected mice.
Results
Two different inbred mouse strains were investigated: DBA/2J as a highly susceptible and C57Bl/6J as a more resistant strain to influenza virus infection. The serine proteases from lung homogenates of mice exhibited pH optima of 10.00. Using the substrate Bz-Val-Gly-Arg-p-nitroanilide or in zymograms, the intensities of proteolysis increased in homogenates from both mouse strains with time post infection (p.i.) with the mouse-adapted influenza virus A/Puerto Rico/8/34 (H1N1; PR8). In zymograms at day 7 p.i., proteolytic bands were stronger and numerous in lung homogenates from DBA/2J than C57Bl/6J mice. Real-time PCR results confirmed differential expression of several lung proteases before and after infecting mice with the H1N1 virus. The most strongly up-regulated proteases were Gzma, Tmprss4, Elane, Ctrl, Gzmc and Gzmb. Pretreatment of mouse and human lung cell lines with the serine protease inhibitors AEBSF or pAB or a cocktail of both prior to infection with the H1N1 or the A/Seal/Massachusetts/1/80 (H7N7; SC35M) virus resulted in a decrease in virus replication. Pretreatment of C57Bl/6J mice with either AEBSF or a cocktail of AEBSF and pAB prior to infection with the H1N1 virus significantly reduced weight loss and led to a faster recovery of treated versus untreated mice while pAB alone exerted a very poor effect. After infection with the H7N7 virus, the most significant reduction of weight loss was obtained upon pretreatment with either the protease inhibitor cocktail or pAB. Furthermore, pretreatment of C57BL/6J mice with AEBSF prior to infection resulted in a significant reduction in the levels of both the H1N1 and H7N7 nucleoproteins in mice lungs and also a significant reduction in the levels of the HA transcript in the lungs of the H1N1- but not the H7N7-infected mice.
Conclusion
Multiple serine protease activities might be implicated in mediating influenza infection. Blocking influenza A virus infection in cultured lung epithelia and in mice by the used serine protease inhibitors may provide an alternative approach for treatment of influenza infection.oai:repository.helmholtz-hzi.de:10033/6207552018-06-12T23:42:59Zcom_10033_620626col_10033_620627
Nedelko, Tatiana
Kollmus, Heike
Klawonn, Frank
Spijker, Sabine
Lu, Lu
Heßman, Manuela
Alberts, Rudi
Williams, Robert W
Schughart, Klaus
2017-01-27T08:31:39Z
2017-01-27T08:31:39Z
2012-08-20
2015-09-04T08:29:37Z
BMC Genomics. 2012 Aug 20;13(1):411
http://dx.doi.org/10.1186/1471-2164-13-411
http://hdl.handle.net/10033/620755
Abstract Background There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible. Results To map regions of the genome responsible for differences in influenza susceptibility, we infected a family of 53 BXD-type lines derived from a cross between C57BL/6J and DBA/2J strains with influenza A virus (PR8, H1N1). We monitored body weight, survival, and mean time to death for 13 days after infection. Qivr5 (quantitative trait for influenza virus resistance on chromosome 5) was the largest and most significant QTL for weight loss. The effect of Qivr5 was detectable on day 2 post infection, but was most pronounced on days 5 and 6. Survival rate mapped to Qivr5, but additionally revealed a second significant locus on chromosome 19 (Qivr19). Analysis of mean time to death affirmed both Qivr5 and Qivr19. In addition, we observed several regions of the genome with suggestive linkage. There are potentially complex combinatorial interactions of the parental alleles among loci. Analysis of multiple gene expression data sets and sequence variants in these strains highlights about 30 strong candidate genes across all loci that may control influenza A susceptibility and resistance. Conclusions We have mapped influenza susceptibility loci to chromosomes 2, 5, 16, 17, and 19. Body weight and survival loci have a time-dependent profile that presumably reflects the temporal dynamic of the response to infection. We highlight candidate genes in the respective intervals and review their possible biological function during infection.
Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner
Journal Article
en
Nedelko et al.; licensee BioMed Central Ltd.2018-06-12T23:42:59ZAbstract
Background
There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.
Results
To map regions of the genome responsible for differences in influenza susceptibility, we infected a family of 53 BXD-type lines derived from a cross between C57BL/6J and DBA/2J strains with influenza A virus (PR8, H1N1). We monitored body weight, survival, and mean time to death for 13 days after infection. Qivr5 (quantitative trait for influenza virus resistance on chromosome 5) was the largest and most significant QTL for weight loss. The effect of Qivr5 was detectable on day 2 post infection, but was most pronounced on days 5 and 6. Survival rate mapped to Qivr5, but additionally revealed a second significant locus on chromosome 19 (Qivr19). Analysis of mean time to death affirmed both Qivr5 and Qivr19. In addition, we observed several regions of the genome with suggestive linkage. There are potentially complex combinatorial interactions of the parental alleles among loci. Analysis of multiple gene expression data sets and sequence variants in these strains highlights about 30 strong candidate genes across all loci that may control influenza A susceptibility and resistance.
Conclusions
We have mapped influenza susceptibility loci to chromosomes 2, 5, 16, 17, and 19. Body weight and survival loci have a time-dependent profile that presumably reflects the temporal dynamic of the response to infection. We highlight candidate genes in the respective intervals and review their possible biological function during infection.oai:repository.helmholtz-hzi.de:10033/6205702019-08-30T11:30:58Zcom_10033_620626col_10033_620627
Bruck, Normi
Gahr, Manfred
Pessler, Frank
2016-11-04T14:32:17Z
2016-11-04T14:32:17Z
2010-01-14
2015-09-04T08:28:21Z
Pediatric Rheumatology. 2010 Jan 14;8(1):4
http://dx.doi.org/10.1186/1546-0096-8-4
http://hdl.handle.net/10033/620570
Abstract A 12-year-old girl developed influenza B virus infection proven by typical symptoms and detection of the virus in a nasopharyngeal swab by culture and PCR. Two weeks later she developed an otherwise unexplained transient oligoarthritis of small joints of the left foot. Influenza viruses may be a hitherto underappreciated cause of a post-infectious arthritis.
Transient oligoarthritis of the lower extremity following influenza B virus infection: Case report
Journal Article
en
Bruck et al.2018-06-13T03:48:53ZAbstract
A 12-year-old girl developed influenza B virus infection proven by typical symptoms and detection of the virus in a nasopharyngeal swab by culture and PCR. Two weeks later she developed an otherwise unexplained transient oligoarthritis of small joints of the left foot. Influenza viruses may be a hitherto underappreciated cause of a post-infectious arthritis.oai:repository.helmholtz-hzi.de:10033/6207172019-08-30T11:26:42Zcom_10033_620626col_10033_620627
Michaelson, Jacob J
Alberts, Rudi
Schughart, Klaus
Beyer, Andreas
2017-01-17T09:56:24Z
2017-01-17T09:56:24Z
2010-09-17
2015-09-04T08:29:51Z
BMC Genomics. 2010 Sep 17;11(1):502
http://dx.doi.org/10.1186/1471-2164-11-502
http://hdl.handle.net/10033/620717
Abstract Background The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis. Results Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods. Conclusions Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.
Data-driven assessment of eQTL mapping methods
Journal Article
en
Michaelson et al.2018-06-12T20:01:10ZAbstract
Background
The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.
Results
Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods.
Conclusions
Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.oai:repository.helmholtz-hzi.de:10033/6207062019-08-30T11:36:32Zcom_10033_620626col_10033_620627col_10033_620629
Bergmann, Silke
Beard, Philippa M
Pasche, Bastian
Lienenklaus, Stefan
Weiss, Siegfried
Gahan, Cormac G M
Schughart, Klaus
Lengeling, Andreas
2017-01-16T15:29:09Z
2017-01-16T15:29:09Z
2013-04-23
2015-09-04T08:30:11Z
BMC Microbiology. 2013 Apr 23;13(1):90
http://dx.doi.org/10.1186/1471-2180-13-90
http://hdl.handle.net/10033/620706
Abstract Background The bacterial surface protein internalin (InlA) is a major virulence factor of the food-born pathogen Listeria monocytogenes. It plays a critical role in the bacteria crossing the host intestinal barrier by a species-specific interaction with the cell adhesion molecule E-cadherin. In mice, the interaction of InlA with murine E-cadherin is impaired due to sequence-specific binding incompatibilities. We have previously used the approach of ‘murinisation’ to establish an oral listeriosis infection model in mice by exchanging two amino acid residues in InlA. This dramatically increases binding to mouse E-cadherin. In the present study, we have used bioluminescent murinised and non-murinised Listeria strains to examine the spatiotemporal dissemination of Listeria in four diverse mouse genetic backgrounds after oral inoculation. Results The murinised Listeria monocytogenes strain showed enhanced invasiveness and induced more severe infections in all four investigated mouse inbred strains compared to the non-murinised Listeria strain. We identified C57BL/6J mice as being most resistant to orally acquired listeriosis whereas C3HeB/FeJ, A/J and BALB/cJ mice were found to be most susceptible to infection. This was reflected in faster kinetics of Listeria dissemination, higher bacterial loads in internal organs, and elevated serum levels of IL-6, IFN-γ, TNF-α and CCL2 in the susceptible strains as compared to the resistant C57BL/6J strain. Importantly, murinisation of InlA did not cause enhanced invasion of Listeria monocytogenes into the brain. Conclusion Murinised Listeria are able to efficiently cross the intestinal barrier in mice from diverse genetic backgrounds. However, expression of murinized InlA does not enhance listerial brain invasion suggesting that crossing of the blood brain barrier and crossing of the intestinal epithelium are achieved by Listeria monocytogenes through different molecular mechanisms.
Influence of internalin a murinisation on host resistance to orally acquired listeriosis in mice
Journal Article
en
Bergmann et al.; licensee BioMed Central Ltd.2018-06-13T04:14:47ZAbstract
Background
The bacterial surface protein internalin (InlA) is a major virulence factor of the food-born pathogen Listeria monocytogenes. It plays a critical role in the bacteria crossing the host intestinal barrier by a species-specific interaction with the cell adhesion molecule E-cadherin. In mice, the interaction of InlA with murine E-cadherin is impaired due to sequence-specific binding incompatibilities. We have previously used the approach of ‘murinisation’ to establish an oral listeriosis infection model in mice by exchanging two amino acid residues in InlA. This dramatically increases binding to mouse E-cadherin. In the present study, we have used bioluminescent murinised and non-murinised Listeria strains to examine the spatiotemporal dissemination of Listeria in four diverse mouse genetic backgrounds after oral inoculation.
Results
The murinised Listeria monocytogenes strain showed enhanced invasiveness and induced more severe infections in all four investigated mouse inbred strains compared to the non-murinised Listeria strain. We identified C57BL/6J mice as being most resistant to orally acquired listeriosis whereas C3HeB/FeJ, A/J and BALB/cJ mice were found to be most susceptible to infection. This was reflected in faster kinetics of Listeria dissemination, higher bacterial loads in internal organs, and elevated serum levels of IL-6, IFN-γ, TNF-α and CCL2 in the susceptible strains as compared to the resistant C57BL/6J strain. Importantly, murinisation of InlA did not cause enhanced invasion of Listeria monocytogenes into the brain.
Conclusion
Murinised Listeria are able to efficiently cross the intestinal barrier in mice from diverse genetic backgrounds. However, expression of murinized InlA does not enhance listerial brain invasion suggesting that crossing of the blood brain barrier and crossing of the intestinal epithelium are achieved by Listeria monocytogenes through different molecular mechanisms.oai:repository.helmholtz-hzi.de:10033/6207052019-08-30T11:25:43Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
Preusse, Matthias
Tantawy, Mohamed A
Klawonn, Frank
Schughart, Klaus
Pessler, Frank
2017-01-16T15:28:50Z
2017-01-16T15:28:50Z
2013-12-17
2015-09-04T08:30:14Z
BMC Microbiology. 2013 Dec 17;13(1):293
http://dx.doi.org/10.1186/1471-2180-13-293
http://hdl.handle.net/10033/620705
Abstract Background Investigating the host response in the early stage of influenza A virus (IAV) infection is of considerable interest. However, it is conceivable that effects due to the anesthesia and/or intranasal infection procedure might introduce artifacts. We therefore aimed to evaluate the effects of anesthesia and/or intranasal infection on transcription of selected pulmonary mRNAs in two inbred mouse strains with differential susceptibility to IAV infection. Results DBA/2J and C57BL/6J mice were evaluated in a time course experiment in which lung tissue was sampled after 6, 12, 18, 24, 48 and 120 h. After anesthesia with ketamine and xylazine, a suspension of mouse-adapted IAV strain PR8_Mun in 20 μl sterile buffer, or 20 μl sterile buffer only, was instilled intranasally. The mice receiving anesthesia and PBS only were designated the “mock treatment” group. Pulmonary expression of 10 host mRNAs (Fos, Retnla, Irg1, Il6, Il1b, Cxcl10, Stat1, Ifng, Ifnl2, and Mx1) and viral hemagglutinin (HA) mRNA were determined at the designated time points. As expected, weight loss and viral replication were greater in the DBA/2J strain (which is more susceptible to IAV infection). Four mRNAs (Retnla, Irg1, Il6, and Cxcl10) were procedure-dependently regulated in DBA/2J mice between 6 and 24 h, and two (Retnla and Il6) in C57BL/6J mice, although to a lesser extent. All 10 mRNAs rose after infection, but one (Fos) only in DBA/2J mice. These infection-dependent effects could be separated from procedure-dependent effects beginning around 12 h in DBA/2J and 18 h in C57BL/6J mice. The interferon-related mRNAs Stat1, Ifng, Infl2, and Mx1 were unaffected by mock treatment in either mouse strain. Mx1 and Infl2 correlated best with HA mRNA expression (r = 0.97 and 0.93, respectively, in DBA/2J). Conclusions These results demonstrate effects of the anesthesia and/or intranasal infection procedure on pulmonary gene expression, which are detectable between approximately 6 and 24 h post procedure and vary in intensity and temporal evolution depending on the mouse strain used. Mock infection controls should be included in all studies on pulmonary gene expression in the early phase of infection with IAV and, likely, other respiratory pathogens.
Infection- and procedure-dependent effects on pulmonary gene expression in the early phase of influenza A virus infection in mice
Journal Article
en
Preusse et al.; licensee BioMed Central Ltd.2018-06-12T17:21:08ZAbstract
Background
Investigating the host response in the early stage of influenza A virus (IAV) infection is of considerable interest. However, it is conceivable that effects due to the anesthesia and/or intranasal infection procedure might introduce artifacts. We therefore aimed to evaluate the effects of anesthesia and/or intranasal infection on transcription of selected pulmonary mRNAs in two inbred mouse strains with differential susceptibility to IAV infection.
Results
DBA/2J and C57BL/6J mice were evaluated in a time course experiment in which lung tissue was sampled after 6, 12, 18, 24, 48 and 120 h. After anesthesia with ketamine and xylazine, a suspension of mouse-adapted IAV strain PR8_Mun in 20 μl sterile buffer, or 20 μl sterile buffer only, was instilled intranasally. The mice receiving anesthesia and PBS only were designated the “mock treatment” group. Pulmonary expression of 10 host mRNAs (Fos, Retnla, Irg1, Il6, Il1b, Cxcl10, Stat1, Ifng, Ifnl2, and Mx1) and viral hemagglutinin (HA) mRNA were determined at the designated time points. As expected, weight loss and viral replication were greater in the DBA/2J strain (which is more susceptible to IAV infection). Four mRNAs (Retnla, Irg1, Il6, and Cxcl10) were procedure-dependently regulated in DBA/2J mice between 6 and 24 h, and two (Retnla and Il6) in C57BL/6J mice, although to a lesser extent. All 10 mRNAs rose after infection, but one (Fos) only in DBA/2J mice. These infection-dependent effects could be separated from procedure-dependent effects beginning around 12 h in DBA/2J and 18 h in C57BL/6J mice. The interferon-related mRNAs Stat1, Ifng, Infl2, and Mx1 were unaffected by mock treatment in either mouse strain. Mx1 and Infl2 correlated best with HA mRNA expression (r = 0.97 and 0.93, respectively, in DBA/2J).
Conclusions
These results demonstrate effects of the anesthesia and/or intranasal infection procedure on pulmonary gene expression, which are detectable between approximately 6 and 24 h post procedure and vary in intensity and temporal evolution depending on the mouse strain used. Mock infection controls should be included in all studies on pulmonary gene expression in the early phase of infection with IAV and, likely, other respiratory pathogens.oai:repository.helmholtz-hzi.de:10033/6206992019-08-30T11:36:32Zcom_10033_620626col_10033_620627
Alberts, Rudi
Lu, Lu
Williams, Robert W
Schughart, Klaus
2017-01-13T09:52:01Z
2017-01-13T09:52:01Z
2011-05-02
2015-09-04T08:30:58Z
Respiratory Research. 2011 May 02;12(1):61
http://dx.doi.org/10.1186/1465-9921-12-61
http://hdl.handle.net/10033/620699
Abstract Background The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics. Methods Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org. Results Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR. Conclusions Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.
Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures
Journal Article
en
Alberts et al; licensee BioMed Central Ltd.2018-06-13T03:52:37ZAbstract
Background
The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics.
Methods
Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org.
Results
Expression values were highly variable across strains and in many cases exhibited a high heri-tability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 ± 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR.
Conclusions
Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.oai:repository.helmholtz-hzi.de:10033/6206982019-08-30T11:36:32Zcom_10033_620626col_10033_620627
Gruenberger, Michael
Alberts, Rudi
Smedley, Damian
Swertz, Morris
Schofield, Paul
Schughart, Klaus
2017-01-13T09:51:23Z
2017-01-13T09:51:23Z
2010-01-22
2015-09-04T08:31:01Z
BMC Research Notes. 2010 Jan 22;3(1):16
http://dx.doi.org/10.1186/1756-0500-3-16
http://hdl.handle.net/10033/620698
Abstract Background The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases. Results We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, "MUSIG-Gen" starts from a list of gene names and collects a wide range of data types from several distributed databases in a "shopping cart"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, "MUSIG-Phen", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes. Conclusion The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists.
Towards the integration of mouse databases - definition and implementation of solutions to two use-cases in mouse functional genomics
Journal Article
en
Gruenberger et al.2018-06-14T09:16:47ZAbstract
Background
The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases.
Results
We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, "MUSIG-Gen" starts from a list of gene names and collects a wide range of data types from several distributed databases in a "shopping cart"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, "MUSIG-Phen", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes.
Conclusion
The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists.oai:repository.helmholtz-hzi.de:10033/6206942019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Simon, Michelle M
Greenaway, Simon
White, Jacqueline K
Fuchs, Helmut
Gailus-Durner, Valérie
Wells, Sara
Sorg, Tania
Wong, Kim
Bedu, Elodie
Cartwright, Elizabeth J
Dacquin, Romain
Djebali, Sophia
Estabel, Jeanne
Graw, Jochen
Ingham, Neil J
Jackson, Ian J
Lengeling, Andreas
Mandillo, Silvia
Marvel, Jacqueline
Meziane, Hamid
Preitner, Frédéric
Puk, Oliver
Roux, Michel
Adams, David J
Atkins, Sarah
Ayadi, Abdel
Becker, Lore
Blake, Andrew
Brooker, Debra
Cater, Heather
Champy, Marie-France
Combe, Roy
Danecek, Petr
di Fenza, Armida
Gates, Hilary
Gerdin, Anna-Karin
Golini, Elisabetta
Hancock, John M
Hans, Wolfgang
Hölter, Sabine M
Hough, Tertius
Jurdic, Pierre
Keane, Thomas M
Morgan, Hugh
Müller, Werner
Neff, Frauke
Nicholson, George
Pasche, Bastian
Roberson, Laura-Anne
Rozman, Jan
Sanderson, Mark
Santos, Luis
Selloum, Mohammed
Shannon, Carl
Southwell, Anne
Tocchini-Valentini, Glauco P
Vancollie, Valerie E
Westerberg, Henrik
Wurst, Wolfgang
Zi, Min
Yalcin, Binnaz
Ramirez-Solis, Ramiro
Steel, Karen P
Mallon, Ann-Marie
Hrabě de Angelis, Martin
Herault, Yann
Brown, Steve D
2017-01-13T09:46:41Z
2017-01-13T09:46:41Z
2013-07-31
2015-09-04T08:31:22Z
Genome Biology. 2013 Jul 31;14(7):R82
http://dx.doi.org/10.1186/gb-2013-14-7-r82
http://hdl.handle.net/10033/620694
Abstract Background The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms. Results We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems. Conclusions Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains
Journal Article
en
Simon et al.; licensee BioMed Central Ltd.2018-06-13T01:22:32ZAbstract
Background
The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms.
Results
We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems.
Conclusions
Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.oai:repository.helmholtz-hzi.de:10033/6206932019-08-30T11:31:49Zcom_10033_620626col_10033_620627
Hahn, Phillip
Böse, Jens
Edler, Stefanie
Lengeling, Andreas
2017-01-13T09:45:10Z
2017-01-13T09:45:10Z
2008-06-18
2015-09-04T08:31:25Z
BMC Genomics. 2008 Jun 18;9(1):293
http://dx.doi.org/10.1186/1471-2164-9-293
http://hdl.handle.net/10033/620693
Abstract Background The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function. Results We describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded β-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups. Conclusion We give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.
Genomic structure and expression of Jmjd6 and evolutionary analysis in the context of related JmjC domain containing proteins
Journal Article
en
Hahn et al.2018-06-13T04:20:41ZAbstract
Background
The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function.
Results
We describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded β-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups.
Conclusion
We give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.oai:repository.helmholtz-hzi.de:10033/5786892019-08-30T11:27:16Zcom_10033_620626col_10033_620627
Wilk, Esther
Pandey, Ashutosh K
Leist, Sarah Rebecca
Hatesuer, Bastian
Preusse, Matthias
Pommerenke, Claudia
Wang, Junxi
Schughart, Klaus
Helmholtz Centre for Infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2015-09-24T15:12:18Z
2015-09-24T15:12:18Z
2015
RNAseq expression analysis of resistant and susceptible mice after influenza A virus infection identifies novel genes associated with virus replication and important for host resistance to infection. 2015, 16:655 BMC Genomics
1471-2164
26329040
10.1186/s12864-015-1867-8
http://hdl.handle.net/10033/578689
BMC genomics
The host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection.
en
RNAseq expression analysis of resistant and susceptible mice after influenza A virus infection identifies novel genes associated with virus replication and important for host resistance to infection.
Article2018-06-13T04:08:35ZThe host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection.oai:repository.helmholtz-hzi.de:10033/5800702019-08-30T11:36:33Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
Preusse, Matthias
Schughart, Klaus
Wilk, Esther
Klawonn, Frank
Pessler, Frank
Helmholz Centre for Infection Research
2015-10-22T10:22:07Z
2015-10-22T10:22:07Z
2015
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains. 2015, 8:225 BMC Res Notes
1756-0500
26047817
10.1186/s13104-015-1195-8
http://hdl.handle.net/10033/580070
BMC research notes
Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters.
en
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains.
Article2018-06-12T23:05:36ZHematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters.oai:repository.helmholtz-hzi.de:10033/5928572019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Lough, Graham
Kyriazakis, Ilias
Bergmann, Silke
Lengeling, Andreas
Doeschl-Wilson, Andrea B
Helmholtz Centre for Infection Research, Inhoffenstr.7, 28124 Braunschweig, Germany.
2016-01-05T15:08:50Z
2016-01-05T15:08:50Z
2015-11-22
Health trajectories reveal the dynamic contributions of host genetic resistance and tolerance to infection outcome. 2015, 282 (1819): Proc. Biol. Sci.
1471-2954
26582028
10.1098/rspb.2015.2151
http://hdl.handle.net/10033/592857
Proceedings. Biological sciences / The Royal Society
Resistance and tolerance are two alternative strategies hosts can adopt to survive infections. Both strategies may be genetically controlled. To date, the relative contribution of resistance and tolerance to infection outcome is poorly understood. Here, we use a bioluminescent Listeria monocytogenes (Lm) infection challenge model to study the genetic determination and dynamic contributions of host resistance and tolerance to listeriosis in four genetically diverse mouse strains. Using conventional statistical analyses, we detect significant genetic variation in both resistance and tolerance, but cannot capture the time-dependent relative importance of either host strategy. We overcome these limitations through the development of novel statistical tools to analyse individual infection trajectories portraying simultaneous changes in infection severity and health. Based on these tools, early expression of resistance followed by expression of tolerance emerge as important hallmarks for surviving Lm infections. Our trajectory analysis further reveals that survivors and non-survivors follow distinct infection paths (which are also genetically determined) and provides new survival thresholds as objective endpoints in infection experiments. Future studies may use trajectories as novel traits for mapping and identifying genes that control infection dynamics and outcome. A Matlab script for user-friendly trajectory analysis is provided.
en
Health trajectories reveal the dynamic contributions of host genetic resistance and tolerance to infection outcome.
Article2018-06-13T05:36:57ZResistance and tolerance are two alternative strategies hosts can adopt to survive infections. Both strategies may be genetically controlled. To date, the relative contribution of resistance and tolerance to infection outcome is poorly understood. Here, we use a bioluminescent Listeria monocytogenes (Lm) infection challenge model to study the genetic determination and dynamic contributions of host resistance and tolerance to listeriosis in four genetically diverse mouse strains. Using conventional statistical analyses, we detect significant genetic variation in both resistance and tolerance, but cannot capture the time-dependent relative importance of either host strategy. We overcome these limitations through the development of novel statistical tools to analyse individual infection trajectories portraying simultaneous changes in infection severity and health. Based on these tools, early expression of resistance followed by expression of tolerance emerge as important hallmarks for surviving Lm infections. Our trajectory analysis further reveals that survivors and non-survivors follow distinct infection paths (which are also genetically determined) and provides new survival thresholds as objective endpoints in infection experiments. Future studies may use trajectories as novel traits for mapping and identifying genes that control infection dynamics and outcome. A Matlab script for user-friendly trajectory analysis is provided.oai:repository.helmholtz-hzi.de:10033/5928672019-08-30T11:27:46Zcom_10033_620626col_10033_620627
Hellert, Jan
Weidner-Glunde, Magdalena
Krausze, Joern
Lünsdorf, Heinrich
Ritter, Christiane
Schulz, Thomas F
Lührs, Thorsten
2016-01-05T16:42:19Z
2016-01-05T16:42:19Z
2015-05-26
The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA. 2015, 112 (21):6694-9 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
25947153
10.1073/pnas.1421804112
http://hdl.handle.net/10033/592867
Proceedings of the National Academy of Sciences of the United States of America
Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains ("LANA speckles"), a hallmark of KSHV latency.
en
Amino Acid Sequence
Antigens, Viral
Base Sequence
Binding Sites
Crystallography, X-Ray
DNA, Viral
DNA-Binding Proteins
Herpesvirus 8, Human
Humans
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Nuclear Proteins
Protein Structure, Quaternary
Protein Structure, Tertiary
Scattering, Small Angle
Static Electricity
X-Ray Diffraction
The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA.
Article2018-06-12T17:56:04ZKaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains ("LANA speckles"), a hallmark of KSHV latency.oai:repository.helmholtz-hzi.de:10033/5944112019-08-30T11:31:23Zcom_10033_620626col_10033_620627
Dimitrakopoulou, Konstantina
Tsimpouris, Charalampos
Papadopoulos, George
Pommerenke, Claudia
Wilk, Esther
Sgarbas, Kyriakos N
Schughart, Klaus
Bezerianos, Anastasios
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-01-20T14:54:04Z
2016-01-20T14:54:04Z
2011
Dynamic gene network reconstruction from gene expression data in mice after influenza A (H1N1) infection. 2011, 1:27 J Clin Bioinforma
2043-9113
22017961
10.1186/2043-9113-1-27
http://hdl.handle.net/10033/594411
Journal of clinical bioinformatics
The immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli.
en
Dynamic gene network reconstruction from gene expression data in mice after influenza A (H1N1) infection.
Article2018-06-13T19:56:54ZThe immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli.oai:repository.helmholtz-hzi.de:10033/5954392019-08-30T11:33:29Zcom_10033_620626col_10033_620627
Bergmann, Silke
Rohde, Manfred
Schughart, Klaus
Lengeling, Andreas
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-02-02T13:47:14Z
2016-02-02T13:47:14Z
2013
The bioluminescent Listeria monocytogenes strain Xen32 is defective in flagella expression and highly attenuated in orally infected BALB/cJ mice. 2013, 5 (1):19 Gut Pathog
1757-4749
23856386
10.1186/1757-4749-5-19
http://hdl.handle.net/10033/595439
Gut pathogens
In vivo bioluminescence imaging (BLI) is a powerful method for the analysis of host-pathogen interactions in small animal models. The commercially available bioluminescent Listeria monocytogenes strain Xen32 is commonly used to analyse immune functions in knockout mice and pathomechanisms of listeriosis.
en
The bioluminescent Listeria monocytogenes strain Xen32 is defective in flagella expression and highly attenuated in orally infected BALB/cJ mice.
Article2018-06-13T00:16:55ZIn vivo bioluminescence imaging (BLI) is a powerful method for the analysis of host-pathogen interactions in small animal models. The commercially available bioluminescent Listeria monocytogenes strain Xen32 is commonly used to analyse immune functions in knockout mice and pathomechanisms of listeriosis.oai:repository.helmholtz-hzi.de:10033/6011572019-08-30T11:28:23Zcom_10033_620626col_10033_620627
Kühn, Nora
Bergmann, Silke
Kasnitz, Nadine
Lambertz, Ruth L O
Keppner, Anna
van den Brand, Judith M A
Pöhlmann, Stefan
Weiß, Siegfried
Hummler, Edith
Hatesuer, Bastian
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-03-11T09:45:47Z
2016-03-11T09:45:47Z
2016-02-17
The proteolytic activation of A (H3N2) Influenza virus hemagglutinin is facilitated by different type II transmembrane serine proteases. 2016: J. Virol.
1098-5514
26889029
10.1128/JVI.02693-15
http://hdl.handle.net/10033/601157
Journal of virology
Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g. TMPRSS2, TMPRSS4 and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro. Recently, we reported that inactivation of a single HA-activating protease gene, Tmprss2, in knock-out mice inhibits spread of H1N1 influenza viruses. However, after infection of Tmprss2 knock-out mice with H3N2 only a slight increase was observed in survival and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knock-out mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast, Tmprss2(-/-)Tmprss4(-/-) double knock-out mice showed a remarkably reduced virus spread and lung pathology in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus HA in vivo.
ENG
The proteolytic activation of A (H3N2) Influenza virus hemagglutinin is facilitated by different type II transmembrane serine proteases.
Article2018-06-13T15:14:26ZCleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g. TMPRSS2, TMPRSS4 and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro. Recently, we reported that inactivation of a single HA-activating protease gene, Tmprss2, in knock-out mice inhibits spread of H1N1 influenza viruses. However, after infection of Tmprss2 knock-out mice with H3N2 only a slight increase was observed in survival and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knock-out mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast, Tmprss2(-/-)Tmprss4(-/-) double knock-out mice showed a remarkably reduced virus spread and lung pathology in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus HA in vivo.oai:repository.helmholtz-hzi.de:10033/6012182019-08-30T11:31:23Zcom_10033_620626col_10033_620627
Leist, Sarah R
Pilzner, Carolin
van den Brand, Judith M A
Dengler, Leonie
Geffers, Robert
Kuiken, Thijs
Balling, Rudi
Kollmus, Heike
Schughart, Klaus
Helmholtz Centre for infection research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.
2016-03-11T14:59:02Z
2016-03-11T14:59:02Z
2016
Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice. 2016, 17 (1):143 BMC Genomics
1471-2164
26921172
10.1186/s12864-016-2483-y
http://hdl.handle.net/10033/601218
BMC genomics
Influenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is not only influenced by viral virulence factors but also by individual differences in the host response. To determine the extent to which the genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mouse strains.
en
Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice.
Article2018-06-13T00:12:28ZInfluenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is not only influenced by viral virulence factors but also by individual differences in the host response. To determine the extent to which the genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mouse strains.oai:repository.helmholtz-hzi.de:10033/6060412019-08-30T11:28:23Zcom_10033_620626col_10033_620627
Low, Hui Zhi
Ahrenstorf, Gerrit
Pommerenke, Claudia
Habermann, Nadine
Schughart, Klaus
Ordóñez, David
Stripecke, Renata
Wilk, Esther
Witte, Torsten
Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
2016-04-20T08:00:47Z
2016-04-20T08:00:47Z
2016
TLR8 regulation of LILRA3 in monocytes is abrogated in human immunodeficiency virus infection and correlates to CD4 counts and virus loads. 2016, 13 (1):15 Retrovirology
1742-4690
26969150
10.1186/s12977-016-0248-y
http://hdl.handle.net/10033/606041
Retrovirology
LILRA3 is an immunostimulatory molecule which can conditionally induce the proliferation of cytotoxic cells. LILRA3 has a deletion genotype which is associated with multiple immune disorders. In this study, we wanted to analyze the regulation of LILRA3 and its significance in the context of HIV infection.
en
TLR8 regulation of LILRA3 in monocytes is abrogated in human immunodeficiency virus infection and correlates to CD4 counts and virus loads.
Article2018-06-12T17:48:13ZLILRA3 is an immunostimulatory molecule which can conditionally induce the proliferation of cytotoxic cells. LILRA3 has a deletion genotype which is associated with multiple immune disorders. In this study, we wanted to analyze the regulation of LILRA3 and its significance in the context of HIV infection.oai:repository.helmholtz-hzi.de:10033/6069472019-08-30T11:28:23Zcom_10033_620626col_10033_620627
Leist, Sarah R
Kollmus, Heike
Hatesuer, Bastian
Lambertz, Ruth L O
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-04-25T13:15:55Z
2016-04-25T13:15:55Z
2016
Lst1 deficiency has a minor impact on course and outcome of the host response to influenza A H1N1 infections in mice. 2016, 13 (1):17 Virol. J.
1743-422X
26817701
10.1186/s12985-016-0471-0
http://hdl.handle.net/10033/606947
Virology journal
Previously, we performed a quantitative trait locus (QTL) mapping study in BXD recombinant inbred mice to identify host genetic factors that confer resistance to influenza A virus infection. We found Lst1 (leukocyte specific transcript 1) as one of the most promising candidate genes in the Qivr17-2 locus because it is non-functional in DBA/2 J mice. Several studies have proposed that LST1 plays a role in the immune response to inflammatory diseases in humans and has additional immune-regulatory functions. Here, we evaluated the relevance of LST1 for the host response to influenza A infection in B6-Lst1 (-/-) mutant mice.
en
Lst1 deficiency has a minor impact on course and outcome of the host response to influenza A H1N1 infections in mice.
Article2018-06-13T00:54:37ZPreviously, we performed a quantitative trait locus (QTL) mapping study in BXD recombinant inbred mice to identify host genetic factors that confer resistance to influenza A virus infection. We found Lst1 (leukocyte specific transcript 1) as one of the most promising candidate genes in the Qivr17-2 locus because it is non-functional in DBA/2 J mice. Several studies have proposed that LST1 plays a role in the immune response to inflammatory diseases in humans and has additional immune-regulatory functions. Here, we evaluated the relevance of LST1 for the host response to influenza A infection in B6-Lst1 (-/-) mutant mice.oai:repository.helmholtz-hzi.de:10033/6090112019-08-30T11:28:51Zcom_10033_620626col_10033_620627
Marion, Tony
Elbahesh, Husni
Thomas, Paul G
DeVincenzo, John P
Webby, Richard
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-05-11T08:10:02Z
2016-05-11T08:10:02Z
2016
Respiratory Mucosal Proteome Quantification in Human Influenza Infections. 2016, 11 (4):e0153674 PLoS ONE
1932-6203
27088501
10.1371/journal.pone.0153674
http://hdl.handle.net/10033/609011
PloS one
Respiratory influenza virus infections represent a serious threat to human health. Underlying medical conditions and genetic make-up predispose some influenza patients to more severe forms of disease. To date, only a few studies have been performed in patients to correlate a selected group of cytokines and chemokines with influenza infection. Therefore, we evaluated the potential of a novel multiplex micro-proteomics technology, SOMAscan, to quantify proteins in the respiratory mucosa of influenza A and B infected individuals. The analysis included but was not limited to quantification of cytokines and chemokines detected in previous studies. SOMAscan quantified more than 1,000 secreted proteins in small nasal wash volumes from infected and healthy individuals. Our results illustrate the utility of micro-proteomic technology for analysis of proteins in small volumes of respiratory mucosal samples. Furthermore, when we compared nasal wash samples from influenza-infected patients with viral load ≥ 28 and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection.
en
Respiratory Mucosal Proteome Quantification in Human Influenza Infections.
Article2018-06-13T00:36:31ZRespiratory influenza virus infections represent a serious threat to human health. Underlying medical conditions and genetic make-up predispose some influenza patients to more severe forms of disease. To date, only a few studies have been performed in patients to correlate a selected group of cytokines and chemokines with influenza infection. Therefore, we evaluated the potential of a novel multiplex micro-proteomics technology, SOMAscan, to quantify proteins in the respiratory mucosa of influenza A and B infected individuals. The analysis included but was not limited to quantification of cytokines and chemokines detected in previous studies. SOMAscan quantified more than 1,000 secreted proteins in small nasal wash volumes from infected and healthy individuals. Our results illustrate the utility of micro-proteomic technology for analysis of proteins in small volumes of respiratory mucosal samples. Furthermore, when we compared nasal wash samples from influenza-infected patients with viral load ≥ 28 and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection.oai:repository.helmholtz-hzi.de:10033/6148832019-08-30T11:24:31Zcom_10033_620626col_10033_620627
Shin, Dai-Lun
Pandey, Ashutosh K
Ziebarth, Jesse Dylan
Mulligan, Megan K
Williams, Robert W
Geffers, Robert
Hatesuer, Bastian
Schughart, Klaus
Wilk, Esther
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-06-28T08:58:32Z
2016-06-28T08:58:32Z
2015-02
Segregation of a spontaneous Klrd1 (CD94) mutation in DBA/2 mouse substrains. 2015, 5 (2):235-9 G3 (Bethesda)
2160-1836
25520036
10.1534/g3.114.015164
http://hdl.handle.net/10033/614883
G3 (Bethesda, Md.)
Current model DBA/2J (D2J) mice lack CD94 expression due to a deletion spanning the last coding exon of the Klrd1 gene that occurred in the mid- to late 1980s. In contrast, DBA/2JRj (D2Rj) mice, crosses derived from DBA/2J before 1984, and C57BL/6J (B6) mice lack the deletion and have normal CD94 expression. For example, BXD lines (BXD1-32) generated in the 1970s by crossing B6 and D2J do not segregate for the exonic deletion and have high expression, whereas BXD lines 33 and greater were generated after 1990 are segregating for the deletion and have highly variable Klrd1 expression. We performed quantitative trait locus analysis of Klrd1 expression by using BXD lines with different generation times and found that the expression difference in Klrd1 in the later BXD set is driven by a strong cis-acting expression quantitative trait locus. Although the Klrd1/CD94 locus is essential for mousepox resistance, the genetic variation among D2 substrains and the later set of BXD strains is not associated with susceptibility to the Influenza A virus PR8 strain. Substrains with nearly identical genetic backgrounds that are segregating functional variants such as the Klrd1 deletion are useful genetic tools to investigate biological function.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Female
Mice, Inbred DBA
Mutation
NK Cell Lectin-Like Receptor Subfamily D
Quantitative Trait Loci
Segregation of a spontaneous Klrd1 (CD94) mutation in DBA/2 mouse substrains.
Article2018-06-12T23:38:52ZCurrent model DBA/2J (D2J) mice lack CD94 expression due to a deletion spanning the last coding exon of the Klrd1 gene that occurred in the mid- to late 1980s. In contrast, DBA/2JRj (D2Rj) mice, crosses derived from DBA/2J before 1984, and C57BL/6J (B6) mice lack the deletion and have normal CD94 expression. For example, BXD lines (BXD1-32) generated in the 1970s by crossing B6 and D2J do not segregate for the exonic deletion and have high expression, whereas BXD lines 33 and greater were generated after 1990 are segregating for the deletion and have highly variable Klrd1 expression. We performed quantitative trait locus analysis of Klrd1 expression by using BXD lines with different generation times and found that the expression difference in Klrd1 in the later BXD set is driven by a strong cis-acting expression quantitative trait locus. Although the Klrd1/CD94 locus is essential for mousepox resistance, the genetic variation among D2 substrains and the later set of BXD strains is not associated with susceptibility to the Influenza A virus PR8 strain. Substrains with nearly identical genetic backgrounds that are segregating functional variants such as the Klrd1 deletion are useful genetic tools to investigate biological function.oai:repository.helmholtz-hzi.de:10033/6156682019-08-30T11:24:31Zcom_10033_620626col_10033_620627
INFRAFRONTIER Consortium
Meehan, T. F.
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-07-07T12:10:46Z
2016-07-07T12:10:46Z
2015-01
INFRAFRONTIER--providing mutant mouse resources as research tools for the international scientific community. 2015, 43 (Database issue):D1171-5 Nucleic Acids Res.
1362-4962
25414328
10.1093/nar/gku1193
http://hdl.handle.net/10033/615668
Nucleic acids research
The laboratory mouse is a key model organism to investigate mechanism and therapeutics of human disease. The number of targeted genetic mouse models of disease is growing rapidly due to high-throughput production strategies employed by the International Mouse Phenotyping Consortium (IMPC) and the development of new, more efficient genome engineering techniques such as CRISPR based systems. We have previously described the European Mouse Mutant Archive (EMMA) resource and how this international infrastructure provides archiving and distribution worldwide for mutant mouse strains. EMMA has since evolved into INFRAFRONTIER (http://www.infrafrontier.eu), the pan-European research infrastructure for the systemic phenotyping, archiving and distribution of mouse disease models. Here we describe new features including improved search for mouse strains, support for new embryonic stem cell resources, access to training materials via a comprehensive knowledgebase and the promotion of innovative analytical and diagnostic techniques.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Databases, Genetic
Embryonic Stem Cells
Internet
Knowledge Bases
Mice, Mutant Strains
Models, Animal
Phenotype
INFRAFRONTIER--providing mutant mouse resources as research tools for the international scientific community.
Article2018-06-12T18:06:13ZThe laboratory mouse is a key model organism to investigate mechanism and therapeutics of human disease. The number of targeted genetic mouse models of disease is growing rapidly due to high-throughput production strategies employed by the International Mouse Phenotyping Consortium (IMPC) and the development of new, more efficient genome engineering techniques such as CRISPR based systems. We have previously described the European Mouse Mutant Archive (EMMA) resource and how this international infrastructure provides archiving and distribution worldwide for mutant mouse strains. EMMA has since evolved into INFRAFRONTIER (http://www.infrafrontier.eu), the pan-European research infrastructure for the systemic phenotyping, archiving and distribution of mouse disease models. Here we describe new features including improved search for mouse strains, support for new embryonic stem cell resources, access to training materials via a comprehensive knowledgebase and the promotion of innovative analytical and diagnostic techniques.oai:repository.helmholtz-hzi.de:10033/6159602019-08-30T11:28:51Zcom_10033_620626col_10033_620627
Shin, Dai-Lun
Hatesuer, Bastian
Bergmann, Silke
Nedelko, Tatiana
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-07-12T10:37:52Z
2016-07-12T10:37:52Z
2015-10
Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background. 2015, 89 (19):9998-10009 J. Virol.
1098-5514
26202236
10.1128/JVI.01305-15
http://hdl.handle.net/10033/615960
Journal of virology
Influenza virus infections represent a serious threat to human health. Both extrinsic and intrinsic factors determine the severity of influenza. The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains, including C57BL/6J, carry nonsense or deletion mutations in Mx1 and thus a nonfunctional allele, whereas wild-derived mouse strains carry a wild-type Mx1 allele. Congenic C57BL/6J (B6-Mx1(r/r)) mice expressing a wild-type allele from the A2G mouse strain are highly resistant to influenza A virus infections, to both mono- and polybasic subtypes. Furthermore, in genetic mapping studies, Mx1 was identified as the major locus of resistance to influenza virus infections. Here, we investigated whether the Mx1 protective function is influenced by the genetic background. For this, we generated a congenic mouse strain carrying the A2G wild-type Mx1 resistance allele on a DBA/2J background (D2-Mx1(r/r)). Most remarkably, congenic D2-Mx1(r/r) mice expressing a functional Mx1 wild-type allele are still highly susceptible to H1N1 virus. However, pretreatment of D2-Mx1(r/r) mice with alpha interferon protected them from lethal infections. Our results showed, for the first time, that the presence of an Mx1 wild-type allele from A2G as such does not fully protect mice from lethal influenza A virus infections. These observations are also highly relevant for susceptibility to influenza virus infections in humans.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Bronchoalveolar Lavage Fluid
Cytokines
Female
Genetic Predisposition to Disease
Host Specificity
Humans
Influenza A Virus, H1N1 Subtype
Influenza A Virus, H3N2 Subtype
Influenza, Human
Interferon-alpha
Mice
Mice, Congenic
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Mutation
Myxovirus Resistance Proteins
Orthomyxoviridae Infections
Virus Replication
Protection from Severe Influenza Virus Infections in Mice Carrying the Mx1 Influenza Virus Resistance Gene Strongly Depends on Genetic Background.
Article2018-06-12T17:42:29ZInfluenza virus infections represent a serious threat to human health. Both extrinsic and intrinsic factors determine the severity of influenza. The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains, including C57BL/6J, carry nonsense or deletion mutations in Mx1 and thus a nonfunctional allele, whereas wild-derived mouse strains carry a wild-type Mx1 allele. Congenic C57BL/6J (B6-Mx1(r/r)) mice expressing a wild-type allele from the A2G mouse strain are highly resistant to influenza A virus infections, to both mono- and polybasic subtypes. Furthermore, in genetic mapping studies, Mx1 was identified as the major locus of resistance to influenza virus infections. Here, we investigated whether the Mx1 protective function is influenced by the genetic background. For this, we generated a congenic mouse strain carrying the A2G wild-type Mx1 resistance allele on a DBA/2J background (D2-Mx1(r/r)). Most remarkably, congenic D2-Mx1(r/r) mice expressing a functional Mx1 wild-type allele are still highly susceptible to H1N1 virus. However, pretreatment of D2-Mx1(r/r) mice with alpha interferon protected them from lethal infections. Our results showed, for the first time, that the presence of an Mx1 wild-type allele from A2G as such does not fully protect mice from lethal influenza A virus infections. These observations are also highly relevant for susceptibility to influenza virus infections in humans.oai:repository.helmholtz-hzi.de:10033/6208182019-08-30T11:29:17Zcom_10033_620626col_10033_620627
Alberts, Rudi
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-02-15T12:40:52Z
2017-02-15T12:40:52Z
2010-10-15
QTLminer: identifying genes regulating quantitative traits. 2010, 11:516 BMC Bioinformatics
1471-2105
20950438
10.1186/1471-2105-11-516
http://hdl.handle.net/10033/620818
BMC bioinformatics
Quantitative trait locus (QTL) mapping identifies genomic regions that likely contain genes regulating a quantitative trait. However, QTL regions may encompass tens to hundreds of genes. To find the most promising candidate genes that regulate the trait, the biologist typically collects information from multiple resources about the genes in the QTL interval. This process is very laborious and time consuming.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Computational Biology
Genome
Molecular Sequence Annotation
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Software
QTLminer: identifying genes regulating quantitative traits.
Article2018-06-13T07:24:07ZQuantitative trait locus (QTL) mapping identifies genomic regions that likely contain genes regulating a quantitative trait. However, QTL regions may encompass tens to hundreds of genes. To find the most promising candidate genes that regulate the trait, the biologist typically collects information from multiple resources about the genes in the QTL interval. This process is very laborious and time consuming.oai:repository.helmholtz-hzi.de:10033/6208192019-08-30T11:34:22Zcom_10033_620626col_10033_620627
Bahgat, Mahmoud M
Błazejewska, Paulina
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-02-15T12:47:51Z
2017-02-15T12:47:51Z
2011-01-20
Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection. 2011, 8:27 Virol. J.
1743-422X
21251300
10.1186/1743-422X-8-27
http://hdl.handle.net/10033/620819
Virology journal
Host serine proteases are essential for the influenza virus life cycle because the viral haemagglutinin is synthesized as a precursor which requires proteolytic maturation. Therefore, we studied the activity and expression of serine proteases in lungs from mice infected with influenza and evaluated the effect of serine protease inhibitors on virus replication both in cell culture and in infected mice.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Body Weight
Cell Line
Epithelial Cells
Humans
Influenza A Virus, H1N1 Subtype
Influenza A Virus, H7N7 Subtype
Lung
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Orthomyxoviridae Infections
Serine Proteases
Serine Proteinase Inhibitors
Virus Replication
Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection.
Article2018-06-13T01:16:20ZHost serine proteases are essential for the influenza virus life cycle because the viral haemagglutinin is synthesized as a precursor which requires proteolytic maturation. Therefore, we studied the activity and expression of serine proteases in lungs from mice infected with influenza and evaluated the effect of serine protease inhibitors on virus replication both in cell culture and in infected mice.oai:repository.helmholtz-hzi.de:10033/6208212019-08-30T11:29:17Zcom_10033_620626col_10033_620627
Akmatov, M K
Pessler, F
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-02-15T15:39:12Z
2017-02-15T15:39:12Z
2011-09
Self-collected nasal swabs to detect infection and colonization: a useful tool for population-based epidemiological studies? 2011, 15 (9):e589-93 Int. J. Infect. Dis.
1878-3511
21641847
10.1016/j.ijid.2011.04.009
http://hdl.handle.net/10033/620821
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
Population-based epidemiological studies on infectious diseases are limited by methodological problems that may not be encountered in other fields of epidemiology. The acute or asymptomatic nature of many infections hinders a timely diagnosis by trained personnel in a study centre, indicating the need for new collection methods of biological specimens. One alternative approach is to have the participants collect the specimens themselves, for instance nasal swabs for the detection of bacterial or viral pathogens. Although self-collection is widely accepted in clinical studies of specific populations (e.g., self-collection of vaginal swabs by young women to diagnose sexually transmitted infections), it has not been employed much in population-based studies. Here, we review recent experience with self-collection of nasal swabs for the detection of microorganisms and discuss future prospects and applications for this technique.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Biopsy
Communicable Diseases
Humans
Nasal Cavity
Self Care
Self-collected nasal swabs to detect infection and colonization: a useful tool for population-based epidemiological studies?
Article2018-06-13T03:43:18ZPopulation-based epidemiological studies on infectious diseases are limited by methodological problems that may not be encountered in other fields of epidemiology. The acute or asymptomatic nature of many infections hinders a timely diagnosis by trained personnel in a study centre, indicating the need for new collection methods of biological specimens. One alternative approach is to have the participants collect the specimens themselves, for instance nasal swabs for the detection of bacterial or viral pathogens. Although self-collection is widely accepted in clinical studies of specific populations (e.g., self-collection of vaginal swabs by young women to diagnose sexually transmitted infections), it has not been employed much in population-based studies. Here, we review recent experience with self-collection of nasal swabs for the detection of microorganisms and discuss future prospects and applications for this technique.oai:repository.helmholtz-hzi.de:10033/6208952019-08-30T11:32:16Zcom_10033_620636com_10033_620626com_10033_311308col_10033_620665col_10033_621053col_10033_620629
Suwandi, Abdulhadi
Bargen, Imke
Pils, Marina C
Krey, Martina
Zur Lage, Susanne
Singh, Anurag K
Basler, Tina
Falk, Christine S
Seidler, Ursula
Hornef, Mathias W
Goethe, Ralph
Weiss, Siegfried
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-04-12T14:43:10Z
2017-04-12T14:43:10Z
2017
CD4 T Cell Dependent Colitis Exacerbation Following Re-Exposure of Mycobacterium avium ssp. paratuberculosis. 2017, 7:75 Front Cell Infect Microbiol
2235-2988
28361039
110.1097/MIB.0000000000000157
http://hdl.handle.net/10033/620895
Frontiers in cellular and infection microbiology
Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic inflammatory bowel disease of cattle characterized by intermittent to chronic diarrhea. In addition, MAP has been isolated from Crohn's disease (CD) patients. The impact of MAP on severity of clinical symptoms in JD as well as its role in CD are yet unknown. We have previously shown that MAP is able to colonize inflamed enteric tissue and to exacerbate the inflammatory tissue response (Suwandi et al., 2014). In the present study, we analyzed how repeated MAP administration influences the course of dextran sulfate sodium (DSS)-induced colitis. In comparison to mice exposed to DSS or MAP only, repeated exposure of DSS-treated mice to MAP (DSS/MAP) revealed a significantly enhanced clinical score, reduction of colon length as well as severe CD4(+) T cell infiltration into the colonic lamina propria. Functional analysis identified a critical role of CD4(+) T cells in the MAP-induced disease exacerbation. Additionally, altered immune responses were observed when closely related mycobacteria species such as M. avium ssp. avium and M. avium ssp. hominissuis were administered. These data reveal the specific ability of MAP to aggravate intestinal inflammation and clinical symptoms. Overall, this phenotype is compatible with similar disease promoting capabilites of MAP in JD and CD.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
CD4 T Cell Dependent Colitis Exacerbation Following Re-Exposure of Mycobacterium avium ssp. paratuberculosis.
Article2018-06-13T00:12:59ZMycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic inflammatory bowel disease of cattle characterized by intermittent to chronic diarrhea. In addition, MAP has been isolated from Crohn's disease (CD) patients. The impact of MAP on severity of clinical symptoms in JD as well as its role in CD are yet unknown. We have previously shown that MAP is able to colonize inflamed enteric tissue and to exacerbate the inflammatory tissue response (Suwandi et al., 2014). In the present study, we analyzed how repeated MAP administration influences the course of dextran sulfate sodium (DSS)-induced colitis. In comparison to mice exposed to DSS or MAP only, repeated exposure of DSS-treated mice to MAP (DSS/MAP) revealed a significantly enhanced clinical score, reduction of colon length as well as severe CD4(+) T cell infiltration into the colonic lamina propria. Functional analysis identified a critical role of CD4(+) T cells in the MAP-induced disease exacerbation. Additionally, altered immune responses were observed when closely related mycobacteria species such as M. avium ssp. avium and M. avium ssp. hominissuis were administered. These data reveal the specific ability of MAP to aggravate intestinal inflammation and clinical symptoms. Overall, this phenotype is compatible with similar disease promoting capabilites of MAP in JD and CD.oai:repository.helmholtz-hzi.de:10033/6209082019-08-30T11:29:47Zcom_10033_620626col_10033_620627
Elbahesh, Husni
Schughart, Klaus
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-05-05T07:27:21Z
2017-05-05T07:27:21Z
2016-05-19
Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature. 2016, 6:26437 Sci Rep
2045-2322
27193691
10.1038/srep26437
http://hdl.handle.net/10033/620908
Scientific reports
Influenza A viruses (IAV) are zoonotic pathogens that pose a major threat to human and animal health. Influenza virus disease severity is influenced by viral virulence factors as well as individual differences in host response. We analyzed gene expression changes in the blood of infected mice using a previously defined set of signature genes that was derived from changes in the blood transcriptome of IAV-infected human volunteers. We found that the human signature was reproduced well in the founder strains of the Collaborative Cross (CC) mice, thus demonstrating the relevance and importance of mouse experimental model systems for studying human influenza disease.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Genetically diverse CC-founder mouse strains replicate the human influenza gene expression signature.
Article2018-05-23T10:10:29ZInfluenza A viruses (IAV) are zoonotic pathogens that pose a major threat to human and animal health. Influenza virus disease severity is influenced by viral virulence factors as well as individual differences in host response. We analyzed gene expression changes in the blood of infected mice using a previously defined set of signature genes that was derived from changes in the blood transcriptome of IAV-infected human volunteers. We found that the human signature was reproduced well in the founder strains of the Collaborative Cross (CC) mice, thus demonstrating the relevance and importance of mouse experimental model systems for studying human influenza disease.oai:repository.helmholtz-hzi.de:10033/6209842019-08-30T11:31:23Zcom_10033_311624com_10033_6839com_10033_620626com_10033_311308com_10033_338554col_10033_621787col_10033_311625col_10033_620721col_10033_620629
Rahim, Muhammad Imran
Babbar, Anshu
Lienenklaus, Stefan
Pils, Marina
Rohde, M
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-06-28T13:41:37Z
2017-06-28T13:41:37Z
2017-06-01
Degradable magnesium implant-associated infections by bacterial biofilms induce robust localized and systemic inflammatory reactions in a mouse model. 2017 Biomed Mater
1748-605X
28569671
10.1088/1748-605X/aa7667
http://hdl.handle.net/10033/620984
Biomedical materials (Bristol, England)
Biomaterial-associated Pseudomonas aeruginosa biofilm infections constitute cascade of host immune reactions ultimately leading towards implant failure. Due to lack of relevant in vivo biofilm models, majority of the studies report host immune responses against free living or planktonic bacteria while bacteria in clinical situations live more frequently as biofilm communities than as single cells. Present study investigated host immune responses against biomaterial-associated P. aeruginosa biofilms in a clinically relevant mouse model. Previously, we reported metallic magnesium, a prospective biodegradable implant, to be permissive for bacterial biofilms in vivo even though it exhibits antibacterial properties in vitro. Therefore, magnesium was employed as biomaterial to investigate in vivo biofilm formation and associated host immune responses by using two P. aeruginosa strains and two mouse strains. P. aeruginosa formed biofilms on subcutaneously implanted magnesium discs. Non-invasive in vivo imaging indicated transient inflammatory responses at control sites whereas robust prolonged interferon-β (IFN-β) expression was observed from biofilms in a transgenic animal reporter. Further, immunohistology and electron microscopic results showed that bacterial biofilms were located in two dimensions immediately on the implant surface and at a short distance in the adjacent tissue. These biofilms were surrounded by inflammatory cells (mainly polymorphonuclear cells) as compared to controls. Interestingly, even though the number of live bacteria in various organs remained below detectable levels, splenomegaly indicated systemic inflammatory processes. Overall, these findings confirmed the resistance of biofilm infections in vivo to potentially antibacterial properties of magnesium degradation products. In vivo imaging and histology indicated the induction of both, local and systemic host inflammatory responses against P. aeruginosa biofilms. Even though the innate host immune defenses could not eliminate the local infection for up to two weeks, there was no apparent systemic bacteremia and all animals investigated survived the infection.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Degradable magnesium implant-associated infections by bacterial biofilms induce robust localized and systemic inflammatory reactions in a mouse model.
ArticleBiomaterial-associated Pseudomonas aeruginosa biofilm infections constitute cascade of host immune reactions ultimately leading towards implant failure. Due to lack of relevant in vivo biofilm models, majority of the studies report host immune responses against free living or planktonic bacteria while bacteria in clinical situations live more frequently as biofilm communities than as single cells. Present study investigated host immune responses against biomaterial-associated P. aeruginosa biofilms in a clinically relevant mouse model. Previously, we reported metallic magnesium, a prospective biodegradable implant, to be permissive for bacterial biofilms in vivo even though it exhibits antibacterial properties in vitro. Therefore, magnesium was employed as biomaterial to investigate in vivo biofilm formation and associated host immune responses by using two P. aeruginosa strains and two mouse strains. P. aeruginosa formed biofilms on subcutaneously implanted magnesium discs. Non-invasive in vivo imaging indicated transient inflammatory responses at control sites whereas robust prolonged interferon-β (IFN-β) expression was observed from biofilms in a transgenic animal reporter. Further, immunohistology and electron microscopic results showed that bacterial biofilms were located in two dimensions immediately on the implant surface and at a short distance in the adjacent tissue. These biofilms were surrounded by inflammatory cells (mainly polymorphonuclear cells) as compared to controls. Interestingly, even though the number of live bacteria in various organs remained below detectable levels, splenomegaly indicated systemic inflammatory processes. Overall, these findings confirmed the resistance of biofilm infections in vivo to potentially antibacterial properties of magnesium degradation products. In vivo imaging and histology indicated the induction of both, local and systemic host inflammatory responses against P. aeruginosa biofilms. Even though the innate host immune defenses could not eliminate the local infection for up to two weeks, there was no apparent systemic bacteremia and all animals investigated survived the infection.oai:repository.helmholtz-hzi.de:10033/6210262019-08-30T11:25:11Zcom_10033_620644com_10033_620626com_10033_620601com_10033_621723col_10033_621724col_10033_620650col_10033_620629col_10033_620602
Błażejewski, Adrian J
Thiemann, Sophie
Schenk, Alexander
Pils, Marina C
Gálvez, Eric J C
Roy, Urmi
Heise, Ulrike
de Zoete, Marcel R
Flavell, Richard A
Strowig, Till
Helmholtz Centre for infection research, Inhoffenstr. 7. 38124 Braunschweig, Germany.
2017-08-01T13:20:36Z
2017-08-01T13:20:36Z
2017-06-13
Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation. 2017, 19 (11):2319-2330 Cell Rep
2211-1247
28614717
10.1016/j.celrep.2017.05.058
http://hdl.handle.net/10033/621026
Cell reports
Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1(-/-) and Casp11(-/-) mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1(-/-) mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.
Article2018-06-12T17:48:52ZInflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1(-/-) and Casp11(-/-) mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1(-/-) mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.oai:repository.helmholtz-hzi.de:10033/6210712019-08-30T11:27:16Zcom_10033_620626com_10033_620601col_10033_620627col_10033_620603
Preusse, Matthias
Schughart, Klaus
Pessler, Frank
2017-08-22T14:00:30Z
2017-08-22T14:00:30Z
2017
Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection. 2017, 8:246 Front Immunol
1664-3224
28377766
10.3389/fimmu.2017.00246
http://hdl.handle.net/10033/621071
Frontiers in immunology
Expression of host microRNAs (miRNAs) changes markedly during influenza A virus (IAV) infection of natural and adaptive hosts, but their role in genetically determined host susceptibility to IAV infection has not been explored. We, therefore, compared pulmonary miRNA expression during IAV infection in two inbred mouse strains with differential susceptibility to IAV infection.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection.
Article2018-06-12T17:23:51ZExpression of host microRNAs (miRNAs) changes markedly during influenza A virus (IAV) infection of natural and adaptive hosts, but their role in genetically determined host susceptibility to IAV infection has not been explored. We, therefore, compared pulmonary miRNA expression during IAV infection in two inbred mouse strains with differential susceptibility to IAV infection.oai:repository.helmholtz-hzi.de:10033/6210762021-11-12T14:44:10Zcom_10033_620626col_10033_620627
Ashrafi, Amer
Garcia, Pierre
Kollmus, Heike
Schughart, Klaus
Del Sol, Antonio
Buttini, Manuel
Glaab, Enrico
HelmholtzCentre of infetion research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-28T12:57:40Z
2017-08-28T12:57:40Z
2017-06-19
Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease. 2017, 58:30-33 Neurobiol. Aging
1558-1497
28697377
10.1016/j.neurobiolaging.2017.06.008
http://hdl.handle.net/10033/621076
Neurobiology of aging
Regulator of G-protein signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson's disease (PD). In the case of PD, the main current options for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects and reduced effectiveness over the long term. Research on new nondopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection end points has not yet been demonstrated. Here, we use the 6-hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA-induced injury and show enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a nondopaminergic target for PD should be approached with caution.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Absence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease.
Article2018-06-12T18:05:58ZRegulator of G-protein signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson's disease (PD). In the case of PD, the main current options for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects and reduced effectiveness over the long term. Research on new nondopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection end points has not yet been demonstrated. Here, we use the 6-hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA-induced injury and show enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a nondopaminergic target for PD should be approached with caution.oai:repository.helmholtz-hzi.de:10033/6212242019-08-30T11:26:42Zcom_10033_128109com_10033_620644com_10033_620626col_10033_128110col_10033_620646col_10033_620629
Pezoldt, Joern
Pisano, Fabio
Heine, Wiebke
Pasztoi, Maria
Rosenheinrich, Maik
Nuss, Aaron M
Pils, Marina C
Prinz, Immo
Förster, Reinhold
Huehn, Jochen
Dersch, Petra
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-01-04T10:58:34Z
2018-01-04T10:58:34Z
2017-09-15
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection. 2017, 216 (6):752-760 J. Infect. Dis.
1537-6613
28329174
10.1093/infdis/jix037
http://hdl.handle.net/10033/621224
The Journal of infectious diseases
To successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Cell Movement
Dendritic Cells
Genetic Predisposition to Disease
Host-Pathogen Interactions
Intestines
Lymph Nodes
Mice
Myeloid Cells
Peyer's Patches
Receptors, CCR7
Th17 Cells
Yersinia pseudotuberculosis
Yersinia pseudotuberculosis Infections
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection.
ArticleTo successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated.oai:repository.helmholtz-hzi.de:10033/6212442019-08-30T11:25:11Zcom_10033_620626com_10033_621723col_10033_621724col_10033_620629col_10033_620629
Roy, Urmi
Gálvez, Eric J C
Iljazovic, Aida
Lesker, Till Robin
Błażejewski, Adrian J
Pils, Marina C
Heise, Ulrike
Huber, Samuel
Flavell, Richard A
Strowig, Till
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-01-19T10:49:13Z
2018-01-19T10:49:13Z
2017-10-24
Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells. 2017, 21 (4):994-1008 Cell Rep
2211-1247
29069606
10.1016/j.celrep.2017.09.097
http://hdl.handle.net/10033/621244
Cell reports
Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4+ T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells.
Article2018-06-13T19:42:27ZInflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4+ T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures.oai:repository.helmholtz-hzi.de:10033/6212682019-08-30T11:26:13Zcom_10033_620626com_10033_620636com_10033_620652col_10033_620666col_10033_620627col_10033_620638
Hatesuer, Bastian
Hoang, Hang Thi Thu
Riese, Peggy
Trittel, Stephanie
Gerhauser, Ingo
Elbahesh, Husni
Geffers, Robert
Wilk, Esther
Schughart, Klaus
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-02-08T15:10:19Z
2018-02-08T15:10:19Z
2017
Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection. 2017, 9 (2):145-161 J Innate Immun
1662-8128
27811478
10.1159/000450705
http://hdl.handle.net/10033/621268
Journal of innate immunity
The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Adaptive Immunity
Animals
Cells, Cultured
Granulocytes
Inflammation
Influenza A virus
Interferon Regulatory Factor-3
Interferon Regulatory Factor-7
Interferon-alpha
Lung
Mice
Mice, Inbred C57BL
Mice, Knockout
Orthomyxoviridae Infections
Signal Transduction
Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection.
Article2018-06-13T21:20:12ZThe interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.oai:repository.helmholtz-hzi.de:10033/6213182019-08-30T11:30:58Zcom_10033_620626col_10033_620627
Yang, W
Punyadarsaniya, D
Lambertz, R L O
Lee, D C C
Liang, C H
Höper, D
Leist, S R
Hernández-Cáceres, A
Stech, J
Beer, M
Wu, C Y
Wong, C H
Schughart, Klaus
Meng, F
Herrler, G
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-03-09T11:43:26Z
2018-03-09T11:43:26Z
2017-04-15
Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice. 2017, 91 (8) J. Virol.
1098-5514
28148793
10.1128/JVI.02125-16
http://hdl.handle.net/10033/621318
Journal of virology
The natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precision-cut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized α2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with α2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190+HA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.IMPORTANCESwine play an important role in the interspecies transmission of influenza viruses. Avian influenza A viruses (IAV) of the H9N2 subtype have successfully infected hosts from different species but have not established a stable lineage. We have analyzed the adaptation of IAV-H9N2 virus to target cells of a new host by passaging the virus three times in differentiated porcine respiratory epithelial cells. Among the four mutations detected, the two HA mutations were analyzed by generating recombinant viruses. Depending on the infection system used, the mutations differed in their phenotypic expression, e.g., sialic acid binding activity, replication kinetics, plaque size, and pathogenicity in inbred mice. However, none of the mutations affected the ciliary activity which serves as a virulence marker. Thus, early adaptive mutation enhances the replication kinetics, but more mutations are required for IAV of the H9N2 subtype to become virulent.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Adaptation, Biological
Animals
DNA Mutational Analysis
Epithelial Cells
Hemagglutinin Glycoproteins, Influenza Virus
Influenza A Virus, H9N2 Subtype
Mice
Mutation, Missense
N-Acetylneuraminic Acid
RNA Replicase
Respiratory Mucosa
Reverse Genetics
Serial Passage
Swine
Viral Nonstructural Proteins
Viral Proteins
Virulence
Virus Attachment
Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice.
Article2018-06-12T20:02:36ZThe natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precision-cut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized α2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with α2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190+HA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.IMPORTANCESwine play an important role in the interspecies transmission of influenza viruses. Avian influenza A viruses (IAV) of the H9N2 subtype have successfully infected hosts from different species but have not established a stable lineage. We have analyzed the adaptation of IAV-H9N2 virus to target cells of a new host by passaging the virus three times in differentiated porcine respiratory epithelial cells. Among the four mutations detected, the two HA mutations were analyzed by generating recombinant viruses. Depending on the infection system used, the mutations differed in their phenotypic expression, e.g., sialic acid binding activity, replication kinetics, plaque size, and pathogenicity in inbred mice. However, none of the mutations affected the ciliary activity which serves as a virulence marker. Thus, early adaptive mutation enhances the replication kinetics, but more mutations are required for IAV of the H9N2 subtype to become virulent.oai:repository.helmholtz-hzi.de:10033/6213922019-08-30T11:26:37Zcom_10033_620626com_10033_620601col_10033_620629col_10033_620603
Loof, Torsten G
Sohail, Aaqib
Bahgat, Mahmoud M
Tallam, Aravind
Arshad, Haroon
Akmatov, Manas K
Pils, Marina C
Heise, Ulrike
Beineke, Andreas
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
2018-06-05T12:52:50Z
2018-06-05T12:52:50Z
29707522
http://hdl.handle.net/10033/621392
Group A streptococci may induce lymphopenia, but the value of lymphocyte loss as early biomarkers for systemic spread and severe infection has not been examined systematically. We evaluated peripheral blood cell indices as biomarkers for severity and spread of infection in a mouse model of skin infection, using two isolates of greatly differing virulence. Internal organs were examined histologically. After subcutaneous inoculation, strain AP1 disseminated rapidly to peripheral blood and internal organs, causing frank sepsis. In contrast, seeding of internal organs by 5448 was mild, this strain could not be isolated from blood, and infection remained mostly localized to skin. Histopathologic examination of liver revealed microvesicular fatty change (steatosis) in AP1 infection, and examination of spleen showed elevated apoptosis and blurring of the white pulp/red pulp border late (40 h post infection) in AP1 infection. Both strains caused profound lymphopenia, but lymphocyte loss was more rapid early in AP1 infection, and lymphocyte count at 6 h post infection was the most accurate early marker for AP1 infection (area under the receiver operator curve [AUC] = 0.93), followed by the granulocyte/lymphocyte ratio (AUC = 0.89). The results suggest that virulence of correlates with the degree of early lymphopenia and underscore the value of peripheral blood indices to predict severity of bacterial infections in mice. Early lymphopenia and elevated granulocyte/lymphocyte ratio merit further investigation as biomarkers for systemic spread of skin infections in humans and, possibly, related pyogenic streptococci in humans and animals.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Streptococcus pyogenes
biomarker
leukocytes
lymphopenia
sepsis
skin infection
Early Lymphocyte Loss and Increased Granulocyte/Lymphocyte Ratio Predict Systemic Spread of in a Mouse Model of Acute Skin Infection.
Article2018-06-05T12:52:51Zoai:repository.helmholtz-hzi.de:10033/6214922019-08-30T11:29:45Zcom_10033_620626com_10033_311308col_10033_620627col_10033_559591
Zmora, Pawel
Hoffmann, Markus
Kollmus, Heike
Moldenhauer, Anna-Sophie
Danov, Olga
Braun, Armin
Winkler, Michael
Schughart, Klaus
Pöhlmann, Stefan
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-09-24T12:46:44Z
2018-09-24T12:46:44Z
2018-09-07
1083-351X
29976755
10.1074/jbc.RA118.001273
http://hdl.handle.net/10033/621492
The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA-activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
TMPRSS11A
influenza virus
protease
protease inhibitor
virology
virus entry
TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1.
Article
The Journal of biological chemistry
oai:repository.helmholtz-hzi.de:10033/6215032018-09-29T03:08:58Zcom_10033_620626col_10033_620627
Yang, W
Punyadarsaniya, D
Lambertz, R L O
Lee, D C C
Liang, C H
Höper, D
Leist, S R
Hernández-Cáceres, A
Stech, J
Beer, M
Wu, C Y
Wong, C H
Schughart, K
Meng, F
Herrler, G
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-09-28T14:30:25Z
2018-09-28T14:30:25Z
2017-04-15
1098-5514
28148793
10.1128/JVI.02125-16
http://hdl.handle.net/10033/621503
The natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precision-cut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized α2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with α2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190+HA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.
en
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H9N2
adaptation
avian viruses
precision-cut lung slices
sialic acid
Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice.
Article
Journal of virology2018-09-28T14:30:26Zoai:repository.helmholtz-hzi.de:10033/6215092019-08-30T11:31:22Zcom_10033_620626com_10033_311308col_10033_620627col_10033_559591
Lambertz, Ruth L O
Pippel, Jan
Gerhauser, Ingo
Kollmus, Heike
Anhlan, Darisuren
Hrincius, Eike R
Krausze, Joern
Kühn, Nora
Schughart, Klaus
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-10-08T13:36:18Z
2018-10-08T13:36:18Z
2018-09-01
1465-2099
30084768
10.1099/jgv.0.001128
http://hdl.handle.net/10033/621509
The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous
studies showed that H1N1 virus cannot replicate efficiently in Tmprss2/ knock-out mice whereas H3N2 viruses are able to
replicate to the same levels in Tmprss2/ as in wild type (WT) mice. Here, we investigated the sequence requirements for
the HA molecule that allow IAV to replicate efficiently in the absence of TMPRSS2. We showed that replacement of the H3 for
the H1-loop sequence (amino acids 320 to 329, at the C-terminus of HA1) was not sufficient for equal levels of virus
replication or severe pathology in Tmprss2/ knock-out mice compared to WT mice. However, exchange of a distant amino
acid from H1 to H3 sequence (E31D) in addition to the HA-loop substitution resulted in virus replication in Tmprss2/ knockout mice that was comparable to WT mice. The higher virus replication and lung damage was associated with increased
epithelial damage and higher mortality. Our results provide further evidence and insights into host proteases as a promising
target for therapeutic intervention of IAV infections.
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hemagglutinin
host protease
influenza A virus
Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice.
Article
The Journal of general virology2018-10-08T13:36:18Zoai:repository.helmholtz-hzi.de:10033/6215232019-08-30T11:29:16Zcom_10033_620626col_10033_620627
Kollmus, Heike
Pilzner, Carolin
Leist, Sarah R
Heise, Mark
Geffers, Robert
Schughart, Klaus
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-10-23T09:37:22Z
2018-10-23T09:37:22Z
2018-08-01
1432-1777
29947965
10.1007/s00335-018-9750-y
http://hdl.handle.net/10033/621523
Influenza virus (IV) infections represent a very serious public health problem. At present, no established biomarkers exist to support diagnosis for respiratory viral infections and more importantly for severe IV disease. Studies in animal models are extremely important to understand the biological, genetic, and environmental factors that contribute to severe IV disease and to validate biomarker candidates from human studies. However, mouse human cross-species comparisons are often compromised by the fact that animal studies concentrate on the infected lungs, whereas in humans almost all studies use peripheral blood from patients. In addition, human studies do not consider genetic background as variable although human populations are genetically very diverse. Therefore, in this study, we performed a cross-species gene expression study of the peripheral blood from human patients and from the highly genetically diverse Collaborative Cross (CC) mouse population after IV infection. Our results demonstrate that changes of gene expression in individual genes are highly similar in mice and humans. The top-regulated genes in humans were also differentially regulated in mice. We conclude that the mouse is a highly valuable in vivo model system to validate and to discover gene candidates which can be used as biomarkers in humans. Furthermore, mouse studies allow confirmation of findings in humans in a well-controlled experimental system adding enormous value to the understanding of expression and function of human candidate genes.
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Of mice and men: the host response to influenza virus infection.
Article
Mammalian genome : official journal of the International Mammalian Genome Society2018-10-23T09:37:23Zoai:repository.helmholtz-hzi.de:10033/6215902019-08-30T11:29:44Zcom_10033_620626com_10033_620601com_10033_620618col_10033_620629col_10033_620603col_10033_620621
Strehlitz, Anja
Goldmann, Oliver
Pils, Marina C
Pessler, Frank
Medina, Eva
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
2018-11-28T10:27:41Z
2018-11-28T10:27:41Z
2018-01-01
1664-3224
29988532
10.3389/fimmu.2018.01424
http://hdl.handle.net/10033/621590
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). Despite the low prevalence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA), CAP patients often receive empirical antibiotic therapy providing coverage for MRSA such as vancomycin or linezolid. An early differentiation between S. pneumoniae and S. aureus pneumonia can help to reduce the use of unnecessary antibiotics. The objective of this study was to identify candidate biomarkers that can discriminate pneumococcal from staphylococcal pneumonia. A genome-wide transcriptional analysis of lung and peripheral blood performed in murine models of S. pneumoniae and S. aureus lung infection identified an interferon signature specifically associated with S. pneumoniae infection. Prediction models built using a support vector machine and Monte Carlo cross-validation, identified the combination of the interferon-induced chemokines CXCL9 and CXCL10 serum concentrations as the set of biomarkers with best sensitivity, specificity, and predictive power that enabled an accurate discrimination between S. pneumoniae and S. aureus pneumonia. The predictive performance of these biomarkers was further validated in an independent cohort of mice. This study highlights the potential of serum CXCL9 and CXCL10 biomarkers as an adjunctive diagnostic tool that could facilitate prompt and correct pathogen-targeted therapy in CAP patients.
Frontiers
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Staphylococcus aureus
Streptococcus pneumoniae
biomarkers
interferon
pneumonia
transcriptome
An Interferon Signature Discriminates Pneumococcal From Staphylococcal Pneumonia.
Article
Frontiers in immunology2018-11-28T10:27:41Zoai:repository.helmholtz-hzi.de:10033/6215912019-08-30T11:29:44Zcom_10033_620636com_10033_620626com_10033_620589col_10033_621803col_10033_620665col_10033_620629
Abdissa, Ketema
Nerlich, Andreas
Beineke, Andreas
Ruangkiattikul, Nanthapon
Pawar, Vinay
Heise, Ulrike
Janze, Nina
Falk, Christine
Bruder, Dunja
Schleicher, Ulrike
Bogdan, Christian
Weiss, Siegfried
Goethe, Ralph
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-11-28T12:49:32Z
2018-11-28T12:49:32Z
2018-01-01
1664-3224
30386330
10.3389/fimmu.2018.02317
http://hdl.handle.net/10033/621591
Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with immunomodulatory function. To study the mechanism by which MDSC affect antimicrobial immunity, we infected mice with two M. avium strains of differential virulence, highly virulent Mycobacterium avium subsp. avium strain 25291 (MAA) and low virulent Mycobacterium avium subsp. hominissuis strain 104 (MAH). Intraperitoneal infection with MAA, but not MAH, caused severe disease and massive splenic infiltration of monocytic MDSC (M-MDSC; Gr-1intCD11bhiCD11cint) expressing inducible NO synthase (Nos2) and bearing high numbers of mycobacteria. Depletion experiments demonstrated that M-MDSC were essential for disease progression. NO production by M-MDSC influenced antigen-uptake and processing by dendritic cells and proliferation of CD4+ T cells. M-MDSC were also induced in MAA-infected mice lacking Nos2. In these mice CD4+ T cell expansion and control of infection were restored. However, T cell inhibition was only partially relieved and arginase (Arg) 1-expressing M-MDSC were accumulated. Likewise, inhibition of Arg1 also partially rescued T cell proliferation. Thus, mycobacterial virulence results in the induction of M-MDSC that block the T cell response in a Nos2- and Arg1-dependent manner.
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Arg1
MDSC
Nos2
T cells
dendritic cells
iNOS
non-tuberculous mycobacteria
Presence of Infected Gr-1CD11bCD11c Monocytic Myeloid Derived Suppressor Cells Subverts T Cell Response and Is Associated With Impaired Dendritic Cell Function in Mycobacterium avium-Infected Mice.
Article
Frontiers in immunology2018-11-28T12:49:32Zoai:repository.helmholtz-hzi.de:10033/6216022019-08-30T11:30:27Zcom_10033_338554com_10033_620626col_10033_621050col_10033_620627
Bussey, Kendra A
Murthy, Sripriya
Reimer, Elisa
Chan, Baca
Hatesuer, Bastian
Schughart, Klaus
Glaunsinger, Britt
Adler, Heiko
Brinkmann, Melanie M
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-12-05T10:06:21Z
2018-12-05T10:06:21Z
2018-11-14
1098-5514
30429335
10.1128/JVI.01173-18
http://hdl.handle.net/10033/621602
Murine gammaherpesvirus 68 (MHV68) is an amenable small animal model for study of the
human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Here,
we have characterized the roles of the endosomal TLR escort protein UNC93B, endosomal
TLR7, 9, and 13, and cell surface TLR2 in MHV68 detection. We found that the interferon α
(IFNα) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/-
cells compared to wildtype (WT), but not completely lost. Tlr7-/- pDC responded similarly
to WT. However, we found that in Unc93b-/- pDC, as well as in Tlr7/Tlr9-/- double knockout
pDC, the IFNα response to MHV68 was completely abolished. Thus, the only pattern
recognition receptors contributing to the IFNα response to MHV68 in pDC are TLR7 and
TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role
of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic
replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and
liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and
spleen of Tlr7/Tlr9-/- mice. The absence of TLR2 or TLR13 did not affect lytic viral titers.
We then compared reactivation of MHV68 from latently infected WT, Unc93b-/-, Tlr7/Tlr9-/-,
Tlr7-/-, and Tlr9-/- splenocytes. We observed enhanced reactivation and latent viral loads,
particularly from Tlr7/Tlr9-/- splenocytes, compared to WT. Our data show that UNC93B-
dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68
infection.
Amercan Society of Microbiology
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The endosomal Toll-like receptors 7 and 9 cooperate in detection of MHV68 infection.
Article
Journal of virology
oai:repository.helmholtz-hzi.de:10033/6216152020-08-12T13:54:07Zcom_10033_311624com_10033_6839com_10033_620626com_10033_620636col_10033_311625col_10033_620629col_10033_620637
Lorenz, Anne
Preuße, Matthias
Bruchmann, Sebastian
Pawar, Vinay
Grahl, Nora
Pils, Marina C
Nolan, Laura M
Filloux, Alain
Weiss, Siegfried
Häussler, Susanne
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-12-13T09:50:30Z
2018-12-13T09:50:30Z
2018-11-08
1462-2920
30411474
10.1111/1462-2920.14468
http://hdl.handle.net/10033/621615
Pseudomonas aeruginosa is an environmental microorganism and a causative agent of diverse acute and chronic, biofilm-associated infections. Advancing research-based knowledge on its adaptation to conditions within the human host is bound to reveal novel strategies and targets for therapeutic intervention. Here, we investigated the traits that P. aeruginosa PA14 as well as a virulence attenuated ΔlasR mutant need to survive in selected murine infection models. Experimentally, the genetic programs that the bacteria use to adapt to biofilm-associated versus acute infections were dissected by passaging transposon mutant libraries through mouse lungs (acute) or mouse tumours (biofilm-infection). Adaptive metabolic changes of P. aeruginosa were generally required during both infection processes. Counter-selection against flagella expression was observed during acute lung infections. Obviously, avoidance of flagella-mediated activation of host immunity is advantageous for the wildtype bacteria. For the ΔlasR mutant, loss of flagella did not confer a selective advantage. Apparently, other pathogenesis mechanisms are active in this virulence attenuated strain. In contrast, the infective process of P. aeruginosa in the chronic biofilm model apparently required expression of flagellin. Together, our findings imply that the host immune reactions against the infectious agent are very decisive for acuteness and duration of the infectious disease. They direct disease outcome.
Wiley-Blackwell
info:eu-repo/grantAgreement/ERC/H2020/ 724290
embargoedAccess
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Importance of flagella in acute and chronic Pseudomonas aeruginosa infections.
Article
Environmental microbiology
oai:repository.helmholtz-hzi.de:10033/6216182018-12-18T01:28:41Zcom_10033_620626col_10033_620627
Lambertz, Ruth L O
Pippel, Jan
Gerhauser, Ingo
Kollmus, Heike
Anhlan, Darisuren
Hrincius, Eike R
Krausze, Joern
Kühn, Nora
Schughart, Klaus
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-12-17T14:03:23Z
2018-12-17T14:03:23Z
2018-09-01
1465-2099
30084768
10.1099/jgv.0.001128
http://hdl.handle.net/10033/621618
The haemagglutinin (HA) of H1N1 and H3N2 influenza A virus (IAV) subtypes has to be activated by host proteases. Previous studies showed that H1N1 virus cannot replicate efficiently in Tmprss2−/− knock-out mice whereas H3N2 viruses are able to replicate to the same levels in Tmprss2−/− as in wild type (WT) mice. Here, we investigated the sequence requirements for the HA molecule that allow IAV to replicate efficiently in the absence of TMPRSS2. We showed that replacement of the H3 for the H1-loop sequence (amino acids 320 to 329, at the C-terminus of HA1) was not sufficient for equal levels of virus replication or severe pathology in Tmprss2−/− knock-out mice compared to WT mice. However, exchange of a distant amino acid from H1 to H3 sequence (E31D) in addition to the HA-loop substitution resulted in virus replication in Tmprss2−/− knock-out mice that was comparable to WT mice. The higher virus replication and lung damage was associated with increased epithelial damage and higher mortality. Our results provide further evidence and insights into host proteases as a promising target for therapeutic intervention of IAV infections.
Microbiology Society
Attribution-NonCommercial-ShareAlike 4.0 International
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hemagglutinin
host protease
influenza A virus
Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice.
Article
The Journal of general virology2018-12-17T14:03:24Zoai:repository.helmholtz-hzi.de:10033/6219682019-10-10T03:39:43Zcom_10033_620626com_10033_620636col_10033_620627col_10033_620638
Waindok, Patrick
Janecek-Erfurth, Elisabeth
Lindenwald, Dimitri
Wilk, Esther
Schughart, Klaus
Geffers, Robert
Balas, Laurence
Durand, Thierry
Rund, Katharina Maria
Schebb, Nils Helge
Strube, Christina
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-10-09T10:11:31Z
2019-10-09T10:11:31Z
2019-09-01
1935-2735
31557153
10.1371/journal.pntd.0007706
http://hdl.handle.net/10033/621968
PLoS neglected tropical diseases
BACKGROUND:
Somatic migration of Toxocara canis- and T. cati-larvae in humans may cause neurotoxocarosis (NT) when larvae accumulate and persist in the central nervous system (CNS). Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis; however, detailed data on involvement of bioactive lipid mediators, e.g. oxylipins or eico-/docosanoids, which are involved in the complex molecular signalling network during infection and inflammation, are lacking.
METHODOLOGY/PRINCIPAL FINDINGS:
To elucidate if T. canis- and T. cati-induced NT affects the homeostasis of oxylipins during the course of infection, a comprehensive lipidomic profiling in brains (cerebra and cerebella) of experimentally infected C57BL/6J mice was conducted at six different time points post infection (pi) by liquid-chromatography coupled to electrospray tandem mass spectrometry (LC-ESI-MS/MS). Only minor changes were detected regarding pro-inflammatory prostaglandins (cyclooxygenase pathway). In contrast, a significant increase of metabolites resulting from lipoxygenase pathways was observed for both infection groups and brain regions, implicating a predominantly anti-inflammatory driven immune response. This observation was supported by a significantly increased 13-hydroxyoctadecadienoic acid (HODE)/9-HODE ratio during the subacute phase of infection, indicating an anti-inflammatory response to neuroinfection. Except for the specialised pro-resolving mediator (SPM) neuroprotectin D1 (NPD1), which was detected in mice infected with both pathogens during the subacute phase of infection, no other SPMs were detected.
CONCLUSIONS/SIGNIFICANCE:
The obtained results demonstrate the influence of Toxocara spp. on oxylipins as part of the immune response of the paratenic hosts. Furthermore, this study shows differences in the alteration of the oxylipin composition between T. canis- and T. cati-brain infection. Results contribute to a further understanding of the largely unknown pathogenesis and mechanisms of host-parasite interactions during NT.
en
PLOS
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Multiplex profiling of inflammation-related bioactive lipid mediators in Toxocara canis- and Toxocara cati-induced neurotoxocarosis.
Article
PLoS neglected tropical diseases2019-10-09T10:11:31Zoai:repository.helmholtz-hzi.de:10033/6220762020-01-14T02:20:58Zcom_10033_620626com_10033_620636col_10033_620627col_10033_620638
Matos, Aline da Rocha
Wunderlich, Katharina
Schloer, Sebastian
Schughart, Klaus
Geffers, Robert
Seders, Martine
Witt, Marlous de
Christersson, Anmari
Wiewrodt, Rainer
Wiebe, Karsten
Barth, Peter
Hocke, Andreas
Hippenstiel, Stefan
Hönzke, Katja
Dittmer, Ulf
Sutter, Kathrin
Rescher, Ursula
Rodionycheva, Svetlana
Matera, Nicoletta
Ludwig, Stephan
Brunotte, Linda
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-01-13T13:31:25Z
2020-01-13T13:31:25Z
2019-01-01
Emerg Microbes Infect. 2019;8(1):1763-1776. doi: 10.1080/22221751.2019.1698271.
2222-1751
31826721
10.1080/22221751.2019.1698271
http://hdl.handle.net/10033/622076
Emerging Microbes and Infections
Influenza is an acute respiratory infection causing high morbidity and mortality in annual outbreaks worldwide. Antiviral drugs are limited and pose the risk of resistance development, calling for new treatment options. IFN-α subtypes are immune-stimulatory cytokines with strong antiviral activities against IAV in vitro and in vivo. However, the clinical use of IFN-α2, the only licensed subtype of this multi-gene family, could not prevent or limit IAV infections in humans. However, the other subtypes were not investigated.Therefore, this study evaluated the induction and antiviral potential of all human IFN-α subtypes during H3N2 IAV infection in human lung explants. We found that subtypes with weak antiviral activities were preferentially induced during IAV infection in human lungs. Intriguingly, non-induced subtypes α16, α5 and α4 suppressed viral replication up to 230-fold more efficiently than α2. Furthermore, our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV. These results corroborate that IFN-α subtypes exhibit differential antiviral activities and emphasize that subtypes α16, α5 and α4 should be further investigated for the prevention and treatment of severe infections with seasonal H3N2 IAV.
en
Taylor & Francis Open
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Human lung explant
IFN-α subtype
ISG induction
MxA
antiviral
influenza
Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities.
Article
Emerging microbes & infections2020-01-13T13:31:26Zoai:repository.helmholtz-hzi.de:10033/6221822020-03-06T04:09:45Zcom_10033_620626col_10033_620627
Kollmus, Heike
Fuchs, Helmut
Lengger, Christoph
Haselimashhadi, Hamed
Bogue, Molly A
Östereicher, Manuela A
Horsch, Marion
Adler, Thure
Aguilar-Pimentel, Juan Antonio
Amarie, Oana Veronica
Becker, Lore
Beckers, Johannes
Calzada-Wack, Julia
Garrett, Lillian
Hans, Wolfgang
Hölter, Sabine M
Klein-Rodewald, Tanja
Maier, Holger
Mayer-Kuckuk, Philipp
Miller, Gregor
Moreth, Kristin
Neff, Frauke
Rathkolb, Birgit
Rácz, Ildikó
Rozman, Jan
Spielmann, Nadine
Treise, Irina
Busch, Dirk
Graw, Jochen
Klopstock, Thomas
Wolf, Eckhard
Wurst, Wolfgang
Yildirim, Ali Önder
Mason, Jeremy
Torres, Arturo
Balling, Rudi
Mehaan, Terry
Gailus-Durner, Valerie
Schughart, Klaus
Hrabě de Angelis, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-02-27T15:03:03Z
2020-02-27T15:03:03Z
2020-02-14
Mammalian genome : official journal of the International Mammalian Genome Society JID - 9100916.
1432-1777
32060626
10.1007/s00335-020-09827-3
http://hdl.handle.net/10033/622182
Mammalian Genome
Myxococcus xanthus DK1622 is known as a proficient producer of different kinds of secondary metabolites (SM) with various biological activities, including myxovirescin A, myxalamide A, myxochromide A and DKxanthene. Low production of SM in the wild type bacteria makes searching for production optimization methods highly desirable. Identification and induction of endogenous key molecular feature(s) regulating the production level of the metabolites remain promising, while heterologous expression of the biosynthetic genes is not always efficient because of various complicating factors including codon usage bias. This study established proteomic and molecular approaches to elucidate the regulatory roles of the ROK regulatory protein in the modification of secondary metabolite biosynthesis. Interestingly, the results revealed that rok inactivation significantly reduced the production of the SM and also changed the motility in the bacteria. Electrophoretic mobility shift assay using purified ROK protein indicated a direct enhancement of the promoters encoding transcription of the DKxanthene, myxochelin A, and myxalamide A biosynthesis machinery. Comparative proteomic analysis by two-dimensional fluorescence difference in-gel electrophoresis (2D-DIGE) was employed to identify the protein profiles of the wild type and rok mutant strains during early and late logarithmic growth phases of the bacterial culture. Resulting data demonstrated overall 130 differently altered proteins by the effect of the rok gene mutation, including putative proteins suspected to be involved in transcriptional regulation, carbohydrate metabolism, development, spore formation, and motility. Except for a slight induction seen in the production of myxovirescin A in a rok over-expression background, no changes were found in the formation of the other SM. From the outcome of our investigation, it is possible to conclude that ROK acts as a pleiotropic regulator of secondary metabolite formation and development in M. xanthus, while its direct effects still remain speculative. More experiments are required to elucidate in detail the variable regulation effects of the protein and to explore applicable approaches for generating valuable SM in this bacterium.
en
Springer
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A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes.
Article
Mammalian genome : official journal of the International Mammalian Genome Society2020-02-27T15:03:04Zoai:repository.helmholtz-hzi.de:10033/6221962020-03-11T02:08:52Zcom_10033_620626col_10033_620627
Zerbib, Yoann
Jenkins, Emily K
Shojaei, Maryam
Meyers, Adrienne F A
Ho, John
Ball, T Blake
Keynan, Yoav
Pisipati, Amarnath
Kumar, Aseem
Kumar, Anand
Nalos, Marek
Tang, Benjamin M
Schughart, Klaus
McLean, Anthony
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-03-10T13:48:08Z
2020-03-10T13:48:08Z
2020-02-17
BMC Med Genomics. 2020 Feb 17;13(1):28. doi: 10.1186/s12920-020-0672-7.
1755-8794
32066441
10.1186/s12920-020-0672-7
http://hdl.handle.net/10033/622196
BMC Medical Genomics
BACKGROUND: Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood.
METHODS: To gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza.
RESULTS: 107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls.
CONCLUSIONS: These findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.
en
BioMedCentral
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Influenza
Neutrophil extracellular trap
Neutrophils
Transcriptome
Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection.
Article
BMC medical genomics2020-03-10T13:48:09Zoai:repository.helmholtz-hzi.de:10033/6222732020-05-26T01:29:33Zcom_10033_620533com_10033_620857com_10033_620626com_10033_620589col_10033_620534col_10033_620858col_10033_620629col_10033_620590
Blockus, Sebastian
Sake, Svenja M
Wetzke, Martin
Grethe, Christina
Graalmann, Theresa
Pils, Marina
Le Goffic, Ronan
Galloux, Marie
Prochnow, Hans
Rox, Katharina
Hüttel, Stephan
Rupcic, Zeljka
Wiegmann, Bettina
Dijkman, Ronald
Rameix-Welti, Marie-Anne
Eléouët, Jean-François
Duprex, W Paul
Thiel, Volker
Hansen, Gesine
Brönstrup, Mark
Haid, Sibylle
Pietschmann, Thomas
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
2020-05-25T14:26:43Z
2020-05-25T14:26:43Z
2020-03-18
Antiviral Res. 2020;177:104774. doi:10.1016/j.antiviral.2020.104774.
32197980
10.1016/j.antiviral.2020.104774
http://hdl.handle.net/10033/622273
1872-9096
Antiviral research
Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC50s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.
en
Elsevier
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Antiviral activity
Human respiratory syncytial virus (hRSV)
Labyrinthopeptin
Lanthipeptide
Virolytic
Virus entry
Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry.
Article
177
104774
Antiviral research
Netherlands
oai:repository.helmholtz-hzi.de:10033/6223122020-06-26T02:39:38Zcom_10033_620722com_10033_620626com_10033_620636col_10033_620723col_10033_620627col_10033_620638
Hosseini, Shirin
Wilk, Esther
Michaelsen-Preusse, Kristin
Gerhauser, Ingo
Baumgärtner, Wolfgang
Geffers, Robert
Schughart, Klaus
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-06-25T09:55:48Z
2020-06-25T09:55:48Z
2018-02-27
. J Neurosci. 2018;38(12):3060-3080. doi:10.1523/JNEUROSCI.1740-17.2018.
29487124
10.1523/JNEUROSCI.1740-17.2018
http://hdl.handle.net/10033/622312
1529-2401
The Journal of neuroscience : the official journal of the Society for Neuroscience
Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.
en
Society for Neuroscience
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
dendritic spines
hippocampus
influenza
microglia
neuroinflammation
structural plasticity
Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function.
Article
Other
38
12
3060
3080
The Journal of neuroscience : the official journal of the Society for Neuroscience
United States2020-06-25T09:55:48Zoai:repository.helmholtz-hzi.de:10033/6224242020-09-03T10:58:51Zcom_10033_620626col_10033_620629
Pils, Marina C
Kränzler, Katrin
Beyer, Petra
Heise, Ulrike
Pasche, Bastian
Riedesel, Hermann
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-09-02T13:46:07Z
2020-09-02T13:46:07Z
2018-11-06
J Am Assoc Lab Anim Sci. 2019;58(1):87-91. doi:10.30802/AALAS-JAALAS-18-000020.
1559-6109
30401066
10.30802/AALAS-JAALAS-18-000020
http://hdl.handle.net/10033/622424
Journal of the American Association for Laboratory Animal Science : JAALAS
The sterilization of potentially infectious animal carcasses is an important biologic safety issue in animal facilities operating as infection or quarantine barriers. However, the literature lacks a validated protocol. Here we describe the validation of an autoclave program suitable for daily use in a small rodent biocontainment unit. We evaluated several procedures for processing mouse carcasses in a standard autoclave. Heat sensors and biologic indicators were implanted inside the peritoneal cavity of dead mice, which were loaded at various densities into IVC cages or metal boxes. Heat sensors revealed broad differences in temperature inside carcasses compared with the autoclave chamber. Achieving the appropriate sterilization temperature was considerably prolonged in carcasses compared with typical laboratory waste material. We show that for 5 cadavers placed well separated inside an IVC, a modified program for mouse cage sterilization using 134 °C for 15 min is suitable. To sterilize approximately 1 kg of carcasses in autoclavable boxes, a period of 6 h is required to reach an effective temperature of 121 °C for 60 min at the center of the waste by using an autoclave program for liquids. In conclusion, we here validated 2 protocols for the sterilization of potentially infectious mouse carcasses, to ensure the application of efficacious procedures.
en
American Association for Laboratory Animal Science
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Validation of an Autoclave Procedure for Sterilization of Mouse (Mus musculus) Carcasses.
Article
58
1
87
91
Journal of the American Association for Laboratory Animal Science : JAALAS
United States2020-09-02T13:46:07Zoai:repository.helmholtz-hzi.de:10033/6225052020-10-10T01:32:07Zcom_10033_620626col_10033_620627
Hendrickx, Diana M
Garcia, Pierre
Ashrafi, Amer
Sciortino, Alessia
Schmit, Kristopher J
Kollmus, Heike
Nicot, Nathalie
Kaoma, Tony
Vallar, Laurent
Buttini, Manuel
Glaab, Enrico
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-10-09T11:24:20Z
2020-10-09T11:24:20Z
2020-09-30
Mol Neurobiol. 2020 Sep 30. doi: 10.1007/s12035-020-02085-z. Epub ahead of print.
32997293
10.1007/s12035-020-02085-z
http://hdl.handle.net/10033/622505
1559-1182
Molecular neurobiology
Understanding Parkinson's disease (PD), in particular in its earliest phases, is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end-stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful in investigating PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatal neurodegeneration across different ages using pathway, gene set, and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected, or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity and neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD.
en
Springer
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Disease-stage
Network analysis
Parkinson’s disease
Pathway analysis
Transgenic mouse model
α-Synuclein
A New Synuclein-Transgenic Mouse Model for Early Parkinson's Reveals Molecular Features of Preclinical Disease.
Article
Molecular neurobiology
United States2020-10-09T11:24:21Zoai:repository.helmholtz-hzi.de:10033/6225412020-11-04T04:37:39Zcom_10033_620626com_10033_621723col_10033_621724col_10033_620629
Iljazovic, Aida
Roy, Urmi
Gálvez, Eric J C
Lesker, Till R
Zhao, Bei
Gronow, Achim
Amend, Lena
Will, Sabine E
Hofmann, Julia D
Pils, Marina C
Schmidt-Hohagen, Kerstin
Neumann-Schaal, Meina
Strowig, Till
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-10-27T14:12:41Z
2020-10-27T14:12:41Z
2020-05-20
Mucosal Immunol. 2020 May 20. doi: 10.1038/s41385-020-0296-4. Epub ahead of print.
32433514
10.1038/s41385-020-0296-4
http://hdl.handle.net/10033/622541
1935-3456
Mucosal immunology
Diverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.
en
Springer Nature
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation.
Article
Mucosal immunology
United States2020-10-27T14:12:42Zoai:repository.helmholtz-hzi.de:10033/6225562020-11-06T01:56:39Zcom_10033_620626col_10033_620627
Gui, Yujuan
Thomas, Mélanie H.
Garcia, Pierre
Karout, Mona
Halder, Rashi
Michelucci, Alessandro
Kollmus, Heike
Zhou, Cuiqi
Melmed, Shlomo
Schughart, Klaus
Balling, Rudi
Mittelbronn, Michel
Nadeau, Joseph H.
Williams, Robert W.
Sauter, Thomas
Buttini, Manuel
Sinkkonen, Lasse
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-11-05T14:11:15Z
2020-11-05T14:11:15Z
2020-09-23
Frontiers in Microbiology,(2020); 11 doi:10.3389/fmicb.2020.562140 .
10.3389/fgene.2020.566734
http://hdl.handle.net/10033/622556
1664-8021
Frontiers in Genetics
10.3389/fgene.2020.566734
Dopaminergic neurons in the midbrain are of particular interest due to their role in
diseases such as Parkinson’s disease and schizophrenia. Genetic variation between
individuals can affect the integrity and function of dopaminergic neurons but the
DNA variants and molecular cascades modulating dopaminergic neurons and other
cells types of ventral midbrain remain poorly defined. Three genetically diverse inbred
mouse strains – C57BL/6J, A/J, and DBA/2J – differ significantly in their genomes
(∼7 million variants), motor and cognitive behavior, and susceptibility to neurotoxins.
To further dissect the underlying molecular networks responsible for these variable
phenotypes, we generated RNA-seq and ChIP-seq data from ventral midbrains
of the 3 mouse strains. We defined 1000–1200 transcripts that are differentially
expressed among them. These widespread differences may be due to altered activity
or expression of upstream transcription factors. Interestingly, transcription factors were
significantly underrepresented among the differentially expressed genes, and only one
transcription factor, Pttg1, showed significant differences between all three strains.
The changes in Pttg1 expression were accompanied by consistent alterations in
histone H3 lysine 4 trimethylation at Pttg1 transcription start site. The ventral midbrain
transcriptome of 3-month-old C57BL/6J congenic Pttg1−=− mutants was only modestly
altered, but shifted toward that of A/J and DBA/2J in 9-month-old mice. Principle
component analysis (PCA) identified the genes underlying the transcriptome shift and
deconvolution of these bulk RNA-seq changes using midbrain single cell RNA-seq data
suggested that the changes were occurring in several different cell types, including
neurons, oligodendrocytes, and astrocytes. Taken together, our results show that Pttg1
contributes to gene regulatory variation between mouse strains and influences mouse
midbrain transcriptome during aging
Fonds National de la Recherche Luxembourg
en
Frontiers Media SA
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Genetics(clinical)
Molecular Medicine
Genetics
Pituitary Tumor Transforming Gene 1 Orchestrates Gene Regulatory Variation in Mouse Ventral Midbrain During Aging
Article
11
Frontiers in Genetics2020-11-05T14:11:15Zoai:repository.helmholtz-hzi.de:10033/6227022021-01-27T01:35:37Zcom_10033_620626com_10033_621723col_10033_621724col_10033_620629
Koeninger, Louis
Osbelt, Lisa
Berscheid, Anne
Wendler, Judith
Berger, Jügen
Hipp, Katharina
Marina C Pils, Marina C.
Nisar P Malek, Nisar P.
Heike Brötz-Oesterhelt, Heike
Strowig, Till
Wehkamp, Jan
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-01-26T16:13:44Z
2021-01-26T16:13:44Z
2021-01-08
Commun Biol. 2021 Jan 8;4(1):47. doi: 10.1038/s42003-020-01582-0.
33420317
10.1038/s42003-020-01582-0
http://hdl.handle.net/10033/622702
2399-3642
Communications biology
The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. In conclusion, our data support the development of defensin-derived antimicrobial agents as a novel approach to fight multidrug-resistant bacteria, where Pam-3 appears as a particularly promising microbiota-preserving candidate.
en
Nature research
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Curbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota.
Article
4
1
47
Communications biology
England2021-01-26T16:13:45Zdim///com_10033_620626/100