2024-03-28T21:12:34Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/2269172019-08-30T11:31:49Zcom_10033_620601col_10033_620602
Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
Diamond, Mark S
Kinder, Michelle
Matsushita, Hirokazu
Mashayekhi, Mona
Dunn, Gavin P
Archambault, Jessica M
Lee, Hsiaoju
Arthur, Cora D
White, J Michael
Kalinke, Ulrich
Murphy, Kenneth M
Schreiber, Robert D
Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN's actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α(+) DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.
2012-05-31T13:54:38Z
2012-05-31T13:54:38Z
2012-05-31T13:54:38Z
2011-09-26
Article
Type I interferon is selectively required by dendritic cells for immune rejection of tumors. 2011, 208 (10):1989-2003 J. Exp. Med.
1540-9538
21930769
10.1084/jem.20101158
http://hdl.handle.net/10033/226917
The Journal of experimental medicine
en
Archived with thanks to The Journal of experimental medicine
oai:repository.helmholtz-hzi.de:10033/2469712019-08-30T11:27:16Zcom_10033_620601col_10033_620602
Transcriptome analysis of early surface-associated growth of Shewanella oneidensis MR-1.
Gödeke, Julia
Binnenkade, Lucas
Thormann, Kai M
Department of Ecophysiology, Max-Planck-Institut für terrestrische Mikrobiologie, Marburg, Germany.
Bacterial biofilm formation starts with single cells attaching to a surface, however, little is known about the initial attachment steps and the adaptation to the surface-associated life style. Here, we describe a hydrodynamic system that allows easy harvest of cells at very early biofilm stages. Using the metal ion-reducing gammaproteobacterium Shewanella oneidensis MR-1 as a model organism, we analyzed the transcriptional changes occurring during surface-associated growth between 15 and 60 minutes after attachment. 230 genes were significantly upregulated and 333 were downregulated by a factor of ≥ 2. Main functional categories of the corresponding gene products comprise metabolism, uptake and transport, regulation, and hypothetical proteins. Among the genes highly upregulated those implicated in iron uptake are highly overrepresented, strongly indicating that S. oneidensis MR-1 has a high demand for iron during surface attachment and initial biofilm stages. Subsequent microscopic analysis of biofilm formation under hydrodynamic conditions revealed that addition of Fe(II) significantly stimulated biofilm formation of S. oneidensis MR-1 while planktonic growth was not affected. Our approach to harvest cells for transcriptional analysis of early biofilm stages is expected to be easily adapted to other bacterial species.
2012-10-04T09:35:18Z
2012-10-04T09:35:18Z
2012-10-04T09:35:18Z
2012
Article
Transcriptome analysis of early surface-associated growth of Shewanella oneidensis MR-1. 2012, 7 (7):e42160 PLoS ONE
1932-6203
22860070
10.1371/journal.pone.0042160
http://hdl.handle.net/10033/246971
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/2488202019-08-30T11:27:46Zcom_10033_620601col_10033_620602
Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS.
Kalinke, Ulrich
Prinz, Marco
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz-Centre for Infection Research, Braunschweig, and the Hannover Medical School, MHH, Hannover, Germany. ulrich.kalinke@twincore.de
Different viruses trigger pattern recognition receptor systems, such as Toll-like receptors or cytosolic RIG-I like helicases (RLH), and thus induce early type I interferon (IFN-I) responses. Such responses may confer protection until adaptive immunity is activated to an extent that the pathogen can be eradicated. Interestingly, the same innate immune mechanisms that are relevant for early pathogen defense have a role in ameliorating experimental autoimmune encephalomyelitis (EAE), a rodent model of human multiple sclerosis. We and others found that mice devoid of a component of the IFN-I receptor (Ifnar1(-/-)) showed significantly enhanced autoimmune disease of the central nervous system (CNS). A detailed analysis revealed that in wild-type mice IFN-I triggering of myeloid cells was instrumental in reducing brain damage. A more recent study indicated that similar to Ifnar1(-/-) mice, RLH-signaling-deficient mice showed enhanced autoimmune disease of the CNS as well. Moreover, when peripherally treated with synthetic RLH ligands wild-type animals with EAE disease showed reduced clinical scores. Under such conditions, IFN-I receptor triggering of dendritic cells had a crucial role. The therapeutic effect of treatment with RLH ligands was associated with negative regulation of Th1 and Th17 T-cell responses within the CNS. These experiments are consistent with the hypothesis that spatiotemporal conditions of, and cell types involved in, disease-ameliorating IFN-I responses differ significantly, depending on whether they were endogenously induced in the context of EAE pathogenesis within the CNS or upon therapeutic RLH triggering in the periphery. It is attractive to speculate that RLH triggering represents a new strategy to treat multiple sclerosis by stimulating endogenous immunoregulatory IFN-I responses.
2012-10-15T14:09:06Z
2012-10-15T14:09:06Z
2012-10-15T14:09:06Z
2012-05
Article
Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS. 2012, 90 (5):505-9 Immunol. Cell Biol.
1440-1711
22430251
10.1038/icb.2012.8
http://hdl.handle.net/10033/248820
Immunology and cell biology
en
Archived with thanks to Immunology and cell biology
oai:repository.helmholtz-hzi.de:10033/2626732019-08-30T11:28:51Zcom_10033_620601col_10033_620602
Differential responses of immune cells to type I interferon contribute to host resistance to viral infection.
Baranek, Thomas
Manh, Thien-Phong Vu
Alexandre, Yannick
Maqbool, Muhammad Ahmad
Cabeza, Joaquin Zacarias
Tomasello, Elena
Crozat, Karine
Bessou, Gilles
Zucchini, Nicolas
Robbins, Scott H
Vivier, Eric
Kalinke, Ulrich
Ferrier, Pierre
Dalod, Marc
Centre d'Immunologie de Marseille-Luminy, UNIV UM2, Aix-Marseille Université, Parc scientifique et technologique de Luminy, 13288 Marseille, France; Institut National de la Santé et de la Recherche Medicale (Inserm), UMR1104, 13288 Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, 13288 Marseille, France.
Type I interferons (IFNs) are central to antiviral defense, but how they orchestrate immune cell function is incompletely understood. We determined that IFNs produced during murine cytomegalovirus (MCMV) infection differentially affect dendritic cells (DCs) and natural killer (NK) cells. IFNs induce cell-intrinsic responses in DCs, activating antiproliferative, antiviral, and lymphocyte-activating gene networks, consistent with high activity of the transcription factor STAT1 in these cells. By comparison, NK cells exhibit lower STAT1 expression and reduced IFN responsiveness. Rather, IFNs indirectly affect NK cells by inducing IL-15, which activates the transcription factor E2F and stimulates genes promoting cell expansion. IFN cell-intrinsic responses are necessary in DCs, but not NK cells, for MCMV resistance. Thus, sensitivity to IFN-induced cytokines and differences in IFN receptor signaling program immune cells to mount distinct responses that promote viral control.
2012-12-14T11:55:13Z
2012-12-14T11:55:13Z
2012-12-14T11:55:13Z
2012-10-18
Article
Differential responses of immune cells to type I interferon contribute to host resistance to viral infection. 2012, 12 (4):571-84 Cell Host Microbe
1934-6069
23084923
10.1016/j.chom.2012.09.002
http://hdl.handle.net/10033/262673
Cell host & microbe
en
Archived with thanks to Cell host & microbe
oai:repository.helmholtz-hzi.de:10033/2693522019-08-30T11:28:51Zcom_10033_620601col_10033_620602
Biosimilars: what clinicians should know.
Weise, Martina
Bielsky, Marie-Christine
De Smet, Karen
Ehmann, Falk
Ekman, Niklas
Giezen, Thijs J
Gravanis, Iordanis
Heim, Hans-Karl
Heinonen, Esa
Ho, Kowid
Moreau, Alexandre
Narayanan, Gopalan
Kruse, Nanna A
Reichmann, Gabriele
Thorpe, Robin
van Aerts, Leon
Vleminckx, Camille
Wadhwa, Meenu
Schneider, Christian K
Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany. martina.weise@bfarm.de
Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators.
2013-02-13T13:13:43Z
2013-02-13T13:13:43Z
2013-02-13T13:13:43Z
2012-12-20
Article
Biosimilars: what clinicians should know. 2012, 120 (26):5111-7 Blood
1528-0020
23093622
10.1182/blood-2012-04-425744
http://hdl.handle.net/10033/269352
Blood
en
Archived with thanks to Blood
oai:repository.helmholtz-hzi.de:10033/2720422019-08-30T11:28:47Zcom_10033_620601col_10033_620602
In support of the European Union biosimilar framework.
Schneider, Christian K
Borg, John J
Ehmann, Falk
Ekman, Niklas
Heinonen, Esa
Ho, Kowid
Hoefnagel, Marcel H
van der Plas, Roeland Martijn
Ruiz, Sol
van der Stappen, Antonius J
Thorpe, Robin
Tiitso, Klara
Tsiftsoglou, Asterios S
Vleminckx, Camille
Waxenecker, Guenter
Welin, Mats
Weise, Martina
Trouvin, Jean-Hugues
2013-03-13T14:07:32Z
2013-03-13T14:07:32Z
2013-03-13T14:07:32Z
2012-08
Article
In support of the European Union biosimilar framework. 2012, 30 (8):745-8; author reply 748-9 Nat. Biotechnol.
1546-1696
22871707
10.1038/nbt.2322
http://hdl.handle.net/10033/272042
Nature biotechnology
en
Archived with thanks to Nature biotechnology
oai:repository.helmholtz-hzi.de:10033/2720432019-08-30T11:28:19Zcom_10033_620601col_10033_620602
Setting the stage for biosimilar monoclonal antibodies.
Schneider, Christian K
Vleminckx, Camille
Gravanis, Iordanis
Ehmann, Falk
Trouvin, Jean-Hugues
Weise, Martina
Thirstrup, Steffen
Danish Health and Medicines Authority, Copenhagen, Denmark. c_schneid@web.de
2013-03-13T14:45:49Z
2013-03-13T14:45:49Z
2013-03-13T14:45:49Z
2012-12
Article
Setting the stage for biosimilar monoclonal antibodies. 2012, 30 (12):1179-85 Nat. Biotechnol.
1546-1696
23222783
10.1038/nbt.2447
http://hdl.handle.net/10033/272043
Nature biotechnology
en
Archived with thanks to Nature biotechnology
oai:repository.helmholtz-hzi.de:10033/2758382019-08-30T11:28:50Zcom_10033_620601col_10033_620602
Biosimilars in rheumatology: the wind of change.
Schneider, Christian K
2013-03-25T13:57:27Z
2013-03-25T13:57:27Z
2013-03-25T13:57:27Z
2013-03
Article
Biosimilars in rheumatology: the wind of change. 2013, 72 (3):315-8 Ann. Rheum. Dis.
1468-2060
23390018
10.1136/annrheumdis-2012-202941
http://hdl.handle.net/10033/275838
Annals of the rheumatic diseases
en
Archived with thanks to Annals of the rheumatic diseases
oai:repository.helmholtz-hzi.de:10033/2970382019-08-30T11:25:43Zcom_10033_620601col_10033_620602
Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.
Prete, Francesca
Catucci, Marco
Labrada, Mayrel
Gobessi, Stefania
Castiello, Maria Carmina
Bonomi, Elisa
Aiuti, Alessandro
Vermi, William
Cancrini, Caterina
Metin, Ayse
Hambleton, Sophie
Bredius, Robbert
Notarangelo, Luigi Daniele
van der Burg, Mirjam
Kalinke, Ulrich
Villa, Anna
Benvenuti, Federica
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pDCs numbers, and hyperresponsiveness to TLR9. Importantly, ablating IFN-I signaling in WASp null mice rescued chronic activation of conventional DCs, splenomegaly, and colitis. Using WASp-deficient mice, we demonstrated that WASp null pDCs are intrinsically more responsive to multimeric agonist of TLR9 and constitutively secrete type-I IFN but become progressively tolerant to further stimulation. By acute silencing of WASp and actin inhibitors, we show that WASp-mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in pDCs restraining exaggerated activation of the TLR9-IFN-α pathway. Together, these data highlight the role of actin dynamics in pDC innate functions and imply the pDC-IFN-α axis as a player in the onset of autoimmune phenomena in WAS disease.
2013-07-25T10:40:02Z
2013-07-25T10:40:02Z
2013-07-25T10:40:02Z
2013-02-11
Article
Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. 2013, 210 (2):355-74 J. Exp. Med.
1540-9538
23337808
10.1084/jem.20120363
http://hdl.handle.net/10033/297038
The Journal of experimental medicine
en
Archived with thanks to The Journal of experimental medicine
oai:repository.helmholtz-hzi.de:10033/3058792019-08-30T11:36:59Zcom_10033_620601col_10033_620602
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.
Goulet, Marie-Line
Olagnier, David
Xu, Zhengyun
Paz, Suzanne
Belgnaoui, S Mehdi
Lafferty, Erin I
Janelle, Valérie
Arguello, Meztli
Paquet, Marilene
Ghneim, Khader
Richards, Stephanie
Smith, Andrew
Wilkinson, Peter
Cameron, Mark
Kalinke, Ulrich
Qureshi, Salman
Lamarre, Alain
Haddad, Elias K
Sekaly, Rafick Pierre
Peri, Suraj
Balachandran, Siddharth
Lin, Rongtuan
Hiscott, John
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Canada.
The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
2013-11-28T11:52:06Z
2013-11-28T11:52:06Z
2013-11-28T11:52:06Z
2013-04
Article
Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. 2013, 9 (4):e1003298 PLoS Pathog.
1553-7374
23633948
10.1371/journal.ppat.1003298
http://hdl.handle.net/10033/305879
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3059302019-08-30T11:28:49Zcom_10033_620601col_10033_620602
The evolution of nonclinical regulatory science: advanced therapy medicinal products as a paradigm.
Vestergaard, Henrik Tang
D'Apote, Lucia
Schneider, Christian K
Herberts, Carla
Danish Health and Medicines Authority, Copenhagen, Denmark.
2013-11-29T12:57:42Z
2013-11-29T12:57:42Z
2013-11-29T12:57:42Z
2013-09
Article
The evolution of nonclinical regulatory science: advanced therapy medicinal products as a paradigm. 2013, 21 (9):1644-8 Mol. Ther.
1525-0024
24137820
http://hdl.handle.net/10033/305930
Molecular therapy : the journal of the American Society of Gene Therapy
en
Archived with thanks to Molecular therapy : the journal of the American Society of Gene Therapy
oai:repository.helmholtz-hzi.de:10033/3115292019-08-30T11:37:00Zcom_10033_620601col_10033_620602
The committee for advanced therapies' of the European Medicines Agency reflection paper on management of clinical risks deriving from insertional mutagenesis.
Aiuti, Alessandro
Cossu, Giulio
de Felipe, Pablo
Galli, Maria Cristina
Narayanan, Gopalan
Renner, Matthias
Stahlbom, Axel
Schneider, Christian K
Voltz-Girolt, Caroline
In the European Union, the Committee for Advanced Therapies of the European Medicines Agency takes the lead in the scientific assessment for marketing authorization applications for advanced therapy medicinal products, which include gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products. The Committee for Advanced Therapies also takes the lead in defining the scientific framework for the quality, nonclinical and clinical development of such products. This reflection paper represents the Committee's current thinking on management of clinical risks deriving from insertional mutagenesis. A multidisciplinary approach to insertional mutagenesis is provided. This reflection paper has been adopted by the committee in its April 2013 meeting.
2014-01-17T15:08:37Z
2014-01-17T15:08:37Z
2014-01-17T15:08:37Z
2013-06
Article
The committee for advanced therapies' of the European Medicines Agency reflection paper on management of clinical risks deriving from insertional mutagenesis. 2013, 24 (2):47-54 Hum Gene Ther Clin Dev
2324-8645
23862696
10.1089/humc.2013.119
http://hdl.handle.net/10033/311529
Human gene therapy. Clinical development
en
Archived with thanks to Human gene therapy. Clinical development
oai:repository.helmholtz-hzi.de:10033/3158872019-08-30T11:27:16Zcom_10033_620601col_10033_620602
Impaired functionality of antiviral T cells in G-CSF mobilized stem cell donors: implications for the selection of CTL donor.
Bunse, Carola E
Borchers, Sylvia
Varanasi, Pavankumar R
Tischer, Sabine
Figueiredo, Constança
Immenschuh, Stephan
Kalinke, Ulrich
Köhl, Ulrike
Goudeva, Lilia
Maecker-Kolhoff, Britta
Ganser, Arnold
Blasczyk, Rainer
Weissinger, Eva M
Eiz-Vesper, Britta
HZI Außenstelle TWINCORE, Feodor-Lynen-Str. 7, D-30625 Hannover
Adoptive transfer of antiviral T cells enhances immune reconstitution and decreases infectious complications after stem cell transplantation. Information on number and function of antiviral T cells in stem cell grafts is scarce. We investigated (1) immunomodulatory effects of G-CSF on antiviral T cells, (2) the influence of apheresis, and (3) the optimal time point to collect antiviral cells. CMV-, EBV- and ADV-specific T cells were enumerated in 170 G-CSF-mobilized stem cell and 24 non-mobilized platelet donors using 14 HLA-matched multimers. T-cell function was evaluated by IFN-γ ELISpot and granzyme B secretion. Immunophenotyping was performed by multicolor flow cytometry. G-CSF treatment did not significantly influence frequency of antiviral T cells nor their in vitro expansion rate upon antigen restimulation. However, T-cell function was significantly impaired, as expressed by a mean reduction in secretion of IFN-γ (75% in vivo, 40% in vitro) and granzyme B (32% target-independent, 76% target-dependent) as well as CD107a expression (27%). Clinical follow up data indicate that the first CMV-reactivation in patients and with it the need for T-cell transfer occurs while the donor is still under the influence of G-CSF. To overcome these limitations, T-cell banking before mobilization or recruitment of third party donors might be an option to optimize T-cell production.
2014-04-16T09:56:28Z
2014-04-16T09:56:28Z
2014-04-16T09:56:28Z
2013
Article
Impaired functionality of antiviral T cells in G-CSF mobilized stem cell donors: implications for the selection of CTL donor. 2013, 8 (12):e77925 PLoS ONE
1932-6203
24324576
10.1371/journal.pone.0077925
http://hdl.handle.net/10033/315887
PloS one
en
Archived with thanks to PloS one
PLOS
oai:repository.helmholtz-hzi.de:10033/3167422019-08-30T11:27:16Zcom_10033_620601col_10033_620602
Multifunctional silica nanoparticles for optical and magnetic resonance imaging.
Joshi, Rajendra
Feldmann, Verena
Koestner, Wolfgang
Detje, Claudia
Gottschalk, Sven
Mayer, Hermann A
Sauer, Martin G
Engelmann, Jörn
Institute for Experimental Infection Research, TWINCORE , Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Straβe 7, D-30625 Hannover, Germany
The surface of spherical, nonporous silica nanoparticles (SiO2-NPs) was modified with gadolinium (Gd) complexes, fluorophores, and cell-penetrating peptides to achieve multifunctionality on a single particle. The Gd surface concentrations were 9-16 μmol/g resulting in nanomaterials with high local longitudinal and transversal relaxivities (~1×10(5) and ~5×10(5) /mm/s/NP, respectively). Rapid cellular uptake was observed in vitro; however, larger extracellular agglomerates were also formed. In vivo administration revealed a fast distribution throughout the body followed by a nearly complete disappearance of fluorescence in all organs except the lungs, liver, and spleen after 24 h. Such NPs have the potential to serve as efficient multimodal probes in molecular imaging.
2014-05-13T14:56:54Z
2014-05-13T14:56:54Z
2014-05-13T14:56:54Z
2013-01
Article
Multifunctional silica nanoparticles for optical and magnetic resonance imaging. 2013, 394 (1):125-35 Biol. Chem.
1437-4315
23096570
10.1515/hsz-2012-0251
http://hdl.handle.net/10033/316742
Biological chemistry
en
Archived with thanks to Biological chemistry
oai:repository.helmholtz-hzi.de:10033/3218042019-08-30T11:36:33Zcom_10033_620601col_10033_620603
Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells.
Pessler, Frank
Ogdie, Alexis R
Mayer, Christian T
Kretzschmar, Warren W
Dai, Lie
Elsaman, Ahmed M
Einhorn, Eugene
Krenn, Veit
Schumacher, H Ralph
To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM).
2014-06-18T09:56:01Z
2014-06-18T09:56:01Z
2014-06-18T09:56:01Z
2014-03
Article
Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+ or CD38+ cells. 2014, 21 (1):28-34 Amyloid
1744-2818
24286442
10.3109/13506129.2013.862229
http://hdl.handle.net/10033/321804
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
en
Archived with thanks to Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
oai:repository.helmholtz-hzi.de:10033/3260702019-08-30T11:30:32Zcom_10033_620601col_10033_620602
Antigenic and 3D structural characterization of soluble X4 and hybrid X4-R5 HIV-1 Env trimers.
Arnold, Philipp
Himmels, Patricia
Weiß, Svenja
Decker, Tim-Michael
Markl, Jürgen
Gatterdam, Volker
Tampé, Robert
Bartholomäus, Patrick
Dietrich, Ursula
Dürr, Ralf
HIV-1 is decorated with trimeric glycoprotein spikes that enable infection by engaging CD4 and a chemokine coreceptor, either CCR5 or CXCR4. The variable loop 3 (V3) of the HIV-1 envelope protein (Env) is the main determinant for coreceptor usage. The predominant CCR5 using (R5) HIV-1 Env has been intensively studied in function and structure, whereas the trimeric architecture of the less frequent, but more cytopathic CXCR4 using (X4) HIV-1 Env is largely unknown, as are the consequences of sequence changes in and near V3 on antigenicity and trimeric Env structure.
2014-09-12T10:54:52Z
2014-09-12T10:54:52Z
2014-09-12T10:54:52Z
2014
Article
Antigenic and 3D structural characterization of soluble X4 and hybrid X4-R5 HIV-1 Env trimers. 2014, 11:42 Retrovirology
1742-4690
24884925
10.1186/1742-4690-11-42
http://hdl.handle.net/10033/326070
Retrovirology
en
Archived with thanks to Retrovirology
oai:repository.helmholtz-hzi.de:10033/3327232019-08-30T11:28:51Zcom_10033_620601col_10033_620602
Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union.
Narayanan, Gopalan
Cossu, Giulio
Galli, Maria Cristina
Flory, Egbert
Ovelgonne, Hans
Salmikangas, Paula
Schneider, Christian K
Trouvin, Jean-Hugues
Gene therapy is a rapidly evolving field that needs an integrated approach, as acknowledged in the concept article on the revision of the guideline on gene transfer medicinal products. The first gene therapy application for marketing authorization was approved in the International Conference on Harmonisation (ICH) region in 2012, the product being Alipogene tiparvovec. The regulatory process for this product has been commented on extensively, highlighting the challenges posed by such a novel technology. Here, as current or previous members of the Committee for Advanced Therapies, we share our perspectives and views on gene therapy as a treatment modality based on current common understanding and regulatory experience of gene therapy products in the European Union to date. It is our view that a tailored approach is needed for a given gene therapy product in order to achieve successful marketing authorization.
2014-10-13T08:49:00Z
2014-10-13T08:49:00Z
2014-10-13T08:49:00Z
2014-03
Article
Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union. 2014, 25 (1):1-6 Hum Gene Ther Clin Dev
2324-8645
24649836
10.1089/humc.2013.230
http://hdl.handle.net/10033/332723
Human gene therapy. Clinical development
en
Archived with thanks to Human gene therapy. Clinical development
oai:repository.helmholtz-hzi.de:10033/3335962019-08-30T11:28:51Zcom_10033_620601col_10033_620602
Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations.
Shankar, G
Arkin, S
Cocea, L
Devanarayan, V
Kirshner, S
Kromminga, A
Quarmby, V
Richards, S
Schneider, C K
Subramanyam, M
Swanson, S
Verthelyi, D
Yim, S
Janssen Research & Development, LLC (Johnson & Johnson), 1400 McKean Road, P.O. Box 776, Spring House, Pennsylvania, 19477, USA, Gshanka3@its.jnj.com.
Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.
2014-11-03T15:42:28Z
2014-11-03T15:42:28Z
2014-11-03T15:42:28Z
2014-07
Article
Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. 2014, 16 (4):658-73 AAPS J
1550-7416
24764037
10.1208/s12248-014-9599-2
http://hdl.handle.net/10033/333596
The AAPS journal
en
oai:repository.helmholtz-hzi.de:10033/3337292019-08-30T11:34:48Zcom_10033_620601col_10033_620602
Mechanisms for interferon-α-induced depression and neural stem cell dysfunction.
Zheng, Lian-Shun
Hitoshi, Seiji
Kaneko, Naoko
Takao, Keizo
Miyakawa, Tsuyoshi
Tanaka, Yasuhito
Xia, Hongjing
Kalinke, Ulrich
Kudo, Koutaro
Kanba, Shigenobu
Ikenaka, Kazuhiro
Sawamoto, Kazunobu
Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China ; Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.
2014-11-05T14:42:34Z
2014-11-05T14:42:34Z
2014-11-05T14:42:34Z
2014-07-08
Article
Mechanisms for interferon-α-induced depression and neural stem cell dysfunction. 2014, 3 (1):73-84 Stem Cell Reports
2213-6711
25068123
10.1016/j.stemcr.2014.05.015
http://hdl.handle.net/10033/333729
Stem cell reports
en
oai:repository.helmholtz-hzi.de:10033/3337372019-08-30T11:34:48Zcom_10033_620601col_10033_620602
Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity.
Haque, Ashraful
Best, Shannon E
Montes de Oca, Marcela
James, Kylie R
Ammerdorffer, Anne
Edwards, Chelsea L
de Labastida Rivera, Fabian
Amante, Fiona H
Bunn, Patrick T
Sheel, Meru
Sebina, Ismail
Koyama, Motoko
Varelias, Antiopi
Hertzog, Paul J
Kalinke, Ulrich
Gun, Sin Yee
Rénia, Laurent
Ruedl, Christiane
MacDonald, Kelli P A
Hill, Geoffrey R
Engwerda, Christian R
Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8- cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8- splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens.
2014-11-05T15:47:23Z
2014-11-05T15:47:23Z
2014-11-05T15:47:23Z
2014-06-02
Article
Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. 2014, 124 (6):2483-96 J. Clin. Invest.
1558-8238
24789914
10.1172/JCI70698
http://hdl.handle.net/10033/333737
The Journal of clinical investigation
en
oai:repository.helmholtz-hzi.de:10033/3390382019-08-30T11:35:39Zcom_10033_620601col_10033_620602
Host strategies against virus entry via the olfactory system.
Kalinke, Ulrich
Bechmann, Ingo
Detje, Claudia N
In mammals, odorants are inhaled through the nose and inside the nasal cavity they trigger olfactory sensory neurons (OSN) that are located within the olfactory epithelium. OSN project their axons into glomerular structures of the olfactory bulb. There they synapse with dendrites of second-order neurons that project their axons to the olfactory cortex. Thus, olfaction is based on direct interaction of environmental matters with OSN. This poses the question of how neurotropic viruses are prevented from infecting OSN and entering the central nervous system. Recent evidence indicates that upon instillation of neurotropic virus OSN are readily infected. By axonal transport virus reaches the glomerular layer of the olfactory bulb where it is efficiently curbed by a type I IFN dependent mechanism. In this review local mechanisms limiting virus entry via the olfactory system and virus spread within the CNS are recapitulated in the context of anatomical properties of the olfactory system.
2015-01-29T12:57:45Z
2015-01-29T12:57:45Z
2015-01-29T12:57:45Z
2015-01-29
Article
Host strategies against virus entry via the olfactory system., 2 (4):367-70 Virulence
2150-5608
21758005
http://hdl.handle.net/10033/339038
Virulence
en
oai:repository.helmholtz-hzi.de:10033/3464542019-08-30T11:37:24Zcom_10033_620601col_10033_620602
Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis.
Detje, Claudia N
Lienenklaus, Stefan
Chhatbar, Chintan
Spanier, Julia
Prajeeth, Chittappen K
Soldner, Claudia
Tovey, Michael G
Schlüter, Dirk
Weiss, Siegfried
Stangel, Martin
Kalinke, Ulrich
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-β was induced proximally, we studied spatiotemporal conditions of VSV-mediated IFN-β induction. To this end, we performed infection studies with IFN-β reporter mice. One day after intravenous (i.v.) VSV infection, luciferase induction was detected in lymph nodes. Upon i.n. infection, luciferase induction was discovered at similar sites with delayed kinetics, whereas on days 3 and 4 postinfection enhanced luciferase expression additionally was detected in the foreheads of reporter mice. A detailed analysis of cell type-specific IFN-β reporter mice revealed that within the olfactory bulb IFN-β was expressed by neuroectodermal cells, primarily by astrocytes and to a lesser extent by neurons. Importantly, locally induced type I IFN triggered distal parts of the brain as indicated by the analysis of ISRE-eGFP mice which after i.n. VSV infection showed enhanced green fluorescent protein (eGFP) expression throughout the brain. Compared to wild-type mice, IFN-β(-/-) mice showed increased mortality to i.n. VSV infection, whereas upon i.v. infection no such differences were detected highlighting the biological significance of intracerebrally expressed IFN-β. In conclusion, upon i.n. VSV instillation, IFN-β responses mounted by astrocytes within the olfactory bulb critically contribute to the antiviral defense by stimulating distal IFN-β-negative brain areas and thus arresting virus spread.
2015-03-10T10:25:33Z
2015-03-10T10:25:33Z
2015-03-10T10:25:33Z
2015-03-01
Article
Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis. 2015, 89 (5):2731-8 J. Virol.
1098-5514
25540366
10.1128/JVI.02044-14
http://hdl.handle.net/10033/346454
Journal of virology
en
oai:repository.helmholtz-hzi.de:10033/3464562019-08-30T11:37:44Zcom_10033_620601col_10033_620602
Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells.
Grabski, Elena
Wappler, Ilka
Pfaender, Stephanie
Steinmann, Eike
Haid, Sibylle
Dzionek, Andrzej
Pietschmann, Thomas
Kalinke, Ulrich
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV.
2015-03-10T10:37:45Z
2015-03-10T10:37:45Z
2015-03-10T10:37:45Z
2015-03-15
Article
Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. 2015, 89 (6):3200-8 J. Virol.
1098-5514
25552725
10.1128/JVI.03229-14
http://hdl.handle.net/10033/346456
Journal of virology
en
oai:repository.helmholtz-hzi.de:10033/3465162019-08-30T11:25:43Zcom_10033_620601col_10033_620602
Ultrasensitive quantification of TAP-dependent antigen compartmentalization in scarce primary immune cell subsets.
Fischbach, Hanna
Döring, Marius
Nikles, Daphne
Lehnert, Elisa
Baldauf, Christoph
Kalinke, Ulrich
Tampé, Robert
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz-Centre for Infection Research and the Hannover Medical School, Feodor-Lynen Str. 7-9, 30625 Hannover, Germany.
Presentation of peptides on major histocompatibility complex class I (MHC I) is essential for the establishment and maintenance of self-tolerance, priming of antigen-specific CD8(+) T cells and the exertion of several T-cell effector functions. Cytosolic proteasomes continuously degrade proteins into peptides, which are actively transported across the endoplasmic reticulum (ER) membrane by the transporter associated with antigen processing (TAP). In the ER lumen antigenic peptides are loaded onto MHC I, which is displayed on the cell surface. Here we describe an innovative flow cytometric approach to monitor time-resolved ER compartmentalization of antigenic peptides. This assay allows the analysis of distinct primary human immune cell subsets at reporter peptide concentrations of 1 nM. Thus, this ultrasensitive method for the first time permits quantification of TAP activity under close to physiological conditions in scarce primary cell subsets such as antigen cross-presenting dendritic cells.
2015-03-11T09:41:46Z
2015-03-11T09:41:46Z
2015-03-11T09:41:46Z
2015
Article
Ultrasensitive quantification of TAP-dependent antigen compartmentalization in scarce primary immune cell subsets. 2015, 6:6199 Nat Commun
2041-1723
25656091
10.1038/ncomms7199
http://hdl.handle.net/10033/346516
Nature communications
en
oai:repository.helmholtz-hzi.de:10033/3471552019-08-30T11:26:42Zcom_10033_620601col_10033_620602
Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity.
Ohnmacht, Caspar
Marques, Rute
Presley, Laura
Sawa, Shinichiro
Lochner, Matthias
Eberl, Gérard
The mammalian intestine provides a unique niche for a large community of bacterial symbionts that complements the host in digestive and anabolic pathways, as well as in protection from pathogens. Only a few bacterial phyla have adapted to this predominantly anaerobic environment, but hundreds of different species create an ecosystem that affects many facets of the host's physiology. Recent data show how particular symbionts are involved in the maturation of the immune system, in the intestine and beyond, and how dysbiosis, or alteration of that community, can deregulate immunity and lead to immunopathology. The extensive and dynamic interactions between the symbionts and the immune system are key to homeostasis and health, and require all the blends of so-called regulatory and pro-inflammatory immune reactions. Unfortunately, pro-inflammatory immunity leading to the generation of Th17 cells has been mainly associated with its role in immunopathology. Here we discuss the view that the immune system in general, and type 17 immunity in particular, develop to maintain the equilibrium of the host with its symbionts.
2015-03-26T10:38:15Z
2015-03-26T10:38:15Z
2015-03-26T10:38:15Z
2011-05
Article
Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity. 2011, 13 (5):653-9 Cell. Microbiol.
1462-5822
21338464
10.1111/j.1462-5822.2011.01577.x
http://hdl.handle.net/10033/347155
Cellular microbiology
en
oai:repository.helmholtz-hzi.de:10033/6209552019-08-30T11:24:31Zcom_10033_620601col_10033_620603
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature
Möller, Jana C
Cron, Randy Q
Young, Daniel W
Girschick, Hermann J
Levy, Deborah M
Sherry, David D
Kukita, Akiko
Saijo, Kaoru
Pessler, Frank
Abstract Spinal epidural lipomatosis is a rare complication of chronic corticosteroid treatment. We report a new pediatric case and an analysis of this and 19 pediatric cases identified in the international literature. The youngest of these combined 20 patients was 5 years old when lipomatosis was diagnosed. Lipomatosis manifested after a mean of 1.3 (+/- 1.5) years (SD) (median, 0.8 years; range, 3 weeks - 6.5 years) of corticosteroid treatment. The corticosteroid dose at the time of presentation of the lipomatosis ranged widely, between 5 and 80 mg of prednisone/day. Back pain was the most common presenting symptom. Imaging revealed that lipomatosis almost always involved the thoracic spine, extending into the lumbosacral region in a subset of patients. Predominantly lumbosacral involvement was documented in only two cases. Although a neurological deficit at presentation was documented in about half of the cases, surgical decompression was not performed in the cases reported after 1996. Instead, reducing the corticosteroid dose (sometimes combined with dietary restriction to mobilize fat) sufficed to induce remission. In summary, pediatric spinal epidural lipomatosis remains a potentially serious untoward effect of corticosteroid treatment, which, if recognized in a timely manner, can have a good outcome with conservative treatment.
2017-06-16T08:07:40Z
2017-06-16T08:07:40Z
2017-06-16T08:07:40Z
2011-02-01
Journal Article
Pediatric Rheumatology. 2011 Feb 01;9(1):5
http://dx.doi.org/10.1186/1546-0096-9-5
http://hdl.handle.net/10033/620955
en
Möller et al; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/6207152019-08-30T11:26:42Zcom_10033_620601col_10033_620603
Analysis of contingency tables based on generalised median polish with power transformations and non-additive models
Klawonn, Frank
Jayaram, Balasubramaniam
Crull, Katja
Kukita, Akiko
Pessler, Frank
Abstract Contingency tables are a very common basis for the investigation of effects of different treatments or influences on a disease or the health state of patients. Many journals put a strong emphasis on p-values to support the validity of results. Therefore, even small contingency tables are analysed by techniques like t-test or ANOVA. Both these concepts are based on normality assumptions for the underlying data. For larger data sets, this assumption is not so critical, since the underlying statistics are based on sums of (independent) random variables which can be assumed to follow approximately a normal distribution, at least for a larger number of summands. But for smaller data sets, the normality assumption can often not be justified. Robust methods like the Wilcoxon-Mann-Whitney-U test or the Kruskal-Wallis test do not lead to statistically significant p-values for small samples. Median polish is a robust alternative to analyse contingency tables providing much more insight than just a p-value. Median polish is a technique that provides more information than just a p-value. It explains the contingency table in terms of an overall effect, row and columns effects and residuals. The underlying model for median polish is an additive model which is sometimes too restrictive. In this paper, we propose two related approach to generalise median polish. A power transformation can be applied to the values in the table, so that better results for median polish can be achieved. We propose a graphical method how to find a suitable power transformation. If the original data should be preserved, one can apply other transformations – based on so-called additive generators – that have an inverse transformation. In this way, median polish can be applied to the original data, but based on a non-additive model. The non-linearity of such a model can also be visualised to better understand the joint effects of rows and columns in a contingency table.
2017-01-17T09:49:01Z
2017-01-17T09:49:01Z
2017-01-17T09:49:01Z
2013-05-30
Journal Article
Health Information Science and Systems. 2013 May 30;1(1):11
http://dx.doi.org/10.1186/2047-2501-1-11
http://hdl.handle.net/10033/620715
en
Klawonn et al.; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/6207052019-08-30T11:25:43Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
Infection- and procedure-dependent effects on pulmonary gene expression in the early phase of influenza A virus infection in mice
Preusse, Matthias
Tantawy, Mohamed A
Klawonn, Frank
Schughart, Klaus
Pessler, Frank
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.
2017-01-16T15:28:50Z
2017-01-16T15:28:50Z
2017-01-16T15:28:50Z
2013-12-17
Journal Article
BMC Microbiology. 2013 Dec 17;13(1):293
http://dx.doi.org/10.1186/1471-2180-13-293
http://hdl.handle.net/10033/620705
en
Preusse et al.; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/5797922019-08-30T11:37:44Zcom_10033_620601col_10033_620602
The antiviral drug ganciclovir does not inhibit microglial proliferation and activation.
Skripuletz, Thomas
Salinas Tejedor, Laura
Prajeeth, Chittappen K
Hansmann, Florian
Chhatbar, Chintan
Kucman, Valeria
Zhang, Ning
Raddatz, Barbara B
Detje, Claudia N
Sühs, Kurt-Wolfram
Pul, Refik
Gudi, Viktoria
Kalinke, Ulrich
Baumgärtner, Wolfgang
Stangel, Martin
TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen Str. 7, 30625, Hannover, Germany.
Ganciclovir is effective in the treatment of human infections with viruses of the Herpesviridae family. Beside antiviral properties, recently ganciclovir was described to inhibit microglial proliferation and disease severity of experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Microglial activation and proliferation are main characteristics of neuroinflammatory CNS diseases and inhibition of microglial functions might be beneficial in autoimmune diseases, or detrimental in infectious diseases. The objective of this study was to determine potential inhibitory effects of ganciclovir in three different murine animal models of CNS neuroinflammation in which microglia play an important role: Theiler´s murine encephalomyelitis, the cuprizone model of de- and remyelination, and the vesicular stomatitis virus encephalitis model. In addition, in vitro experiments with microglial cultures were performed to test the hypothesis that ganciclovir inhibits microglial proliferation. In all three animal models, neither microglial proliferation or recruitment nor disease activity was changed by ganciclovir. In vitro experiments confirmed that microglial proliferation was not affected by ganciclovir. In conclusion, our results show that the antiviral drug ganciclovir does not inhibit microglial activation and proliferation in the murine CNS.
2015-10-16T09:57:44Z
2015-10-16T09:57:44Z
2015-10-16T09:57:44Z
2015
Article
The antiviral drug ganciclovir does not inhibit microglial proliferation and activation. 2015, 5:14935 Sci Rep
2045-2322
26447351
10.1038/srep14935
http://hdl.handle.net/10033/579792
Scientific reports
en
oai:repository.helmholtz-hzi.de:10033/5801112019-08-30T11:35:14Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
Improved coverage and timing of childhood vaccinations in two post-Soviet countries, Armenia and Kyrgyzstan.
Schweitzer, A
Krause, Gerard
Pessler, F
Akmatov, M K
Timing of childhood vaccinations has received close attention in many countries. Little is known about the trends in correctly timed vaccination in former Soviet countries. We examined trends in vaccination coverage and correct timing of vaccination in two post-Soviet countries, Armenia and Kyrgyzstan, and analyzed factors associated with delayed vaccinations.
2015-10-22T08:39:41Z
2015-10-22T08:39:41Z
2015-10-22T08:39:41Z
2015
Article
Improved coverage and timing of childhood vaccinations in two post-Soviet countries, Armenia and Kyrgyzstan. 2015, 15 (1):798 BMC Public Health
1471-2458
26285702
10.1186/s12889-015-2091-9
http://hdl.handle.net/10033/580111
BMC public health
en
oai:repository.helmholtz-hzi.de:10033/5800702019-08-30T11:36:33Zcom_10033_620626com_10033_620601com_10033_311308col_10033_620721col_10033_620627col_10033_620603
Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains.
Preusse, Matthias
Schughart, Klaus
Wilk, Esther
Klawonn, Frank
Pessler, Frank
Helmholz Centre for Infection Research
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.
2015-10-22T10:22:07Z
2015-10-22T10:22:07Z
2015-10-22T10:22:07Z
2015
Article
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
en
oai:repository.helmholtz-hzi.de:10033/5824402019-08-30T11:25:11Zcom_10033_620601col_10033_620602
Antigen presenting cell-selective drug delivery by glycan-decorated nanocarriers.
Frenz, Theresa
Grabski, Elena
Durán, Verónica
Hozsa, Constantin
Stępczyńska, Anna
Furch, Marcus
Gieseler, Robert K
Kalinke, Ulrich
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
Targeted drug delivery systems hold promise for selective provision of active compounds to distinct tissues or cell subsets. Thus, locally enhanced drug concentrations are obtained that would confer improved efficacy. As a consequence adverse effects should be diminished, as innocent bystander cells are less affected. Currently, several controlled drug delivery systems based on diverse materials are being developed. Some systems exhibit material-associated toxic effects and/or show low drug loading capacity. In contrast, liposomal nanocarriers are particularly favorable because they are well tolerated, poorly immunogenic, can be produced in defined sizes, and offer a reasonable payload capacity. Compared with other immune cells, professional antigen-presenting cells (APCs) demonstrate enhanced liposome uptake mediated by macropinocytosis, phagocytosis and presumably also by clathrin- and caveolae-mediated endocytosis. In order to further enhance the targeting efficacy toward APCs, receptor-mediated uptake appears advisable. Since APC subsets generally do not express single linage-specific receptors, members of the C-type lectin receptor (CLR) family are compelling targets. Examples of CLR expressed by APCs include DEC-205 (CD205) expressed by myeloid dendritic cells (DC) and monocytes, the mannose receptor C type 1 (MR, CD206) expressed by DC, monocytes and macrophages, DC-SIGN (CD209) expressed by DC, and several others. These receptors bind glycans, which are typically displayed by pathogens and thus support pathogen uptake and endocytosis. Further research will elucidate whether glycan-decorated liposomes will not only enhance APCs targeting but also enable preferential delivery of their payload to discrete subcellular compartments.
2015-11-20T13:26:37Z
2015-11-20T13:26:37Z
2015-11-20T13:26:37Z
2015-09
Article
Antigen presenting cell-selective drug delivery by glycan-decorated nanocarriers. 2015, 95 (Pt A):13-7 Eur J Pharm Biopharm
1873-3441
25701806
10.1016/j.ejpb.2015.02.008
http://hdl.handle.net/10033/582440
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V
en
oai:repository.helmholtz-hzi.de:10033/5833982019-08-30T11:30:32Zcom_10033_620601col_10033_620602
Synergy between CD40 and MyD88 Does Not Influence Host Survival to Salmonella Infection.
Wenzel, Ulf Alexander
Fernandez-Santoscoy, Maria
Tam, Miguel A
Tegtmeyer, Pia
Wick, Mary Jo
TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen Str. 7, 30625, Hannover, Germany.
Previous studies using purified toll-like receptor (TLR) ligands plus agonistic anti-CD40 antibodies showed that TLRs and CD40 can act synergistically on dendritic cells (DCs) to optimize T cell activation and Th1 differentiation. However, a synergistic effect of TLRs and CD40 during bacterial infection is not known. Here, we show that mice lacking the TLR adaptor MyD88 alone, or lacking both MyD88 and CD40 [double knockout (DKO) mice], are compromised in survival to Salmonella infection but have intact recruitment of neutrophils and inflammatory monocytes as well as unaltered abundance of DC subsets and DC activation in infected tissues. In contrast to infected wildtype and CD40(-/-) mice, both MyD88(-/-) mice and DKO mice lack detectable serum IFN-γ and have elevated IL-10. A synergistic effect of TLRs and CD40 was revealed in co-culture experiments where OT-II T cell proliferation was compromised when DKO DCs were pulsed with OVA protein and OVA323-339 peptide, but not with heat-killed Salmonella expressing OVA (HKSOVA), relative to MyD88(-/-) DCs. By contrast, MyD88(-/-) or DKO DCs pulsed with any of the antigens had a similar ability to induce IFN-γ that was lower than WT or CD40(-/-) DCs. DKO DCs pulsed with HKSOVA, but not with OVA or OVA323-339, had increased IL-10 relative to MyD88(-/-) DCs. Finally, HKSOVA-pulsed MyD88(-/-) and DKO DCs had similar and low induction of NFκB-dependent and -independent genes upon co-culture with OT-II cells. Overall, our data revealed that synergistic effects of CD40 and MyD88 do not influence host survival to Salmonella infection or serum levels of IFN-γ or IL-10. However, synergistic effects of MyD88 and CD40 may be apparent on some (IL-10 production) but not all (OT-II proliferation and IFN-γ production) DC functions and depend on the complexity of the antigen. Indeed, synergistic effects observed using purified ligands and well-defined antigens may not necessarily apply when complex antigens, such as live bacteria, challenge the immune system.
2015-12-08T10:06:02Z
2015-12-08T10:06:02Z
2015-12-08T10:06:02Z
2015
Article
Synergy between CD40 and MyD88 Does Not Influence Host Survival to Salmonella Infection. 2015, 6:460 Front Immunol
1664-3224
26441965
10.3389/fimmu.2015.00460
http://hdl.handle.net/10033/583398
Frontiers in immunology
en
oai:repository.helmholtz-hzi.de:10033/5834022019-08-30T11:25:11Zcom_10033_620601col_10033_620602
A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform.
Malczyk, Anna H
Kupke, Alexandra
Prüfer, Steffen
Scheuplein, Vivian A
Hutzler, Stefan
Kreuz, Dorothea
Beissert, Tim
Bauer, Stefanie
Hubich-Rau, Stefanie
Tondera, Christiane
Eldin, Hosam Shams
Schmidt, Jörg
Vergara-Alert, Júlia
Süzer, Yasemin
Seifried, Janna
Hanschmann, Kay-Martin
Kalinke, Ulrich
Herold, Susanne
Sahin, Ugur
Cichutek, Klaus
Waibler, Zoe
Eickmann, Markus
Becker, Stephan
Mühlebach, Michael D
TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 3-7, 30625 Hannover, Germany.
In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR(-/-))-CD46Ge mice with 2 × 10(5) 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice.
2015-12-08T12:45:04Z
2015-12-08T12:45:04Z
2015-12-08T12:45:04Z
2015-11-15
Article
A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform. 2015, 89 (22):11654-67 J. Virol.
1098-5514
26355094
10.1128/JVI.01815-15
http://hdl.handle.net/10033/583402
Journal of virology
en
oai:repository.helmholtz-hzi.de:10033/5944072019-08-30T11:37:44Zcom_10033_620601col_10033_620603
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature.
Möller, Jana C
Cron, Randy Q
Young, Daniel W
Girschick, Hermann J
Levy, Deborah M
Sherry, David D
Kukita, Akiko
Saijo, Kaoru
Pessler, Frank
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Spinal epidural lipomatosis is a rare complication of chronic corticosteroid treatment. We report a new pediatric case and an analysis of this and 19 pediatric cases identified in the international literature. The youngest of these combined 20 patients was 5 years old when lipomatosis was diagnosed. Lipomatosis manifested after a mean of 1.3 (+/- 1.5) years (SD) (median, 0.8 years; range, 3 weeks - 6.5 years) of corticosteroid treatment. The corticosteroid dose at the time of presentation of the lipomatosis ranged widely, between 5 and 80 mg of prednisone/day. Back pain was the most common presenting symptom. Imaging revealed that lipomatosis almost always involved the thoracic spine, extending into the lumbosacral region in a subset of patients. Predominantly lumbosacral involvement was documented in only two cases. Although a neurological deficit at presentation was documented in about half of the cases, surgical decompression was not performed in the cases reported after 1996. Instead, reducing the corticosteroid dose (sometimes combined with dietary restriction to mobilize fat) sufficed to induce remission. In summary, pediatric spinal epidural lipomatosis remains a potentially serious untoward effect of corticosteroid treatment, which, if recognized in a timely manner, can have a good outcome with conservative treatment.
2016-01-20T14:24:12Z
2016-01-20T14:24:12Z
2016-01-20T14:24:12Z
2011
Article
Corticosteroid-induced spinal epidural lipomatosis in the pediatric age group: report of a new case and updated analysis of the literature. 2011, 9 (1):5 Pediatr Rheumatol Online J
1546-0096
21284882
10.1186/1546-0096-9-5
http://hdl.handle.net/10033/594407
Pediatric rheumatology online journal
en
oai:repository.helmholtz-hzi.de:10033/6035092019-08-30T11:37:00Zcom_10033_620601col_10033_620602
Critical role of perforin-dependent CD8+ T cell immunity for rapid protective vaccination in a murine model for human smallpox.
Kremer, Melanie
Suezer, Yasemin
Volz, Asisa
Frenz, Theresa
Majzoub, Monir
Hanschmann, Kay-Martin
Lehmann, Michael H
Kalinke, Ulrich
Sutter, Gerd
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and Hannover Medical School, Hannover, Germany.
Vaccination is highly effective in preventing various infectious diseases, whereas the constant threat of new emerging pathogens necessitates the development of innovative vaccination principles that also confer rapid protection in a case of emergency. Although increasing evidence points to T cell immunity playing a critical role in vaccination against viral diseases, vaccine efficacy is mostly associated with the induction of antibody responses. Here we analyze the immunological mechanism(s) of rapidly protective vaccinia virus immunization using mousepox as surrogate model for human smallpox. We found that fast protection against lethal systemic poxvirus disease solely depended on CD4 and CD8 T cell responses induced by vaccination with highly attenuated modified vaccinia virus Ankara (MVA) or conventional vaccinia virus. Of note, CD4 T cells were critically required to allow for MVA induced CD8 T cell expansion and perforin-mediated cytotoxicity was a key mechanism of MVA induced protection. In contrast, selected components of the innate immune system and B cell-mediated responses were fully dispensable for prevention of fatal disease by immunization given two days before challenge. In conclusion, our data clearly demonstrate that perforin-dependent CD8 T cell immunity plays a key role in MVA conferred short term protection against lethal mousepox. Rapid induction of T cell immunity might serve as a new paradigm for treatments that need to fit into a scenario of protective emergency vaccination.
2016-03-22T15:51:49Z
2016-03-22T15:51:49Z
2016-03-22T15:51:49Z
2012
Article
Critical role of perforin-dependent CD8+ T cell immunity for rapid protective vaccination in a murine model for human smallpox. 2012, 8 (3):e1002557 PLoS Pathog.
1553-7374
22396645
10.1371/journal.ppat.1002557
http://hdl.handle.net/10033/603509
PLoS pathogens
en
'info:eu-repo/grantAgreement/EC/FP7/'261466
openAccess
oai:repository.helmholtz-hzi.de:10033/6052762019-08-30T11:31:49Zcom_10033_620601col_10033_620602
cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.
Paijo, Jennifer
Döring, Marius
Spanier, Julia
Grabski, Elena
Nooruzzaman, Mohammed
Schmidt, Tobias
Witte, Gregor
Messerle, Martin
Hornung, Veit
Kaever, Volkhard
Kalinke, Ulrich
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
Human cytomegalovirus (HCMV) infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS) senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING) and thus induces antiviral type I interferon (IFN-I) responses. We found that plasmacytoid dendritic cells (pDC) as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages.
2016-04-14T13:34:34Z
2016-04-14T13:34:34Z
2016-04-14T13:34:34Z
2016-04
Article
cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells. 2016, 12 (4):e1005546 PLoS Pathog.
1553-7374
27058035
10.1371/journal.ppat.1005546
http://hdl.handle.net/10033/605276
PLoS pathogens
en
oai:repository.helmholtz-hzi.de:10033/6060592019-08-30T11:26:12Zcom_10033_620601col_10033_620602
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.
Weißmüller, Sabrina
Kronhart, Stefanie
Kreuz, Dorothea
Schnierle, Barbara
Kalinke, Ulrich
Kirberg, Jörg
Hanschmann, Kay-Martin
Waibler, Zoe
Helmholtzzentrum für Infektionsforschung
Therapeutic monoclonal antibodies (mAbs) such as the superagonistic, CD28-specific antibody TGN1412, or OKT3, an anti-CD3 mAb, can cause severe adverse events including cytokine release syndrome. A predictive model for mAb-mediated adverse effects, for which no previous knowledge on severe adverse events to be expected or on molecular mechanisms underlying is prerequisite, is not available yet. We used a humanized mouse model of human peripheral blood mononuclear cell-reconstituted NOD-RAG1-/-Aβ-/-HLADQ(tg+ or tg-)IL-2Rγc-/- mice to evaluate its predictive value for preclinical testing of mAbs. 2-6 hours after TGN1412 treatment, mice showed a loss of human CD45+ cells from the peripheral blood and loss of only human T cells after OKT3 injection, reminiscent of effects observed in mAb-treated humans. Moreover, upon OKT3 injection we detected selective CD3 downmodulation on T cells, a typical effect of OKT3. Importantly, we detected release of human cytokines in humanized mice upon both OKT3 and TGN1412 application. Finally, humanized mice showed severe signs of illness, a rapid drop of body temperature, and succumbed to antibody application 2-6 hours after administration. Hence, the humanized mouse model used here reproduces several effects and adverse events induced in humans upon application of the therapeutic mAbs OKT3 and TGN1412.
2016-04-20T10:49:50Z
2016-04-20T10:49:50Z
2016-04-20T10:49:50Z
2016
Article
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. 2016, 11 (3):e0149093 PLoS ONE
1932-6203
26959227
10.1371/journal.pone.0149093
http://hdl.handle.net/10033/606059
PloS one
en
oai:repository.helmholtz-hzi.de:10033/6115752019-08-30T11:33:25Zcom_10033_620601col_10033_620602
Deciphering the EU clinical trials regulation.
Abou-El-Enein, Mohamed
Schneider, Christian K
Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
2016-06-02T14:14:49Z
2016-06-02T14:14:49Z
2016-06-02T14:14:49Z
2016-03-10
Article
Deciphering the EU clinical trials regulation. 2016, 34 (3):231-3 Nat. Biotechnol.
1546-1696
26963541
10.1038/nbt.3492
http://hdl.handle.net/10033/611575
Nature biotechnology
en
oai:repository.helmholtz-hzi.de:10033/6091642019-08-30T11:34:18Zcom_10033_620601col_10033_620602
Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue
Castiglia, Virginia
Piersigilli, Alessandra
Ebner, Florian
Janos, Marton
Goldmann, Oliver
Damböck, Ursula
Kröger, Andrea
Weiss, Sigfried
Knapp, Sylvia
Jamieson, Amanda M.
Kirschning, Carsten
Kalinke, Ulrich
Strobl, Birgit
Müller, Mathias
Stoiber, Dagmar
Lienenklaus, Stefan
Kovarik, Pavel
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
2016-05-12T13:17:04Z
2016-05-12T13:17:04Z
2016-05-12T13:17:04Z
2016-03
Article
Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue 2016, 19 (3):375 Cell Host & Microbe
19313128
10.1016/j.chom.2016.02.003
http://hdl.handle.net/10033/609164
Cell Host & Microbe
http://linkinghub.elsevier.com/retrieve/pii/S1931312816300440
oai:repository.helmholtz-hzi.de:10033/6106862019-08-30T11:30:58Zcom_10033_620601col_10033_620603
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages.
Tallam, Aravind
Perumal, Thaneer M
Antony, Paul M
Jäger, Christian
Fritz, Joëlle V
Vallar, Laurent
Balling, Rudi
Del Sol, Antonio
Michelucci, Alessandro
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. To this end, we studied IRG1 expression in human immune cells under different inflammatory stimuli, such as TNFα and IFNγ, in addition to lipopolysaccharides. Under these conditions, as previously shown in mouse macrophages, IRG1/CAD accumulates in mitochondria. Furthermore, using literature information and transcription factor prediction models, we re-constructed raw gene regulatory networks (GRNs) for IRG1 in mouse and human macrophages. We further implemented a contextualization algorithm that relies on genome-wide gene expression data to infer putative cell type-specific gene regulatory interactions in mouse and human macrophages, which allowed us to predict potential transcriptional regulators of IRG1. Among the computationally identified regulators, siRNA-mediated gene silencing of interferon regulatory factor 1 (IRF1) in macrophages significantly decreased the expression of IRG1/CAD at the gene and protein level, which correlated with a reduced production of itaconic acid. Using a synergistic approach of both computational and experimental methods, we here shed more light on the transcriptional machinery of IRG1 expression and could pave the way to therapeutic approaches targeting itaconic acid levels.
2016-05-25T13:35:19Z
2016-05-25T13:35:19Z
2016-05-25T13:35:19Z
2016
Article
Gene Regulatory Network Inference of Immunoresponsive Gene 1 (IRG1) Identifies Interferon Regulatory Factor 1 (IRF1) as Its Transcriptional Regulator in Mammalian Macrophages. 2016, 11 (2):e0149050 PLoS ONE
1932-6203
26872335
10.1371/journal.pone.0149050
http://hdl.handle.net/10033/610686
PloS one
en
oai:repository.helmholtz-hzi.de:10033/6119822019-08-30T11:30:32Zcom_10033_620601col_10033_620603
Small Non-coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications.
Samir, Mohamed
Pessler, Frank
Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
MicroRNAs (miRNAs) represent a class of small non-coding RNA (sncRNA) molecules that can regulate mRNAs by inducing their degradation or by blocking translation. Considering that miRNAs are ubiquitous, stable, and conserved across animal species, it seems feasible to exploit them for clinical applications. Unlike in human viral diseases, where some miRNA-based molecules have progressed to clinical application, in veterinary medicine, this concept is just starting to come into view. Clinically, miRNAs could represent powerful diagnostic tools to pinpoint animal viral diseases and/or prognostic tools to follow up disease progression or remission. Additionally, the possible consequences of miRNA dysregulation make them potential therapeutic targets and open the possibilities to use them as tools to generate viral disease-resistant livestock. This review presents an update of preclinical studies on using sncRNAs to combat viral diseases that affect pet and farm animals. Moreover, we discuss the possibilities and challenges of bringing these bench-based discoveries to the veterinary clinic.
2016-06-07T13:09:29Z
2016-06-07T13:09:29Z
2016-06-07T13:09:29Z
2016
Article
Small Non-coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications. 2016, 3:22 Front Vet Sci
2297-1769
27092305
10.3389/fvets.2016.00022
http://hdl.handle.net/10033/611982
Frontiers in veterinary science
en
oai:repository.helmholtz-hzi.de:10033/6156212019-08-30T11:26:42Zcom_10033_620601col_10033_620602
Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation.
Waffarn, Elizabeth E
Hastey, Christine J
Dixit, Neha
Soo Choi, Youn
Cherry, Simon
Kalinke, Ulrich
Simon, Scott I
Baumgarth, Nicole
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Innate-like B-1a lymphocytes rapidly redistribute to regional mediastinal lymph nodes (MedLNs) during influenza infection to generate protective IgM. Here we demonstrate that influenza infection-induced type I interferons directly stimulate body cavity B-1 cells and are a necessary signal required for B-1 cell accumulation in MedLNs. Vascular mimetic flow chamber studies show that type I interferons increase ligand-mediated B-1 cell adhesion under shear stress by inducing high-affinity conformation shifts of surface-expressed integrins. In vivo trafficking experiments identify CD11b as the non-redundant, interferon-activated integrin required for B-1 cell accumulation in MedLNs. Thus, CD11b on B-1 cells senses infection-induced innate signals and facilitates their rapid sequester into secondary lymphoid tissues, thereby regulating the accumulation of polyreactive IgM producers at sites of infection.
2016-07-06T08:35:21Z
2016-07-06T08:35:21Z
2016-07-06T08:35:21Z
2015
Article
Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. 2015, 6:8991 Nat Commun
2041-1723
26612263
10.1038/ncomms9991
http://hdl.handle.net/10033/615621
Nature communications
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6156692019-08-30T11:30:32Zcom_10033_620601col_10033_620602
Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells.
Vogel, Stephanie
Grabski, Elena
Buschjäger, Daniela
Klawonn, Frank
Döring, Marius
Wang, Junxi
Fletcher, Erika
Bechmann, Ingo
Witte, Torsten
Durisin, Martin
Schraven, Burkhart
Mangsbo, Sara M
Schönfeld, Kurt
Czeloth, Niklas
Kalinke, Ulrich
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Straße 7, D30625 Hannover, Germany.
Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64(+) monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients' inflamed joints that comprised enhanced numbers of CD64(+) cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64(+) cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64(+) cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions.
2016-07-07T12:29:54Z
2016-07-07T12:29:54Z
2016-07-07T12:29:54Z
2015
Article
Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells. 2015, 5:18308 Sci Rep
2045-2322
26670584
10.1038/srep18308
http://hdl.handle.net/10033/615669
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6190432019-08-30T11:30:58Zcom_10033_620601col_10033_620603
Exhaled breath analysis in childhood rheumatic disorders--a longitudinal study.
Hendel, N
Akmatov, M K
Hamel, J
Vogelberg, C
Pessler, F
TWINCORE Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7 30625 Hannover, Germany.
We aimed to evaluate the fraction of exhaled nitric oxide (FENO50) and deaerated exhaled breath condensate pH (dEBCpH) as non-invasive markers of subclinical airway inflammation in pediatric patients with rheumatologic disorders. We determined FENO50 and dEBCpH in a prospective study spanning at least 12 months, comprising 85 pediatric patients with rheumatologic disorders, including juvenile idiopathic arthritis (JIA, n = 63), chronic recurrent multifocal osteomyelitis (CRMO, n = 6), systemic lupus erythematosus (SLE, n = 3), juvenile dermatomyositis (JDM, n = 1) and other rheumatic disorders (n = 12). dEBCpH was determined once in a group of children without evidence of rheumatologic or pulmonary disease (controls, n = 90). Findings were correlated with results of pulmonary function tests. Atopic sensitization was assessed by RAST or skin prick test in 76 patients. Atopic sensitization was detected in 34% (26/76) of patients. Neither FENO50 nor dEBCpH correlated with disease activity, but intermediately (20-35 ppb) or highly elevated (>35 ppb) levels were observed at least once in 26 patients (31%), 19 of whom had atopic sensitization. Median dEBCpH did not differ between cases and controls (8.05 versus 8.02; p = 0.48). Median dEBCpH decreased slightly over the study period (p = 0.02), whereas FENO50 values did not change significantly (p = 0.89). There were several patients with significantly abnormal dEBCpH values that could not be readily explained by diagnosis, higher disease activity, medications, or atopic sensitization. Thus, there were no consistent abnormalities in FENO50 or dEBCpH in this cohort of Caucasian patients with relatively stable rheumatologic disorders, but there were some patients with abnormal values of unknown significance.
2016-08-30T11:19:08Z
2016-08-30T11:19:08Z
2016-08-30T11:19:08Z
2016-06
Article
Exhaled breath analysis in childhood rheumatic disorders--a longitudinal study. 2016, 10 (2):021001 J Breath Res
1752-7163
27093271
10.1088/1752-7155/10/2/021001
http://hdl.handle.net/10033/619043
Journal of breath research
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6190492019-08-30T11:30:58Zcom_10033_620601col_10033_620603
Real-life practice of methotrexate toxicity monitoring in juvenile idiopathic arthritis in Germany, Switzerland and Austria: results of a cross-sectional assessment conducted in 2012.
Akmatov, Manas K
Stumme, Melanie
Pessler, Frank
TWINCORE Centre for Experimental and Clinical Infection Research Feodor-Lynen-Str. 7 30625 Hannover, Germany.
Methotrexate (MTX) is used at low doses to treat rheumatologic disorders in the paediatric age group. Toxicity is observed despite the low doses used. Even though recommendations for monitoring of early signs of toxicity exist in many countries, real-life practice may vary. We therefore assessed current practice in Germany, Switzerland and Austria.
2016-08-30T15:08:52Z
2016-08-30T15:08:52Z
2016-08-30T15:08:52Z
2016-08-30
Article
Real-life practice of methotrexate toxicity monitoring in juvenile idiopathic arthritis in Germany, Switzerland and Austria: results of a cross-sectional assessment conducted in 2012., 34 (3):548-53 Clin. Exp. Rheumatol.
0392-856X
27156925
http://hdl.handle.net/10033/619049
Clinical and experimental rheumatology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6192652019-08-30T11:30:32Zcom_10033_620601col_10033_620603
Impact of rotavirus vaccination on coverage and timing of pentavalent vaccination - Experience from 2 Latin American countries.
Schweitzer, A
Pessler, F.
Akmatov, M K
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
We examined the coverage and timing of rotavirus vaccination and the impact of rotavirus vaccine introduction on coverage and timing of the pentavalent vaccine. We used data from the Demographic and Health Surveys in Honduras (2011/2012) and Peru (2012). The samples were divided into 2 subcohorts: children born before and after the introduction of rotavirus vaccine. We compared coverage and timing of the pentavalent vaccine in the aforementioned subcohorts. Coverage with the first and second doses of rotavirus vaccination was 95% (95% confidence intervals: 93-97%) and 91% (89-95%) in Honduras and 79% (77-82%) and 72% (69-75%) in Peru, respectively. Coverage increased in both countries over the years. The proportion of children vaccinated according to age-appropriate vaccination schedules varied between 67% (second dose of rotavirus vaccinations in Peru) and 89% (first dose of rotavirus vaccination in Honduras). Coverage with the first and second doses of pentavalent vaccination remained constant over the years in Honduras, while in Peru there was a significant increase in coverage over the years (p for trend, <0.0001). In both countries, timing of pentavalent vaccination was better in post-rota-cohorts than in pre-rota-cohorts. Since its introduction, coverage of rotavirus vaccination has improved over time in both countries. An introduction of rotavirus vaccination in both countries appears to have improved the coverage and timing of other similarly scheduled vaccinations.
2016-09-02T09:22:12Z
2016-09-02T09:22:12Z
2016-09-02T09:22:12Z
2016-05-03
Article
Impact of rotavirus vaccination on coverage and timing of pentavalent vaccination - Experience from 2 Latin American countries. 2016, 12 (5):1250-6 Hum Vaccin Immunother
2164-554X
26833132
10.1080/21645515.2015.1127486
http://hdl.handle.net/10033/619265
Human vaccines & immunotherapeutics
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6205402019-08-30T11:27:16Zcom_10033_620601col_10033_620603
Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection.
Dudek, M
Puttur, F
Arnold-Schrauf, C
Kühl, A A
Holzmann, B
Henriques-Normark, B
Berod, L
Sparwasser, T
Twincore
The Gram-positive bacterium Streptococcus pneumoniae causes life-threatening infections, especially among immunocompromised patients. The host's immune system senses S. pneumoniae via different families of pattern recognition receptors, in particular the Toll-like receptor (TLR) family that promotes immune cell activation. Yet, while single TLRs are dispensable for initiating inflammatory responses against S. pneumoniae, the central TLR adapter protein myeloid differentiation factor 88 (MyD88) is of vital importance, as MyD88-deficient mice succumb rapidly to infection. Since MyD88 is ubiquitously expressed in hematopoietic and non-hematopoietic cells, the extent to which MyD88 signaling is required in different cell types to control S. pneumoniae is unknown. Therefore, we used novel conditional knockin mice to investigate the necessity of MyD88 signaling in distinct lung-resident myeloid and epithelial cells for the initiation of a protective immune response against S. pneumoniae. Here, we show that MyD88 signaling in lysozyme M (LysM)- and CD11c-expressing myeloid cells, as well as in pulmonary epithelial cells, is critical to restore inflammatory cytokine and antimicrobial peptide production, leading to efficient neutrophil recruitment and enhanced bacterial clearance. Overall, we show a novel synergistic requirement of compartment-specific MyD88 signaling in S. pneumoniae immunity.
2016-09-29T09:03:26Z
2016-09-29T09:03:26Z
2016-09-29T09:03:26Z
2016-09
Article
Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection. 2016, 9 (5):1288-302 Mucosal Immunol
1935-3456
26627460
10.1038/mi.2015.128
http://hdl.handle.net/10033/620540
Mucosal immunology
en
oai:repository.helmholtz-hzi.de:10033/6206792019-08-30T11:37:24Zcom_10033_620601col_10033_620603
Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood.
de Araujo, Leonardo S
Vaas, Lea A I
Ribeiro-Alves, Marcelo
Geffers, Robert
Mello, Fernanda C Q
de Almeida, Alexandre S
Moreira, Adriana da S R
Kritski, Afrânio L
Lapa E Silva, José R
Moraes, Milton O
Pessler, Frank
Saad, Maria H F
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation of DOCK9, EPHA4, and NPC2 mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil, n = 129) or reanalysis of public microarray data (UK: n = 96; South Africa: n = 51; Germany: n = 26; and UK/France: n = 63). In the Brazilian cohort, significant modulation of all target-genes was observed comparing TB vs. healthy recent close TB contacts (rCt). With a 92% specificity, NPC2 mRNA high expression (NPC2(high)) showed the highest sensitivity (85%, 95% CI 65%-96%; area under the ROC curve [AUROC] = 0.88), followed by EPHA4 (53%, 95% CI 33%-73%, AUROC = 0.73) and DOCK9 (19%, 95% CI 7%-40%; AUROC = 0.66). All the other reanalyzed cohorts corroborated the potential of NPC2(high) as a biomarker for TB (sensitivity: 82-100%; specificity: 94-97%). An NPC2(high) profile was also observed in 60% (29/48) of the tuberculin skin test positive rCt, and additional follow-up evaluation revealed changes in the expression levels of NPC2 during the different stages of Mycobacterium tuberculosis infection, suggesting that further studies are needed to evaluate modulation of this gene during latent TB and/or progression to active disease. Considering its high specificity, our data indicate, for the first time, that NPC2(high) might serve as an accurate single-gene biomarker for TB.
2017-01-05T10:48:04Z
2017-01-05T10:48:04Z
2017-01-05T10:48:04Z
2016
Article
Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood. 2016, 7:1586 Front Microbiol
27826286
10.3389/fmicb.2016.01586
http://hdl.handle.net/10033/620679
Frontiers in microbiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208682019-08-30T11:35:13Zcom_10033_620601col_10033_620602
A polymorphism within the internal fusion loop of the Ebola virus glycoprotein modulates host cell entry.
Hoffmann, Markus
Crone, Lisa
Dietzel, Erik
Paijo, Jennifer
González-Hernández, Mariana
Nehlmeier, Inga
Kalinke, Ulrich
Becker, Stephan
Pöhlmann, Stefan
Twincore Centre of Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
The large scale of the Ebola virus disease (EVD) outbreak in West Africa in 2013-2016 raised the question whether the host cell interactions of the responsible Ebola virus (EBOV) strain differed from those of other ebolaviruses. We previously reported that the glycoprotein (GP) of the virus circulating in West Africa in 2014 (EBOV2014) exhibited reduced ability to mediate entry into two non-human primate (NHP)-derived cell lines relative to the GP of EBOV1976. Here, we investigated the molecular determinants underlying the differential entry efficiency. We found that EBOV2014-GP-driven entry into diverse NHP-derived cell lines as well as human monocyte-derived macrophages and dendritic cells was reduced as compared to EBOV1976-GP, although entry into most human- and all bat-derived cell lines tested was comparable. Moreover, EBOV2014 replication in NHP but not human cells was diminished relative to EBOV1976, suggesting that reduced cell entry translated into reduced viral spread. Mutagenic analysis of EBOV2014-GP and EBOV1976-GP revealed that an amino acid polymorphism in the receptor-binding domain, A82V, modulated entry efficiency in a cell line-independent manner and did not account for the reduced EBOV2014-GP-driven entry into NHP cells. In contrast, polymorphism T544I, located in the internal fusion loop in the GP2 subunit, was found to be responsible for the entry phenotype. These results suggest that position 544 is an important determinant of EBOV infectivity for NHP- and certain human target cells.IMPORTANCE The Ebola virus disease outbreak in West Africa in 2013 entailed more than 10,000 deaths. The scale of the outbreak and its dramatic impact on human health raised the question whether the responsible virus was particularly adept at infecting human cells. Our study shows that an amino acid exchange, A82V, that the virus acquired during the epidemic and that was not observed in previously circulating viruses, increases viral entry into diverse target cells. In contrast, the epidemic virus showed a reduced ability to enter cells of non-human primates as compared to the virus circulating in 1976 and a single amino acid exchange in the internal fusion loop of the viral glycoprotein was found to account for this phenotype.
2017-03-24T09:03:00Z
2017-03-24T09:03:00Z
2017-03-24T09:03:00Z
2017-02-22
Article
A polymorphism within the internal fusion loop of the Ebola virus glycoprotein modulates host cell entry. 2017 J. Virol.
1098-5514
28228590
10.1128/JVI.00177-17
http://hdl.handle.net/10033/620868
Journal of virology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208852019-08-30T11:36:04Zcom_10033_620601col_10033_620603
Seroprevalence of hepatitis B, hepatitis C, human immunodeficiency virus, Treponema pallidum, and co-infections among blood donors in Kyrgyzstan: a retrospective analysis (2013-2015).
Karabaev, Bakyt B
Beisheeva, Nurgul J
Satybaldieva, Aiganysh B
Ismailova, Aikul D
Pessler, Frank
Akmatov, Manas K
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Post-Soviet Kyrgyzstan has experienced a major surge in blood-borne infections, but data from adequately powered, up-to-date studies are lacking. We thus examined a) the seroprevalences of hepatitis B virus surface antigen (HBsAg), HIV-1 p24 antigen and antibodies against hepatitis C virus (anti-HCV), human immunodeficiency viruses (anti-HIV-1/2, HIV-1 group O), and Treponema pallidum among blood donors in Kyrgyzstan and assess their distribution according to sex, age, and provinces of residence; b) trends in the respective seroprevalences; and c) co-infection rates among the pathogens studied.
2017-04-04T14:01:28Z
2017-04-04T14:01:28Z
2017-04-04T14:01:28Z
2017-02-21
Article
Seroprevalence of hepatitis B, hepatitis C, human immunodeficiency virus, Treponema pallidum, and co-infections among blood donors in Kyrgyzstan: a retrospective analysis (2013-2015). 2017, 6 (1):45 Infect Dis Poverty
2049-9957
28222792
10.1186/s40249-017-0255-9
http://hdl.handle.net/10033/620885
Infectious diseases of poverty
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208922019-08-30T11:29:47Zcom_10033_267632com_10033_211390com_10033_620601col_10033_267633col_10033_211409col_10033_620603
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design.
Rübsamen, Nicole
Akmatov, Manas K
Castell, Stefanie
Karch, André
Mikolajczyk, Rafael T
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice).
2017-04-07T10:09:11Z
2017-04-07T10:09:11Z
2017-04-07T10:09:11Z
2017
Article
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design. 2017, 14:4 Emerg Themes Epidemiol
28344629
10.1186/s12982-017-0058-2
http://hdl.handle.net/10033/620892
Emerging themes in epidemiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208962019-08-30T11:29:47Zcom_10033_620601col_10033_620603
Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination.
Akmatov, Manas K
Jentsch, Leonhard
Riese, Peggy
May, Marcus
Ahmed, Malik W
Werner, Damaris
Rösel, Anja
Prokein, Jana
Bernemann, Inga
Klopp, Norman
Prochnow, Blair
Illig, Thomas
Schindler, Christoph
Guzman, Carlos A
Pessler, Frank
Twincore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Participation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly.
2017-04-13T13:15:22Z
2017-04-13T13:15:22Z
2017-04-13T13:15:22Z
2017-02-02
Article
Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination. 2017, 17 (1):18 BMC Med Res Methodol
1471-2288
28148221
10.1186/s12874-017-0302-z
http://hdl.handle.net/10033/620896
BMC medical research methodology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209222019-08-30T11:29:47Zcom_10033_620601com_10033_620533col_10033_621891col_10033_620603
Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study - findings from Pretest 1 of the German National Cohort.
Akmatov, Manas K
Koch, Nadine
Vital, Marius
Ahrens, Wolfgang
Flesch-Janys, Dieter
Fricke, Julia
Gatzemeier, Anja
Greiser, Halina
Günther, Kathrin
Illig, Thomas
Kaaks, Rudolf
Krone, Bastian
Kühn, Andrea
Linseisen, Jakob
Meisinger, Christine
Michels, Karin
Moebus, Susanne
Nieters, Alexandra
Obi, Nadia
Schultze, Anja
Six-Merker, Julia
Pieper, Dietmar H
Pessler, Frank
TWINCORE; Zentrum für experimentelle und klinische Infectionsforsching GmbH, Feodor-Lynen Str. 17, 30625 Hannover, Germany.
We examined acceptability, preference and feasibility of collecting nasal and oropharyngeal swabs, followed by microbiome analysis, in a population-based study with 524 participants. Anterior nasal and oropharyngeal swabs were collected by certified personnel. In addition, participants self-collected nasal swabs at home four weeks later. Four swab types were compared regarding (1) participants' satisfaction and acceptance and (2) detection of microbial community structures based on deep sequencing of the 16 S rRNA gene V1-V2 variable regions. All swabbing methods were highly accepted. Microbial community structure analysis revealed 846 phylotypes, 46 of which were unique to oropharynx and 164 unique to nares. The calcium alginate tipped swab was found unsuitable for microbiome determinations. Among the remaining three swab types, there were no differences in oropharyngeal microbiomes detected and only marginal differences in nasal microbiomes. Microbial community structures did not differ between staff-collected and self-collected nasal swabs. These results suggest (1) that nasal and oropharyngeal swabbing are highly feasible methods for human population-based studies that include the characterization of microbial community structures in these important ecological niches, and (2) that self-collection of nasal swabs at home can be used to reduce cost and resources needed, particularly when serial measurements are to be taken.
2017-05-17T12:45:45Z
2017-05-17T12:45:45Z
2017-05-17T12:45:45Z
2017-05-12
Article
Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study - findings from Pretest 1 of the German National Cohort. 2017, 7 (1):1855 Sci Rep
2045-2322
28500287
10.1038/s41598-017-01212-6
http://hdl.handle.net/10033/620922
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209412019-08-30T11:32:16Zcom_10033_620601col_10033_620602
Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration.
González-Motos, Víctor
Jürgens, Carina
Ritter, Birgit
Kropp, Kai A
Durán, Verónica
Larsen, Olav
Binz, Anne
Ouwendijk, Werner J D
Lenac Rovis, Tihana
Jonjic, Stipan
Verjans, Georges M G M
Sodeik, Beate
Krey, Thomas
Bauerfeind, Rudolf
Schulz, Thomas F
Kaufer, Benedikt B
Kalinke, Ulrich
Proudfoot, Amanda E I
Rosenkilde, Mette M
Viejo-Borbolla, Abel
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Varicella zoster virus (VZV) is a highly prevalent human pathogen that establishes latency in neurons of the peripheral nervous system. Primary infection causes varicella whereas reactivation results in zoster, which is often followed by chronic pain in adults. Following infection of epithelial cells in the respiratory tract, VZV spreads within the host by hijacking leukocytes, including T cells, in the tonsils and other regional lymph nodes, and modifying their activity. In spite of its importance in pathogenesis, the mechanism of dissemination remains poorly understood. Here we addressed the influence of VZV on leukocyte migration and found that the purified recombinant soluble ectodomain of VZV glycoprotein C (rSgC) binds chemokines with high affinity. Functional experiments show that VZV rSgC potentiates chemokine activity, enhancing the migration of monocyte and T cell lines and, most importantly, human tonsillar leukocytes at low chemokine concentrations. Binding and potentiation of chemokine activity occurs through the C-terminal part of gC ectodomain, containing predicted immunoglobulin-like domains. The mechanism of action of VZV rSgC requires interaction with the chemokine and signalling through the chemokine receptor. Finally, we show that VZV viral particles enhance chemokine-dependent T cell migration and that gC is partially required for this activity. We propose that VZV gC activity facilitates the recruitment and subsequent infection of leukocytes and thereby enhances VZV systemic dissemination in humans.
2017-06-12T12:27:43Z
2017-06-12T12:27:43Z
2017-06-12T12:27:43Z
2017-05
Article
Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration. 2017, 13 (5):e1006346 PLoS Pathog.
1553-7374
28542541
10.1371/journal.ppat.1006346
http://hdl.handle.net/10033/620941
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209972019-08-30T11:33:30Zcom_10033_620601col_10033_620602
A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle.
Matschulla, Tony
Berry, Richard
Gerke, Carolin
Döring, Marius
Busch, Julia
Paijo, Jennifer
Kalinke, Ulrich
Momburg, Frank
Hengel, Hartmut
Halenius, Anne
TWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The transporter associated with antigen processing (TAP) translocates antigenic peptides into the endoplasmic reticulum (ER) lumen for loading onto MHC class I molecules. This is a key step in the control of viral infections through CD8+ T-cells. The herpes simplex virus type-1 encodes an 88 amino acid long species-specific TAP inhibitor, ICP47, that functions as a high affinity competitor for the peptide binding site on TAP. It has previously been suggested that the inhibitory function of ICP47 resides within the N-terminal region (residues 1-35). Here we show that mutation of the highly conserved 50PLL52 motif within the central region of ICP47 attenuates its inhibitory capacity. Taking advantage of the human cytomegalovirus-encoded TAP inhibitor US6 as a luminal sensor for conformational changes of TAP, we demonstrated that the 50PLL52 motif is essential for freezing of the TAP conformation. Moreover, hierarchical functional interaction sites on TAP dependent on 50PLL52 could be defined using a comprehensive set of human-rat TAP chimeras. This data broadens our understanding of the molecular mechanism underpinning TAP inhibition by ICP47, to include the 50PLL52 sequence as a stabilizer that tethers the TAP-ICP47 complex in an inward-facing conformation.
2017-07-05T14:25:58Z
2017-07-05T14:25:58Z
2017-07-05T14:25:58Z
2017-06-07
Article
A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle. 2017, 7 (1):2933 Sci Rep
2045-2322
28592828
10.1038/s41598-017-02994-5
http://hdl.handle.net/10033/620997
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210072019-08-30T11:33:05Zcom_10033_620601col_10033_620602
Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.
Kindler, Eveline
Gil-Cruz, Cristina
Spanier, Julia
Li, Yize
Wilhelm, Jochen
Rabouw, Huib H
Züst, Roland
Hwang, Mihyun
V'kovski, Philip
Stalder, Hanspeter
Marti, Sabrina
Habjan, Matthias
Cervantes-Barragan, Luisa
Elliot, Ruth
Karl, Nadja
Gaughan, Christina
van Kuppeveld, Frank J M
Silverman, Robert H
Keller, Markus
Ludewig, Burkhard
Bergmann, Cornelia C
Ziebuhr, John
Weiss, Susan R
Kalinke, Ulrich
Thiel, Volker
TWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.
2017-07-11T13:43:29Z
2017-07-11T13:43:29Z
2017-07-11T13:43:29Z
2017-02
Article
Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication. 2017, 13 (2):e1006195 PLoS Pathog.
1553-7374
28158275
10.1371/journal.ppat.1006195
http://hdl.handle.net/10033/621007
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210102019-08-30T11:36:32Zcom_10033_620601com_10033_620589col_10033_620602col_10033_620590col_10033_620590
Immune protection against reinfection with nonprimate hepacivirus.
Pfaender, Stephanie
Walter, Stephanie
Grabski, Elena
Todt, Daniel
Bruening, Janina
Romero-Brey, Inés
Gather, Theresa
Brown, Richard J P
Hahn, Kerstin
Puff, Christina
Pfankuche, Vanessa M
Hansmann, Florian
Postel, Alexander
Becher, Paul
Thiel, Volker
Kalinke, Ulrich
Wagner, Bettina
Bartenschlager, Ralf
Baumgärtner, Wolfgang
Feige, Karsten
Pietschmann, Thomas
Cavalleri, Jessika M V
Steinmann, Eike
TWINCORE, Zentrum für experimentelle und klinische Infectionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Hepatitis C virus (HCV) displays a restricted host species tropism and only humans and chimpanzees are susceptible to infection. A robust immunocompetent animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control, and prophylactic vaccine development. The closest homolog of HCV is the equine nonprimate hepacivirus (NPHV), which shares similar features with HCV and thus represents an animal model to study hepacivirus infections in their natural hosts. We aimed to dissect equine immune responses after experimental NPHV infection and conducted challenge experiments to investigate immune protection against secondary NPHV infections. Horses were i.v. injected with NPHV containing plasma. Flow cytometric analysis was used to monitor immune cell frequencies and activation status. All infected horses became viremic after 1 or 2 wk and viremia could be detected in two horses for several weeks followed by a delayed seroconversion and viral clearance. Histopathological examinations of liver biopsies revealed mild, periportally accentuated infiltrations of lymphocytes, macrophages, and plasma cells with some horses displaying subclinical signs of hepatitis. Following viral challenge, an activation of equine immune responses was observed. Importantly, after a primary NPHV infection, horses were protected against rechallenge with the homologous as well as a distinct isolate with only minute amounts of circulating virus being detectable.
2017-07-13T11:52:32Z
2017-07-13T11:52:32Z
2017-07-13T11:52:32Z
2017-03-21
Article
Immune protection against reinfection with nonprimate hepacivirus. 2017, 114 (12):E2430-E2439 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
28275093
10.1073/pnas.1619380114
http://hdl.handle.net/10033/621010
Proceedings of the National Academy of Sciences of the United States of America
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210132019-08-30T11:26:13Zcom_10033_211390com_10033_620601com_10033_620652col_10033_620666col_10033_211409col_10033_620603
Anti-nuclear autoantibodies in the general German population: prevalence and lack of association with selected cardiovascular and metabolic disorders-findings of a multicenter population-based study.
Akmatov, Manas K
Röber, Nadja
Ahrens, Wolfgang
Flesch-Janys, Dieter
Fricke, Julia
Greiser, Halina
Günther, Kathrin
Kaaks, Rudolf
Kemmling, Yvonne
Krone, Bastian
Linseisen, Jakob
Meisinger, Christa
Moebus, Susanne
Obi, Nadia
Guzman, Carlos A
Conrad, Karsten
Pessler, Frank
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
We determined the prevalence of anti-nuclear autoantibodies (ANAs) in the German adult population and examined the association between ANAs and cardiovascular and metabolic disorders.
2017-07-14T13:15:38Z
2017-07-14T13:15:38Z
2017-07-14T13:15:38Z
2017-06-06
Article
Anti-nuclear autoantibodies in the general German population: prevalence and lack of association with selected cardiovascular and metabolic disorders-findings of a multicenter population-based study. 2017, 19 (1):127 Arthritis Res. Ther.
1478-6362
28587625
10.1186/s13075-017-1338-5
http://hdl.handle.net/10033/621013
Arthritis research & therapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
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
Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.
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.
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.
2017-08-01T13:20:36Z
2017-08-01T13:20:36Z
2017-08-01T13:20:36Z
2017-06-13
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210282019-08-30T11:34:48Zcom_10033_620601col_10033_620602
Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo.
Hirche, Christoph
Frenz, Theresa
Haas, Simon F
Döring, Marius
Borst, Katharina
Tegtmeyer, Pia-K
Brizic, Ilija
Jordan, Stefan
Keyser, Kirsten
Chhatbar, Chintan
Pronk, Eline
Lin, Shuiping
Messerle, Martin
Jonjic, Stipan
Falk, Christine S
Trumpp, Andreas
Essers, Marieke A G
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynnen Str. 7, 30625 Hannover, Germany.
Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute inflammatory stimuli in bone marrow donors can affect the reconstitution potential of bone marrow transplants.
2017-08-01T14:19:12Z
2017-08-01T14:19:12Z
2017-08-01T14:19:12Z
2017-06-13
Article
Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo. 2017, 19 (11):2345-2356 Cell Rep
2211-1247
28614719
10.1016/j.celrep.2017.05.063
http://hdl.handle.net/10033/621028
Cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210372019-08-30T11:31:23Zcom_10033_620601com_10033_620652col_10033_620666col_10033_620602
Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway.
Lirussi, Darío
Ebensen, Thomas
Schulze, Kai
Trittel, Stephanie
Duran, Veronica
Liebich, Ines
Kalinke, Ulrich
Guzmán, Carlos Alberto
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
Cyclic di-nucleotides (CDN) are potent stimulators of innate and adaptive immune responses. Cyclic di-AMP (CDA) is a promising adjuvant that generates humoral and cellular immunity. The strong STING-dependent stimulation of type I IFN represents a key feature of CDA. However, recent studies suggested that this is dispensable for adjuvanticity. Here we demonstrate that stimulation of IFN-γ-secreting CD8(+) cytotoxic T lymphocytes (CTL) is significantly decreased after vaccination in the absence of type I IFN signaling. The biological significance of this CTL response was confirmed by the stimulation of MHC class I-restricted protection against influenza virus challenge. We show here that type I IFN (and not TNF-α) is essential for CDA-mediated cross-presentation by a cathepsin independent, TAP and proteosome dependent cytosolic antigen processing pathway, which promotes effective cross-priming and further CTL induction. Our data clearly demonstrate that type I IFN signaling is critical for CDN-mediated cross-presentation.
2017-08-03T13:05:38Z
2017-08-03T13:05:38Z
2017-08-03T13:05:38Z
2017-07-19
Article
Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway. 2017 EBioMedicine
2352-3964
28754303
10.1016/j.ebiom.2017.07.016
http://hdl.handle.net/10033/621037
EBioMedicine
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210652019-08-30T11:27:16Zcom_10033_620601col_10033_620602
Development of the First World Health Organization Lentiviral Vector Standard: Toward the Production Control and Standardization of Lentivirus-Based Gene Therapy Products.
Zhao, Yuan
Stepto, Hannah
Schneider, Christian K
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Gene therapy is a rapidly evolving field. So far, there have been >2,400 gene therapy products in clinical trials and four products on the market. A prerequisite for producing gene therapy products is ensuring their quality and safety. This requires appropriately controlled and standardized production and testing procedures that result in consistent safety and efficacy. Assuring the quality and safety of lentivirus-based gene therapy products in particular presents a great challenge because they are cell-based multigene products that include viral and therapeutic proteins as well as modified cells. In addition to the continuous refinement of a product, changes in production sites and manufacturing processes have become more and more common, posing challenges to developers regarding reproducibility and comparability of results. This paper discusses the concept of developing a first World Health Organization International Standard, suitable for the standardization of assays and enabling comparison of cross-trial and cross-manufacturing results for this important vector platform. The standard will be expected to optimize the development of gene therapy medicinal products, which is especially important, given the usually orphan nature of the diseases to be treated, naturally hampering reproducibility and comparability of results.
2017-08-21T09:16:34Z
2017-08-21T09:16:34Z
2017-08-21T09:16:34Z
2017-08
Article
Development of the First World Health Organization Lentiviral Vector Standard: Toward the Production Control and Standardization of Lentivirus-Based Gene Therapy Products. 2017, 28 (4):205-214 Hum Gene Ther Methods
1946-6544
28747142
10.1089/hgtb.2017.078
http://hdl.handle.net/10033/621065
Human gene therapy methods
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210712019-08-30T11:27:16Zcom_10033_620626com_10033_620601col_10033_620627col_10033_620603
Host Genetic Background Strongly Affects Pulmonary microRNA Expression before and during Influenza A Virus Infection.
Preusse, Matthias
Schughart, Klaus
Pessler, Frank
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.
2017-08-22T14:00:30Z
2017-08-22T14:00:30Z
2017-08-22T14:00:30Z
2017
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211892019-08-30T11:33:57Zcom_10033_620601col_10033_620602
Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection.
Ivin, Masa
Dumigan, Amy
de Vasconcelos, Filipe N
Ebner, Florian
Borroni, Martina
Kavirayani, Anoop
Przybyszewska, Kornelia N
Ingram, Rebecca J
Lienenklaus, Stefan
Kalinke, Ulrich
Stoiber, Dagmar
Bengoechea, Jose A
Kovarik, Pavel
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7 30625 Hannover, Germany.
Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in Ifnar1-deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of Ifnar1-deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations.
2017-11-29T15:45:30Z
2017-11-29T15:45:30Z
2017-11-29T15:45:30Z
2017-11
Article
Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection. 2017, 13 (11):e1006696 PLoS Pathog.
1553-7374
29112952
10.1371/journal.ppat.1006696
http://hdl.handle.net/10033/621189
PLoS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212082019-08-30T11:28:23Zcom_10033_620601col_10033_620602
RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury.
Fischer, Julius C
Bscheider, Michael
Eisenkolb, Gabriel
Lin, Chia-Ching
Wintges, Alexander
Otten, Vera
Lindemans, Caroline A
Heidegger, Simon
Rudelius, Martina
Monette, Sébastien
Porosnicu Rodriguez, Kori A
Calafiore, Marco
Liebermann, Sophie
Liu, Chen
Lienenklaus, Stefan
Weiss, Siegfried
Kalinke, Ulrich
Ruland, Jürgen
Peschel, Christian
Shono, Yusuke
Docampo, Melissa
Velardi, Enrico
Jenq, Robert R
Hanash, Alan M
Dudakov, Jarrod A
Haas, Tobias
van den Brink, Marcel R M
Poeck, Hendrik
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.
2017-12-18T13:51:01Z
2017-12-18T13:51:01Z
2017-12-18T13:51:01Z
2017-04-19
Article
RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. 2017, 9 (386) Sci Transl Med
1946-6242
28424327
10.1126/scitranslmed.aag2513
http://hdl.handle.net/10033/621208
Science translational medicine
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212132019-01-03T07:58:16Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori
Filomena, Angela
Pessler, Frank
Akmatov, Manas K
Krause, Gérard
Duffy, Darragh
Gärtner, Barbara
Gerhard, Markus
Albert, Matthew
Joos, Thomas
Schneiderhan-Marra, Nicole
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-12-20T14:12:08Z
2017-12-20T14:12:08Z
2017-12-20T14:12:08Z
2017-10-30
Article
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori 2017, 6 (4):14 High-Throughput
2571-5135
29855458
10.3390/ht6040014
http://hdl.handle.net/10033/621213
High-Throughput
http://www.mdpi.com/2571-5135/6/4/14
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212162021-07-06T12:05:05Zcom_10033_620652com_10033_620601com_10033_620591com_10033_622921col_10033_620725col_10033_620666col_10033_622926col_10033_620602
Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver.
Volckmar, Julia
Gereke, Marcus
Ebensen, Thomas
Riese, Peggy
Philipsen, Lars
Lienenklaus, Stefan
Wohlleber, Dirk
Klopfleisch, Robert
Stegemann-Koniszewski, Sabine
Müller, Andreas J
Gruber, Achim D
Knolle, Percy
Guzman, Carlos A
Bruder, Dunja
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.
2018-01-02T13:05:22Z
2018-01-02T13:05:22Z
2018-01-02T13:05:22Z
2017-03-07
Article
Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver. 2017, 7:43985 Sci Rep
2045-2322
28266658
10.1038/srep43985
http://hdl.handle.net/10033/621216
Scientific reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212202019-08-30T11:25:11Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
Hepatitis B vaccination timing: results from demographic health surveys in 47 countries.
Schweitzer, Aparna
Akmatov, Manas K
Krause, Gerard
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
To examine the impact of hepatitis B vaccination schedules and types of vaccines on hepatitis B vaccination timing.
2018-01-03T08:52:06Z
2018-01-03T08:52:06Z
2018-01-03T08:52:06Z
2017-03-01
Article
Hepatitis B vaccination timing: results from demographic health surveys in 47 countries. 2017, 95 (3):199-209G Bull. World Health Organ.
1564-0604
28250533
10.2471/BLT.16.178822
http://hdl.handle.net/10033/621220
Bulletin of the World Health Organization
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212212019-08-30T11:35:13Zcom_10033_620601col_10033_620603
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus.
De Jaime-Soguero, Anchel
Aulicino, Francesco
Ertaylan, Gokhan
Griego, Anna
Cerrato, Aniello
Tallam, Aravind
Del Sol, Antonio
Cosma, Maria Pia
Lluis, Frederic
TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Understanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naïve pluripotency by holding back differentiation. The canonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/β-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of β-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors.
2018-01-03T09:14:00Z
2018-01-03T09:14:00Z
2018-01-03T09:14:00Z
2017-03
Article
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. 2017, 13 (3):e1006682 PLoS Genet.
1553-7404
28346462
10.1371/journal.pgen.1006682
http://hdl.handle.net/10033/621221
PLoS genetics
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212432019-08-30T11:35:39Zcom_10033_620636com_10033_620601col_10033_620665col_10033_620602
cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice.
Ruangkiattikul, Nanthapon
Nerlich, Andreas
Abdissa, Ketema
Lienenklaus, Stefan
Suwandi, Abdulhadi
Janze, Nina
Laarmann, Kristin
Spanier, Julia
Kalinke, Ulrich
Weiss, Siegfried
Goethe, Ralph
TWNCORe, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynnen-Str. 7, 30625 Hannover, Germany.
Type I interferons (IFN-I), such as IFN-α and IFN-β are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-β than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focused on the obligate pathogen Mycobacterium avium ssp paratuberculosis (MAP) and the opportunistic M. smegmatis. Viability of both bacteria was required for induction of IFN-β in macrophages. Both bacteria induced IFN-β via the cGAS-STING-TBK1-IRF3/7-pathway of IFN-β activation. Stronger phosphorylation of TBK1 and higher amounts of extracellular bacterial DNA in the macrophage cytosol were found in M. smegmatis infected macrophages than in MAP infected macrophages. After intraperitoneal infection of mice, a strong Ifnb induction by M. smegmatis correlated with clearance of the bacteria. In contrast, MAP only induced weak Ifnb expression which correlated with bacterial persistence and increased number of granulomas in the liver. In mice lacking the type I interferon receptor we observed improved survival of M. smegmatis while survival of MAP was similar to that in wildtype mice. On the other hand, treatment of MAP infected wildtype mice with the IFN-I inducer poly(I:C) or recombinant IFN-β impaired the survival of MAP. This indicates an essential role of IFN-I in clearing infections by MAP and M. smegmatis. The expression level of IFN-I is decisive for transient versus persistent NTM infection.
2018-01-19T10:35:48Z
2018-01-19T10:35:48Z
2018-01-19T10:35:48Z
2017-10-03
Article
cGAS-STING-TBK1-IRF3/7 induced interferon-β contributes to the clearing of non tuberculous mycobacterial infection in mice. 2017, 8 (7):1303-1315 Virulence
2150-5608
28422568
10.1080/21505594.2017.1321191
http://hdl.handle.net/10033/621243
Virulence
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212472019-08-30T11:31:49Zcom_10033_620601col_10033_620602
Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.
Neehus, Anna-Lena
Lam, Jenny
Haake, Kathrin
Merkert, Sylvia
Schmidt, Nico
Mucci, Adele
Ackermann, Mania
Schubert, Madline
Happle, Christine
Kühnel, Mark Philipp
Blank, Patrick
Philipp, Friederike
Goethe, Ralph
Jonigk, Danny
Martin, Ulrich
Kalinke, Ulrich
Baumann, Ulrich
Schambach, Axel
Roesler, Joachim
Lachmann, Nico
TWiNCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany.
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNγR1 deficiency and received bone-marrow transplantation. Loss of IFNγR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNγR1 in iMSMD-cohet macrophages abolished IFNγ-dependent phosphorylation of STAT1 and induction of IFNγ-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNγ signaling in macrophages.
2018-01-22T09:13:41Z
2018-01-22T09:13:41Z
2018-01-22T09:13:41Z
2018-01-09
Article
Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages. 2018, 10 (1):7-16 Stem Cell Reports
2213-6711
29249666
10.1016/j.stemcr.2017.11.011
http://hdl.handle.net/10033/621247
Stem cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213032019-08-30T11:26:42Zcom_10033_620601col_10033_620602
Coadministration of a Plasmid Encoding HIV-1 Gag Enhances the Efficacy of Cancer DNA Vaccines.
Lambricht, Laure
Vanvarenberg, Kevin
De Beuckelaer, Ans
Van Hoecke, Lien
Grooten, Johan
Ucakar, Bernard
Lipnik, Pascale
Sanders, Niek N
Lienenklaus, Stefan
Préat, Véronique
Vandermeulen, Gaëlle
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
DNA vaccination holds great promise for the prevention and treatment of cancer and infectious diseases. However, the clinical ability of DNA vaccines is still controversial due to the limited immune response initially observed in humans. We hypothesized that electroporation of a plasmid encoding the HIV-1 Gag viral capsid protein would enhance cancer DNA vaccine potency. DNA electroporation used to deliver plasmids in vivo, induced type I interferons, thereby supporting the activation of innate immunity. The coadministration of ovalbumin (OVA) and HIV-1 Gag encoding plasmids modulated the adaptive immune response. This strategy favored antigen-specific Th1 immunity, delayed B16F10-OVA tumor growth and improved mouse survival in both prophylactic and therapeutic vaccination approaches. Similarly, a prophylactic DNA immunization against the melanoma-associated antigen gp100 was enhanced by the codelivery of the HIV-1 Gag plasmid. The adjuvant effect was not driven by the formation of HIV-1 Gag virus-like particles. This work highlights the ability of both electroporation and the HIV-1 Gag plasmid to stimulate innate immunity for enhancing cancer DNA vaccine immunogenicity and demonstrates interesting tracks for the design of new translational genetic adjuvants to overcome the current limitations of DNA vaccines in humans.
2018-03-02T15:43:27Z
2018-03-02T15:43:27Z
2018-03-02T15:43:27Z
2016
Article
Coadministration of a Plasmid Encoding HIV-1 Gag Enhances the Efficacy of Cancer DNA Vaccines. 2016, 24 (9):1686-96 Mol. Ther.
1525-0024
27434590
10.1038/mt.2016.122
http://hdl.handle.net/10033/621303
Molecular therapy : the journal of the American Society of Gene Therapy
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213042019-08-30T11:26:42Zcom_10033_620601col_10033_620602
Type I interferon promotes alveolar epithelial type II cell survival during pulmonary Streptococcus pneumoniae infection and sterile lung injury in mice.
Maier, Barbara B
Hladik, Anastasiya
Lakovits, Karin
Korosec, Ana
Martins, Rui
Kral, Julia B
Mesteri, Ildiko
Strobl, Birgit
Müller, Mathias
Kalinke, Ulrich
Merad, Miriam
Knapp, Sylvia
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Protecting the integrity of the lung epithelial barrier is essential to ensure respiration and proper oxygenation in patients suffering from various types of lung inflammation. Type I interferon (IFN-I) has been associated with pulmonary epithelial barrier function, however, the mechanisms and involved cell types remain unknown. We aimed to investigate the importance of IFN-I with respect to its epithelial barrier strengthening function to better understand immune-modulating effects in the lung with potential medical implications. Using a mouse model of pneumococcal pneumonia, we revealed that IFN-I selectively protects alveolar epithelial type II cells (AECII) from inflammation-induced cell death. Mechanistically, signaling via the IFN-I receptor on AECII is sufficient to promote AECII survival. The net effects of IFN-I are barrier protection, together with diminished tissue damage, inflammation, and bacterial loads. Importantly, we found that the protective role of IFN-I can also apply to sterile acute lung injury, in which loss of IFN-I signaling leads to a significant reduction in barrier function caused by AECII cell death. Our data suggest that IFN-I is an important mediator in lung inflammation that plays a protective role by antagonizing inflammation-associated cell obstruction, thereby strengthening the integrity of the epithelial barrier.
2018-03-05T15:17:58Z
2018-03-05T15:17:58Z
2018-03-05T15:17:58Z
2016
Article
Type I interferon promotes alveolar epithelial type II cell survival during pulmonary Streptococcus pneumoniae infection and sterile lung injury in mice. 2016, 46 (9):2175-86 Eur. J. Immunol.
1521-4141
27312374
10.1002/eji.201546201
http://hdl.handle.net/10033/621304
European journal of immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213242019-08-30T11:37:00Zcom_10033_620601col_10033_620602
Personalized adoptive immunotherapy for patients with EBV-associated tumors and complications: Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes.
Bieling, Maren
Tischer, Sabine
Kalinke, Ulrich
Blasczyk, Rainer
Buus, Søren
Maecker-Kolhoff, Britta
Eiz-Vesper, Britta
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Morbidity and mortality of immunocompromised patients are increased by primary infection with or reactivation of Epstein-Barr virus (EBV), possibly triggering EBV+post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of EBV-specific cytotoxic T cells (EBV-CTLs) promises a non-toxic immunotherapy to effectively prevent or treat these complications. To improve immunotherapy and immunomonitoring this study aimed at identifying and evaluating naturally processed and presented HLA-A*03:01-restricted EBV-CTL epitopes as immunodominant targets. More than 15000 peptides were sequenced from EBV-immortalized B cells transduced with soluble HLA-A*03:01, sorted using different epitope prediction tools and eleven candidates were preselected. T2 and Flex-T peptide-binding and dissociation assays confirmed the stability of peptide-MHC complexes. Their immunogenicity and clinical relevance were evaluated by assessing the frequencies and functionality of EBV-CTLs in healthy donors (n> 10) and EBV+PTLD-patients (n= 5) by multimer staining, Eli- and FluoroSpot assays. All eleven peptides elicited EBV-CTL responses in the donors. Their clinical applicability was determined by small-scale T-cell enrichment using Cytokine Secretion Assay and immunophenotyping. Mixtures of these peptides when added to the EBV Consensus pool revealed enhanced stimulation and enrichment efficacy. These EBV-specific epitopes broadening the repertoire of known targets will improve manufacturing of clinically applicable EBV-CTLs and monitoring of EBV-specific T-cell responses in patients.
2018-03-19T15:18:28Z
2018-03-19T15:18:28Z
2018-03-19T15:18:28Z
2018-01-12
Article
Personalized adoptive immunotherapy for patients with EBV-associated tumors and complications: Evaluation of novel naturally processed and presented EBV-derived T-cell epitopes. 2018, 9 (4):4737-4757 Oncotarget
1949-2553
29435138
10.18632/oncotarget.23531
http://hdl.handle.net/10033/621324
Oncotarget
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213352019-08-30T11:33:30Zcom_10033_620601col_10033_620602
Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections.
Hetzel, Miriam
Mucci, Adele
Blank, Patrick
Nguyen, Ariane Hai Ha
Schiller, Jan
Halle, Olga
Kühnel, Mark-Philipp
Billig, Sandra
Meineke, Robert
Brand, Daniel
Herder, Vanessa
Baumgärtner, Wolfgang
Bange, Franz-Christoph
Goethe, Ralph
Jonigk, Danny
Förster, Reinhold
Gentner, Bernhard
Casanova, Jean-Laurent
Bustamante, Jacinta
Schambach, Axel
Kalinke, Ulrich
Lachmann, Nico
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1orIFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-γ) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that expressIfnγr1either constitutively or myeloid specifically. Transduction of mouseIfnγr1 -/- HSCs led to stable IFNγR1 expression on macrophages, which rescued their cellular responses to IFN-γ. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity againstMycobacterium aviumandMycobacterium bovisBacille Calmette-Guérin (BCG) in vitro. Transplantation of genetically corrected HSCs intoIfnγr1-/-mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNγR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients.
2018-04-03T14:07:47Z
2018-04-03T14:07:47Z
2018-04-03T14:07:47Z
2018-02-01
Article
Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. 2018, 131 (5):533-545 Blood
1528-0020
29233822
10.1182/blood-2017-10-812859
http://hdl.handle.net/10033/621335
Blood
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213412019-08-30T11:34:22Zcom_10033_620659com_10033_620601col_10033_620661col_10033_620603
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck).
Samir, M
Hamed, M
Abdallah, F
Kinh Nguyen, V
Hernandez-Vargas, E A
Seehusen, F
Baumgärtner, W
Hussein, A
Ali, A A H
Pessler,, F
TWINCORE, Zentrum für experimentelle uns klinische Ifektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to cause major problems in poultry and can, although rarely, cause human infection. Being enzootic in domestic poultry, Egyptian isolates are continuously evolving, and novel clades vary in their pathogenicity in avian hosts. Considering the importance of domestic ducks as natural hosts of HPAI H5N1 viruses and their likelihood of physical contact with other avian hosts and humans, it is of utmost importance to characterize the pathogenicity of newly emerged HPAI strains in the domestic duck. The most recently identified Egyptian clade 2.2.1.2 HPAI H5N1 viruses have been isolated from naturally infected pigeons, turkeys and humans. However, essentially nothing is known about their pathogenicity in domestic ducks. We therefore characterized the pathogenicity of an Egyptian HPAI H5N1 isolate A/chicken/Faquos/amn12/2011 (clade 2.2.1.2) in Sudani duck, a domestic duck breed commonly reared in Egypt. While viral transcription (HA mRNA) was highest in lung, heart and kidney peaking between 40 and 48 hpi, lower levels were detected in brain. Weight loss of infected ducks started at 16 hpi and persisted until 120 hpi. The first severe clinical signs were noted by 32 hpi and peaked in severity at 72 and 96 hpi. Haematological analyses showed a decline in total leucocytes, granulocytes, platelets and granulocyte/lymphocyte ratio, but lymphocytosis. Upon necropsy, lesions were obvious in heart, liver, spleen and pancreas and consisted mainly of necrosis and petechial haemorrhage. Histologically, lungs were the most severely affected organs, whereas brain only showed mild neuronal degeneration and gliosis at 48 hpi despite obvious neurological clinical signs. Taken together, our results provide first evidence that this HPAI H5N1 isolate (clade 2.2.1.2) is highly pathogenic to Sudani ducks and highlight the importance of this breed as potential reservoir and disseminator of HPAI strains from this clade.
2018-04-10T08:09:30Z
2018-04-10T08:09:30Z
2018-04-10T08:09:30Z
2018-01-24
Article
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck). 2018 Transbound Emerg Dis
1865-1682
29363279
10.1111/tbed.12816
http://hdl.handle.net/10033/621341
Transboundary and emerging diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213422019-08-30T11:30:31Zcom_10033_620601col_10033_620602
Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis.
Waltl, Inken
Käufer, Christopher
Bröer, Sonja
Chhatbar, Chintan
Ghita, Luca
Gerhauser, Ingo
Anjum, Muneeb
Kalinke, Ulrich
Löscher, Wolfgang
TWINCORE, Zentrum für experimentelle uns klinische Ifektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Viral encephalitis is a major risk factor for the development of seizures and epilepsy, but the underlying mechanisms are only poorly understood. Mouse models such as viral encephalitis induced by intracerebral infection with Theiler's virus in C57BL/6 (B6) mice allow advancing our understanding of the immunological and virological aspects of infection-induced seizures and their treatment. Previous studies using the Theiler's virus model in B6 mice have indicated that brain-infiltrating inflammatory macrophages and the cytokines released by these cells are key to the development of acute seizures and hippocampal damage in this model. However, approaches used to prevent or reduce macrophage infiltration were not specific, so contribution of other mechanisms could not be excluded. In the present study, we used a more selective and widely used approach for macrophage depletion, i.e., systemic administration of clodronate liposomes, to study the contribution of macrophage infiltration to development of seizures and hippocampal damage. By this approach, almost complete depletion of monocytic cells was achieved in spleen and blood of Theiler's virus infected B6 mice, which was associated with a 70% decrease in the number of brain infiltrating macrophages as assessed by flow cytometry. Significantly less clodronate liposome-treated mice exhibited seizures than liposome controls (P<0.01), but the development of hippocampal damage was not prevented or reduced. Clodronate liposome treatment did not reduce the increased Iba1 and Mac3 labeling in the hippocampus of infected mice, indicating that activated microglia may contribute to hippocampal damage. The unexpected mismatch between occurrence of seizures and hippocampal damage is thought-provoking and suggests that the mechanisms involved in degeneration of specific populations of hippocampal neurons in encephalitis-induced epilepsy are more complex than previously thought.
2018-04-11T08:42:05Z
2018-04-11T08:42:05Z
2018-04-11T08:42:05Z
2018-02
Article
Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis. 2018, 110:192-205 Neurobiol. Dis.
1095-953X
29208406
10.1016/j.nbd.2017.12.001
http://hdl.handle.net/10033/621342
Neurobiology of disease
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213482019-08-30T11:33:29Zcom_10033_620601col_10033_620602
Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells.
Vendelova, Emilia
Ashour, Diyaaeldin
Blank, Patrick
Erhard, Florian
Saliba, Antoine-Emmanuel
Kalinke, Ulrich
Lutz, Manfred B
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host's T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.
2018-04-12T13:31:17Z
2018-04-12T13:31:17Z
2018-04-12T13:31:17Z
2018
Article
Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells. 2018, 9:333 Front Immunol
1664-3224
29541071
10.3389/fimmu.2018.00333
http://hdl.handle.net/10033/621348
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213492019-08-30T11:25:11Zcom_10033_620601com_10033_311308col_10033_620721col_10033_620603
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation.
Kuhn, Maike
Sühs, Kurt-Wolfram
Akmatov, Manas K
Klawonn, Frank
Wang, Junxi
Skripuletz, Thomas
Kaever, Volkhard
Stangel, Martin
Pessler, Frank
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Varicella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation.
2018-04-12T13:50:11Z
2018-04-12T13:50:11Z
2018-04-12T13:50:11Z
2018-01-17
Article
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. 2018, 15 (1):20 J Neuroinflammation
1742-2094
29343258
10.1186/s12974-017-1041-0
http://hdl.handle.net/10033/621349
Journal of neuroinflammation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213502019-08-30T11:33:29Zcom_10033_620636com_10033_620601col_10033_620665col_10033_620602
Type I Interferon Signaling Is Required for CpG-Oligodesoxynucleotide-Induced Control of Leishmania major, but Not for Spontaneous Cure of Subcutaneous Primary or Secondary L. major Infection.
Schleicher, Ulrike
Liese, Jan
Justies, Nicole
Mischke, Thomas
Haeberlein, Simone
Sebald, Heidi
Kalinke, Ulrich
Weiss, Siegfried
Bogdan, Christian
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
We previously showed that in mice infected with Leishmania major type I interferons (IFNs) initiate the innate immune response to the parasite at day 1 and 2 of infection. Here, we investigated which type I IFN subtypes are expressed during the first 8 weeks of L. major infection and whether type I IFNs are essential for a protective immune response and clinical cure of the disease. In self-healing C57BL/6 mice infected with a high dose of L. major, IFN-α4, IFN-α5, IFN-α11, IFN-α13, and IFN-β mRNA were most prominently regulated during the course of infection. In C57BL/6 mice deficient for IFN-β or the IFN-α/β-receptor chain 1 (IFNAR1), development of skin lesions and parasite loads in skin, draining lymph node, and spleen was indistinguishable from wild-type (WT) mice. In line with the clinical findings, C57BL/6 IFN-β-/-, IFNAR1-/-, and WT mice exhibited similar mRNA expression levels of IFN-γ, interleukin (IL)-4, IL-12, IL-13, inducible nitric oxide synthase, and arginase 1 during the acute and late phase of the infection. Also, myeloid dendritic cells from WT and IFNAR1-/- mice produced comparable amounts of IL-12p40/p70 protein upon exposure to L. major in vitro. In non-healing BALB/c WT mice, the mRNAs of IFN-α subtypes (α2, α4, α5, α6, and α9) were rapidly induced after high-dose L. major infection. However, genetic deletion of IFNAR1 or IFN-β did not alter the progressive course of infection seen in WT BALB/c mice. Finally, we tested whether type I IFNs and/or IL-12 are required for the prophylactic effect of CpG-oligodesoxynucleotides (ODN) in BALB/c mice. Local and systemic administration of CpG-ODN 1668 protected WT and IFN-β-/- mice equally well from progressive leishmaniasis. By contrast, the protective effect of CpG-ODN 1668 was lost in BALB/c IFNAR1-/- (despite a sustained suppression of IL-4) and in BALB/c IL-12p35-/- mice. From these data, we conclude that IFN-β and IFNAR1 signaling are dispensable for a curative immune response to L. major in C57BL/6 mice and irrelevant for disease development in BALB/c mice, whereas IL-12 and IFN-α subtypes are essential for the disease prevention by CpG-ODNs in this mouse strain.
2018-04-12T14:07:23Z
2018-04-12T14:07:23Z
2018-04-12T14:07:23Z
2018
Article
Type I Interferon Signaling Is Required for CpG-Oligodesoxynucleotide-Induced Control of Leishmania major, but Not for Spontaneous Cure of Subcutaneous Primary or Secondary L. major Infection. 2018, 9:79 Front Immunol
1664-3224
29459858
10.3389/fimmu.2018.00079
http://hdl.handle.net/10033/621350
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213612019-08-30T11:34:48Zcom_10033_620601col_10033_620602
Application of light sheet microscopy for qualitative and quantitative analysis of bronchus-associated lymphoid tissue in mice.
Mzinza, David Twapokera
Fleige, Henrike
Laarmann, Kristin
Willenzon, Stefanie
Ristenpart, Jasmin
Spanier, Julia
Sutter, Gerd
Kalinke, Ulrich
Valentin-Weigand, Peter
Förster, Reinhold
TWINCORE, Zentrum für experimentelle uns klinische Ifektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Bronchus-associated lymphoid tissue (BALT) develops at unpredictable locations around lung bronchi following pulmonary inflammation. The formation and composition of BALT have primarily been investigated by immunohistology that, due to the size of the invested organ, is usually restricted to a limited number of histological sections. To assess the entire BALT of the lung, other approaches are urgently needed. Here, we introduce a novel light sheet microscopy-based approach for assessing lymphoid tissue in the lung. Using antibody staining of whole lung lobes and optical clearing by organic solvents, we present a method that allows in-depth visualization of the entire bronchial tree, the lymphatic vasculature and the immune cell composition of the induced BALT. Furthermore, three-dimensional analysis of the entire lung allows the qualitative and quantitative enumeration of the induced BALT. Using this approach, we show that a single intranasal application of the replication-deficient poxvirus MVA induces BALT that constitutes up to 8% of the entire lung volume in mice deficient in CCR7, in contrast to wild type mice (WT). Furthermore, BALT induced by heat-inactivated E. coli is dominated by a pronounced T cell infiltration in Cxcr5-deficient mice, in contrast to WT mice.Cellular and Molecular Immunology advance online publication, 12 February 2018; doi:10.1038/cmi.2017.150.
2018-04-24T14:18:51Z
2018-04-24T14:18:51Z
2018-04-24T14:18:51Z
2018-02-12
Article
Application of light sheet microscopy for qualitative and quantitative analysis of bronchus-associated lymphoid tissue in mice. 2018 Cell. Mol. Immunol.
2042-0226
29429996
10.1038/cmi.2017.150
http://hdl.handle.net/10033/621361
Cellular & molecular immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213732019-08-30T11:33:29Zcom_10033_620601col_10033_620603
Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture.
Olmer, Ruth
Engels, Lena
Usman, Abdulai
Menke, Sandra
Malik, Muhammad Nasir Hayat
Pessler, Frank
Göhring, Gudrun
Bornhorst, Dorothee
Bolten, Svenja
Abdelilah-Seyfried, Salim
Scheper, Thomas
Kempf, Henning
Zweigerdt, Robert
Martin, Ulrich
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Endothelial cells (ECs) are involved in a variety of cellular responses. As multifunctional components of vascular structures, endothelial (progenitor) cells have been utilized in cellular therapies and are required as an important cellular component of engineered tissue constructs and in vitro disease models. Although primary ECs from different sources are readily isolated and expanded, cell quantity and quality in terms of functionality and karyotype stability is limited. ECs derived from human induced pluripotent stem cells (hiPSCs) represent an alternative and potentially superior cell source, but traditional culture approaches and 2D differentiation protocols hardly allow for production of large cell numbers. Aiming at the production of ECs, we have developed a robust approach for efficient endothelial differentiation of hiPSCs in scalable suspension culture. The established protocol results in relevant numbers of ECs for regenerative approaches and industrial applications that show in vitro proliferation capacity and a high degree of chromosomal stability.
2018-05-16T12:56:46Z
2018-05-16T12:56:46Z
2018-05-16T12:56:46Z
2018-05-08
Article
Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture. 2018, 10 (5):1657-1672 Stem Cell Reports
2213-6711
29681541
10.1016/j.stemcr.2018.03.017
http://hdl.handle.net/10033/621373
Stem cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213922019-08-30T11:26:37Zcom_10033_620626com_10033_620601col_10033_620629col_10033_620603
Early Lymphocyte Loss and Increased Granulocyte/Lymphocyte Ratio Predict Systemic Spread of in a Mouse Model of Acute Skin Infection.
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.
Streptococcus pyogenes
biomarker
leukocytes
lymphopenia
sepsis
skin infection
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.
2018-06-05T12:52:50Z
2018-06-05T12:52:50Z
2018-06-05T12:52:50Z
Article
29707522
http://hdl.handle.net/10033/621392
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
oai:repository.helmholtz-hzi.de:10033/6214322019-08-30T11:25:41Zcom_10033_620601com_10033_620652col_10033_620672col_10033_620602
Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis.
Borst, Katharina
Frenz, Theresa
Spanier, Julia
Tegtmeyer, Pia-Katharina
Chhatbar, Chintan
Skerra, Jennifer
Ghita, Luca
Namineni, Sukumar
Lienenklaus, Stefan
Köster, Mario
Heikenwaelder, Mathias
Sutter, Gerd
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
DNA virus infection
Innate immunity
Liver inflammation
Monocyte infiltration
Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-β induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1 VACV infection induced local IFN-β responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis.
2018-07-31T12:49:10Z
2018-07-31T12:49:10Z
2018-07-31T12:49:10Z
2017-12-21
Article
1600-0641
29274730
10.1016/j.jhep.2017.11.029
http://hdl.handle.net/10033/621432
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Journal of hepatology
oai:repository.helmholtz-hzi.de:10033/6214392019-08-30T11:34:45Zcom_10033_311624com_10033_6839com_10033_620601com_10033_620652col_10033_620672col_10033_311625col_10033_620602
Identification of a Predominantly Interferon-λ-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells.
Selvakumar, Tharini A
Bhushal, Sudeep
Kalinke, Ulrich
Wirth, Dagmar
Hauser, Hansjörg
Köster, Mario
Hornef, Mathias W
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
gastrointestinal tract
interferon-lambda
interleukin 28 receptor
intestinal epithelium
transcription
Type I (α and β) and type III (λ) interferons (IFNs) induce the expression of a large set of antiviral effector molecules
2018-08-07T11:47:28Z
2018-08-07T11:47:28Z
2018-08-07T11:47:28Z
2017-01-01
Article
1664-3224
29085367
10.3389/fimmu.2017.01302
http://hdl.handle.net/10033/621439
en
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6214532019-08-30T11:29:14Zcom_10033_620601col_10033_620603
NS Segment of a 1918 Influenza A Virus-Descendent Enhances Replication of H1N1pdm09 and Virus-Induced Cellular Immune Response in Mammalian and Avian Systems.
Petersen, Henning
Mostafa, Ahmed
Tantawy, Mohamed A
Iqbal, Azeem A
Hoffmann, Donata
Tallam, Aravind
Selvakumar, Balachandar
Pessler, Frank
Beer, Martin
Rautenschlein, Silke
Pleschka, Stephan
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
H1N1pdm09
NS segment
influenza virus
innate immunity
reassortment
The 2009 pandemic influenza A virus (IAV) H1N1 strain (H1N1pdm09) has widely spread and is circulating in humans and swine together with other human and avian IAVs. This fact raises the concern that reassortment between H1N1pdm09 and co-circulating viruses might lead to an increase of H1N1pdm09 pathogenicity in different susceptible host species. Herein, we explored the potential of different NS segments to enhance the replication dynamics, pathogenicity and host range of H1N1pdm09 strain A/Giessen/06/09 (Gi-wt). The NS segments were derived from (i) human H1N1- and H3N2 IAVs, (ii) highly pathogenic- (H5- or H7-subtypes) or (iii) low pathogenic avian influenza viruses (H7- or H9-subtypes). A significant increase of growth kinetics in A549 (human lung epithelia) and NPTr (porcine tracheal epithelia) cells was only noticed
2018-08-27T08:47:40Z
2018-08-27T08:47:40Z
2018-08-27T08:47:40Z
2018-01-01
Article
1664-302X
29623073
10.3389/fmicb.2018.00526
http://hdl.handle.net/10033/621453
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers in microbiology
oai:repository.helmholtz-hzi.de:10033/6214672019-08-30T11:30:30Zcom_10033_211390com_10033_620601col_10033_211409col_10033_620603
Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori.
Filomena, Angela
Pessler, Frank
Akmatov, Manas K
Krause, Gérard
Duffy, Darragh
Gärtner, Barbara
Gerhard, Markus
Albert, Matthew L
Joos, Thomas O
Schneiderhan-Marra, Nicole
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Helicobacter pylori
Toxoplasma gondii
cytomegalovirus (CMV)
hepatitis
multi-pathogen assay
multiplex
seroprevalence
serotest
The spread of infectious diseases and vaccination history are common subjects of epidemiological and immunological research studies. Multiplexed serological assays are useful tools for assessing both current and previous infections as well as vaccination efficacy. We developed a serological multi-pathogen assay for hepatitis A, B and C virus, cytomegalovirus (CMV),
2018-09-04T12:07:08Z
2018-09-04T12:07:08Z
2018-09-04T12:07:08Z
2017-10-30
Article
2571-5135
29855458
10.3390/ht6040014
http://hdl.handle.net/10033/621467
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
High-throughput
oai:repository.helmholtz-hzi.de:10033/6214702019-08-30T11:31:48Zcom_10033_620601com_10033_620636col_10033_620602col_10033_620638
Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice.
Koestner, Wolfgang
Spanier, Julia
Klause, Tanja
Tegtmeyer, Pia-K
Becker, Jennifer
Herder, Vanessa
Borst, Katharina
Todt, Daniel
Lienenklaus, Stefan
Gerhauser, Ingo
Detje, Claudia N
Geffers, Robert
Langereis, Martijn A
Vondran, Florian W R
Yuan, Qinggong
van Kuppeveld, Frank J M
Ott, Michael
Staeheli, Peter
Steinmann, Eike
Baumgärtner, Wolfgang
Wacker, Frank
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany
During Coxsackievirus B3 (CVB3) infection hepatitis is a potentially life threatening complication, particularly in newborns. Studies with type I interferon (IFN-I) receptor (IFNAR)-deficient mice revealed a key role of the IFN-I axis in the protection against CVB3 infection, whereas the source of IFN-I and cell types that have to be IFNAR triggered in order to promote survival are still unknown. We found that CVB3 infected IFN-β reporter mice showed effective reporter induction, especially in hepatocytes and only to a minor extent in liver-resident macrophages. Accordingly, upon in vitro CVB3 infection of primary hepatocytes from murine or human origin abundant IFN-β responses were induced. To identify sites of IFNAR-triggering we performed experiments with Mx reporter mice, which upon CVB3 infection showed massive luciferase induction in the liver. Immunohistological studies revealed that during CVB3 infection MX1 expression of hepatocytes was induced primarily by IFNAR-, and not by IFN-III receptor (IFNLR)-triggering. CVB3 infection studies with primary human hepatocytes, in which either the IFN-I or the IFN-III axis was inhibited, also indicated that primarily IFNAR-, and to a lesser extent IFNLR-triggering was needed for ISG induction. Interestingly, CVB3 infected mice with a hepatocyte-specific IFNAR ablation showed severe liver cell necrosis and ubiquitous viral dissemination that resulted in lethal disease, as similarly detected in classical IFNAR-/- mice. In conclusion, we found that during CVB3 infection hepatocytes are major IFN-I producers and that the liver is also the organ that shows strong IFNAR-triggering. Importantly, hepatocytes need to be IFNAR-triggered in order to prevent virus dissemination and to assure survival. These data are compatible with the hypothesis that during CVB3 infection hepatocytes serve as important IFN-I producers and sensors not only in the murine, but also in the human system.
2018-09-06T13:11:19Z
2018-09-06T13:11:19Z
2018-09-06T13:11:19Z
2018-08-01
Article
1553-7374
30075026
10.1371/journal.ppat.1007235
http://hdl.handle.net/10033/621470
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/6215002019-08-30T11:30:31Zcom_10033_620601col_10033_620602
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures.
Käufer, Christopher
Chhatbar, Chintan
Bröer, Sonja
Waltl, Inken
Ghita, Luca
Gerhauser, Ingo
Kalinke, Ulrich
Löscher, Wolfgang
TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
Theiler’s virus
epilepsy
hippocampus
monocytes
myeloid cells
Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal neurodegeneration developing during and after viral encephalitis are only incompletely understood, hampering the development of preventive treatments. Recent findings suggest that brain invasion of blood-born monocytes may be critically involved in both seizures and brain damage in response to encephalitis, whereas the relative role of microglia, the brain's resident immune cells, in these processes is not clear. CCR2 and CX3CR1 are two chemokine receptors that regulate the responses of myeloid cells, such as monocytes and microglia, during inflammation. We used
2018-09-27T13:24:24Z
2018-09-27T13:24:24Z
2018-09-27T13:24:24Z
2018-09-18
Article
1091-6490
30181265
10.1073/pnas.1806754115
http://hdl.handle.net/10033/621500
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Proceedings of the National Academy of Sciences of the United States of America
oai:repository.helmholtz-hzi.de:10033/6215312020-04-27T12:29:42Zcom_10033_620601com_10033_338554col_10033_621787col_10033_620602
The olfactory epithelium as a port of entry in neonatal neurolisteriosis.
Pägelow, Dennis
Chhatbar, Chintan
Beineke, Andreas
Liu, Xiaokun
Nerlich, Andreas
van Vorst, Kira
Rohde, M
Kalinke, Ulrich
Förster, Reinhold
Halle, Stephan
Valentin-Weigand, Peter
Hornef, Mathias W
Fulde, Marcus
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Bacterial infections of the central nervous system (CNS) remain a major cause of mortality in the neonatal population. Commonly used parenteral infection models, however, do not reflect the early course of the disease leaving this critical step of the pathogenesis largely unexplored. Here, we analyzed nasal exposure of 1-day-old newborn mice to Listeria monocytogenes (Lm). We found that nasal, but not intragastric administration, led to early CNS infection in neonate mice. In particular, upon bacterial invasion of the olfactory epithelium, Lm subsequently spread along the sensory neurons entering the brain tissue at the cribriform plate and causing a significant influx of monocytes and neutrophils. CNS infection required listeriolysin for penetration of the olfactory epithelium and ActA, a mediator of intracellular mobility, for translocation into the brain tissue. Taken together, we propose an alternative port of entry and route of infection for neonatal neurolisteriosis and present a novel infection model to mimic the clinical features of late-onset disease in human neonates.
2018-11-02T10:37:11Z
2018-11-02T10:37:11Z
2018-11-02T10:37:11Z
2018-10-15
Article
2041-1723
30323282
10.1038/s41467-018-06668-2
http://hdl.handle.net/10033/621531
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Nature communications
oai:repository.helmholtz-hzi.de:10033/6215412019-08-30T11:27:40Zcom_10033_620601col_10033_620602
Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis.
Chhatbar, Chintan
Detje, Claudia N
Grabski, Elena
Borst, Katharina
Spanier, Julia
Ghita, Luca
Elliott, David A
Jordão, Marta Joana Costa
Mueller, Nora
Sutton, James
Prajeeth, Chittappen K
Gudi, Viktoria
Klein, Michael A
Prinz, Marco
Bradke, Frank
Stangel, Martin
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
astrocytes
encephalitis
neurons
regulation of microglia activation
type I IFN receptor signaling
In sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis.
2018-11-06T15:12:45Z
2018-11-06T15:12:45Z
2018-11-06T15:12:45Z
2018-10-02
Article
2211-1247
30282022
10.1016/j.celrep.2018.09.003
http://hdl.handle.net/10033/621541
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Cell reports
oai:repository.helmholtz-hzi.de:10033/6215612020-07-09T14:14:18Zcom_10033_620601col_10033_620602
Pulmonale Immunität bei Tuberkulose
Herzmann, C.
Dallenga, T.
Kalinke, U.
Tuberculosis is transmitted by inhalation of Mycobacterium
tuberculosis-containing aerosols; 75 % of all patients show
pulmonary manifestation. Immune responses after exposure that lead to clinical symptoms occur mainly in the respiratory tract and are only poorly understood. In most
cases, cells of the innate immune system are believed to
control the growth of or eradicate inhaled mycobacteria.
However, this cannot be verified in vivo using standard
methods. Subsequently, CD4+ and CD8+ T cell-driven adaptive immune responses are induced that attempt to control
bacterial growth. The humoral defence appears to be less
important. This article gives an overview of the current understanding of pulmonary immune mechanisms during exposure, latent infection, active disease and therapy of tuberculosis.
Übersicht
Herzmann C et al. Pulmonale Immunität bei … Pneumologie
H
2018-11-13T14:18:26Z
2018-11-13T14:18:26Z
2018-11-13T14:18:26Z
Article
0934-8387
1438-8790
10.1055/s-0043-122961
http://hdl.handle.net/10033/621561
http://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-122961
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
72
07
493
502
Pneumologie
oai:repository.helmholtz-hzi.de:10033/6215802019-08-30T11:29:43Zcom_10033_620601com_10033_620652col_10033_620672col_10033_620673col_10033_620602
Human monocyte-derived macrophages inhibit HCMV spread independent of classical antiviral cytokines.
Becker, Jennifer
Kinast, Volker
Döring, Marius
Lipps, Christoph
Duran, Veronica
Spanier, Julia
Tegtmeyer, Pia-Katharina
Wirth, Dagmar
Cicin-Sain, Luka
Alcamí, Antonio
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.; HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig.
Human cytomegalovirus
epithelial cells
macrophages
plasmacytoid dendritic cells
type I interferons
Infection of healthy individuals with human cytomegalovirus (HCMV) is usually unnoticed and results in life-long latency, whereas HCMV reactivation as well as infection of newborns or immunocompromised patients can cause life-threatening disease. To better understand HCMV pathogenesis we studied mechanisms that restrict HCMV spread. We discovered that HCMV-infected cells can directly trigger plasmacytoid dendritic cells (pDC) to mount antiviral type I interferon (IFN-I) responses, even in the absence of cell-free virus. In contrast, monocyte-derived cells only expressed IFN-I when stimulated by cell-free HCMV, or upon encounter of HCMV-infected cells that already produced cell-free virus. Nevertheless, also in the absence of cell-free virus, i.e., upon co-culture of infected epithelial/endothelial cells and monocyte-derived macrophages (moMΦ) or dendritic cells (moDC), antiviral responses were induced that limited HCMV spread. The induction of this antiviral effect was dependent on cell-cell contact, whereas cell-free supernatants from co-culture experiments also inhibited virus spread, implying that soluble factors were critically needed. Interestingly, the antiviral effect was independent of IFN-γ, TNF-α, and IFN-I as indicated by cytokine inhibition experiments using neutralizing antibodies or the vaccinia virus-derived soluble IFN-I binding protein B18R, which traps human IFN-α and IFN-β. In conclusion, our results indicate that human macrophages and dendritic cells can limit HCMV spread by IFN-I dependent as well as independent mechanisms, whereas the latter ones might be particularly relevant for the restriction of HCMV transmission via cell-to-cell spread.
2018-11-23T14:56:42Z
2018-11-23T14:56:42Z
2018-11-23T14:56:42Z
2018-01-01
Article
2150-5608
30403913
10.1080/21505594.2018.1535785
http://hdl.handle.net/10033/621580
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Virulence
oai:repository.helmholtz-hzi.de:10033/6215902019-08-30T11:29:44Zcom_10033_620626com_10033_620601com_10033_620618col_10033_620629col_10033_620603col_10033_620621
An Interferon Signature Discriminates Pneumococcal From Staphylococcal Pneumonia.
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.
Staphylococcus aureus
Streptococcus pneumoniae
biomarkers
interferon
pneumonia
transcriptome
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.
2018-11-28T10:27:41Z
2018-11-28T10:27:41Z
2018-11-28T10:27:41Z
2018-01-01
Article
1664-3224
29988532
10.3389/fimmu.2018.01424
http://hdl.handle.net/10033/621590
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6215932019-08-30T11:27:41Zcom_10033_620601col_10033_620602
Regulatory T-Cells Mediate IFN-α-Induced Resistance against Antigen-Induced Arthritis.
Chenna Narendra, Sudeep
Chalise, Jaya Prakash
Biggs, Sophie
Kalinke, Ulrich
Magnusson, Mattias
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
experimental arthritis
indoleamine 2,3-dioxygenase
interferon-alpha
kynurenine
regulatory T-cells
CD4 Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-α. Depletion of T By activating IDO during antigen sensitization, IFN-α activates T
2018-11-28T13:30:01Z
2018-11-28T13:30:01Z
2018-11-28T13:30:01Z
2018-01-01
Article
1664-3224
29515584
10.3389/fimmu.2018.00285
http://hdl.handle.net/10033/621593
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6216142019-08-30T11:34:18Zcom_10033_620601col_10033_620602
Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage.
Waltl, Inken
Käufer, Christopher
Gerhauser, Ingo
Chhatbar, Chintan
Ghita, Luca
Kalinke, Ulrich
Löscher, Wolfgang
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Hippocampus
Monocytes
Neuroinflammation
Seizures
Spinal cord
T cells
In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.
2018-12-12T12:16:48Z
2018-12-12T12:16:48Z
2018-12-12T12:16:48Z
2018-11-01
Article
1090-2139
30217535
10.1016/j.bbi.2018.09.006
http://hdl.handle.net/10033/621614
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Brain, behavior, and immunity
oai:repository.helmholtz-hzi.de:10033/6216792019-08-30T11:32:39Zcom_10033_620601com_10033_6839col_10033_620602col_10033_621495
Cell therapy products: focus on issues with manufacturing and quality control of chimeric antigen receptor T-cell therapies
Eyles, Jim E
Vessillier, Sandrine
Jones, Anika
Stacey, Glyn
Schneider, Christian K
Price, Jack
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Recent accelerated approvals of Chimeric Antigen Receptor T‐cell (CAR‐T) therapies targeting refractory haematological malignancies underscore the potential for this novel technology platform to provide new therapeutic options for oncology areas with high unmet medical needs. However, these powerful ‘living drugs’ are markedly different to conventional small molecule and biologic therapies on several levels. The highly complex nature and varied composition of CAR‐T based products still requires considerable investigation to resolve the best approaches to ensure reproducible and cost‐effective manufacture, clinical development, and application. This review will focus on key issues for manufacturing and quality control of these exciting new therapeutic modalities, preceded by a brief description of CAR principals and clinical development considerations. © 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
2019-02-05T09:35:09Z
2019-02-05T09:35:09Z
2019-02-05T09:35:09Z
Article
02682575
10.1002/jctb.5829
http://hdl.handle.net/10033/621679
Journal of Chemical Technology and Biotechnology
en
http://doi.wiley.com/10.1002/jctb.5829
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Wiley-Blackwell
Journal of Chemical Technology & Biotechnology
oai:repository.helmholtz-hzi.de:10033/6216912019-11-21T12:02:26Zcom_10033_620601col_10033_620603
Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis.
Ratuszny, Dominica
Sühs, Kurt-Wolfram
Novoselova, Natalia
Kuhn, Maike
Kaever, Volkhard
Skripuletz, Thomas
Pessler, Frank
Stangel, Martin
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CNS infection
biomarker
cerebrospinal fluid
enterovirus
meningitis
metabolomics
phosphatidylcholines
Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10), and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell’s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine PC.ae.C36.3, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, PC.ae.C36.3 alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising PC.ae.C36.3, PC.ae.C36.5, and PC.ae.C38.5 achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.
2019-02-15T13:11:44Z
2019-02-15T13:11:44Z
2019-02-15T13:11:44Z
2019-01-15
Article
1422-0067
30650575
10.3390/ijms20020337
http://hdl.handle.net/10033/621691
International journal of molecular sciences
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MPDI
International journal of molecular sciences
oai:repository.helmholtz-hzi.de:10033/6216932019-02-16T01:23:08Zcom_10033_620601col_10033_620603
Discovery of Leptospira spp. seroreactive peptides using ORFeome phage display.
Ramli, Siti Roszilawati
Moreira, Gustavo M S G
Zantow, Jonas
Goris, Marga G A
Nguyen, Van Kinh
Novoselova, Natalia
Pessler, Frank
Hust, Michael
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Leptospirosis is the most common zoonotic disease worldwide. The diagnostic performance of a serological test for human leptospirosis is mainly influenced by the antigen used in the test assay. An ideal serological test should cover all serovars of pathogenic leptospires with high sensitivity and specificity and use reagents that are relatively inexpensive to produce and can be used in tropical climates. Peptide-based tests fulfil at least the latter two requirements, and ORFeome phage display has been successfully used to identify immunogenic peptides from other pathogens. Two ORFeome phage display libraries of the entire Leptospira spp. genomes from five local strains isolated in Malaysia and seven WHO reference strains were constructed. Subsequently, 18 unique Leptospira peptides were identified in a screen using a pool of sera from patients with acute leptospirosis. Five of these were validated by titration ELISA using different pools of patient or control sera. The diagnostic performance of these five peptides was then assessed against 16 individual sera from patients with acute leptospirosis and 16 healthy donors and was compared to that of two recombinant reference proteins from L. interrogans. This analysis revealed two peptides (SIR16-D1 and SIR16-H1) from the local isolates with good accuracy for the detection of acute leptospirosis (area under the ROC curve: 0.86 and 0.78, respectively; sensitivity: 0.88 and 0.94; specificity: 0.81 and 0.69), which was close to that of the reference proteins LipL32 and Loa22 (area under the ROC curve: 0.91 and 0.80; sensitivity: 0.94 and 0.81; specificity: 0.75 and 0.75). This analysis lends further support for using ORFeome phage display to identify pathogen-associated immunogenic peptides, and it suggests that this technique holds promise for the development of peptide-based diagnostics for leptospirosis and, possibly, of vaccines against this pathogen.
2019-02-15T13:56:34Z
2019-02-15T13:56:34Z
2019-02-15T13:56:34Z
2019-01-01
Article
PLoS Negl Trop Dis. 2019 Jan 24;13(1):e0007131. doi:10.1371/journal.pntd.0007131
1935-2735
30677033
10.1371/journal.pntd.0007131
http://hdl.handle.net/10033/621693
Plos neglected tropical diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
PLOS
PLoS neglected tropical diseases
qdc///com_10033_620601/100