2024-03-29T11:21:12Zhttp://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.
2012-05-31
2012-05-31
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.
2012-10-04
2012-10-04
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.
2012-10-15
2012-10-15
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.
2012-12-14
2012-12-14
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.
2013-02-13
2013-02-13
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
2013-03-13
2013-03-13
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
2013-03-13
2013-03-13
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
2013-03-25
2013-03-25
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.
2013-07-25
2013-07-25
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.
2013-11-28
2013-11-28
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.
2013-11-29
2013-11-29
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.
2014-01-17
2014-01-17
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.
2014-04-16
2014-04-16
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.
2014-05-13
2014-05-13
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:10033/3260702019-08-30T11:30:32Zcom_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.
2014-09-12
2014-09-12
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.
2014-10-13
2014-10-13
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.
2014-11-03
2014-11-03
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.
2014-11-05
2014-11-05
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.
2014-11-05
2014-11-05
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.
2015-01-29
2015-01-29
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.
2015-03-10
2015-03-10
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.
2015-03-10
2015-03-10
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.
2015-03-11
2015-03-11
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.
2015-03-26
2015-03-26
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:10033/5797922019-08-30T11:37:44Zcom_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.
2015-10-16
2015-10-16
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:10033/5824402019-08-30T11:25:11Zcom_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.
2015-11-20
2015-11-20
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.
2015-12-08
2015-12-08
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.
2015-12-08
2015-12-08
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:10033/6035092019-08-30T11:37:00Zcom_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.
2016-03-22
2016-03-22
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.
2016-04-14
2016-04-14
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.
2016-04-20
2016-04-20
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.
2016-06-02
2016-06-02
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.
2016-05-12
2016-05-12
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:10033/6156212019-08-30T11:26:42Zcom_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.
2016-07-06
2016-07-06
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.
2016-07-07
2016-07-07
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:10033/6208682019-08-30T11:35:13Zcom_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.
2017-03-24
2017-03-24
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:10033/6209412019-08-30T11:32:16Zcom_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.
2017-06-12
2017-06-12
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.
2017-07-05
2017-07-05
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.
2017-07-11
2017-07-11
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.
2017-07-13
2017-07-13
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:10033/6210262019-08-30T11:25:11Zcom_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.
2017-08-01
2017-08-01
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.
2017-08-01
2017-08-01
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.
2017-08-03
2017-08-03
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.
2017-08-21
2017-08-21
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:10033/6211892019-08-30T11:33:57Zcom_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.
2017-11-29
2017-11-29
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.
2017-12-18
2017-12-18
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:10033/6212162021-07-06T12:05:05Zcom_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.
2018-01-02
2018-01-02
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:10033/6212432019-08-30T11:35:39Zcom_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.
2018-01-19
2018-01-19
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.
2018-01-22
2018-01-22
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.
2018-03-02
2018-03-02
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.
2018-03-05
2018-03-05
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.
2018-03-19
2018-03-19
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.
2018-04-03
2018-04-03
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:10033/6213422019-08-30T11:30:31Zcom_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.
2018-04-11
2018-04-11
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.
2018-04-12
2018-04-12
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:10033/6213502019-08-30T11:33:29Zcom_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.
2018-04-12
2018-04-12
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.
2018-04-24
2018-04-24
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:10033/6214322019-08-30T11:25:41Zcom_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.
2018-07-31
2018-07-31
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
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
2018-08-07
2018-08-07
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
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.
2018-09-06
2018-09-06
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
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
2018-09-27
2018-09-27
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
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.
2018-11-02
2018-11-02
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
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.
2018-11-06
2018-11-06
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
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
2018-11-13
2018-11-13
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
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.
2018-11-23
2018-11-23
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
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
2018-11-28
2018-11-28
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
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.
2018-12-12
2018-12-12
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
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.
2019-02-05
2019-02-05
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
oai:repository.helmholtz-hzi.de:10033/6217112019-08-30T11:35:13Zcom_10033_620601col_10033_620602
Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1.
Gawish, Riem
Bulat, Tanja
Biaggio, Mario
Lassnig, Caroline
Bago-Horvath, Zsuzsanna
Macho-Maschler, Sabine
Poelzl, Andrea
Simonović, Natalija
Prchal-Murphy, Michaela
Rom, Rita
Amenitsch, Lena
Ferrarese, Luca
Kornhoff, Juliana
Lederer, Therese
Svinka, Jasmin
Eferl, Robert
Bosmann, Markus
Kalinke, Ulrich
Stoiber, Dagmar
Sexl, Veronika
Krmpotić, Astrid
Jonjić, Stipan
Müller, Mathias
Strobl, Birgit
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
Herpesviridae
IFN-I receptor
IFN-II receptor
IL-27 receptor
TLR9 agonist
monocytes
signal transducer and activator of transcription
Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.
2019-03-05
2019-03-05
2019-02-26
Article
Cell Rep. 2019 Feb 26;26(9):2394-2406.e5. doi: 10.1016/j.celrep.2019.02.017.
2211-1247
30811989
10.1016/j.celrep.2019.02.017
http://hdl.handle.net/10033/621711
Cell Reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
oai:repository.helmholtz-hzi.de:10033/6217152019-08-30T11:35:12Zcom_10033_620601col_10033_620602
Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4 T Cells in Chronic Lymphopenic Mice.
Knop, Laura
Frommer, Charlotte
Stoycheva, Diana
Deiser, Katrin
Kalinke, Ulrich
Blankenstein, Thomas
Kammertoens, Thomas
Dunay, Ildiko Rita
Schüler, Thomas
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
CD4+ T cells
dendritic cells
interferon-γ
lymphopenia
lymphopenia-induced proliferation (LIP)
In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4+ T cells. We show that such cells undergo LIP in lymphopenic mice lacking IFN-γ receptor (IFN-γR) expression, a process, which is promoted by the autocrine action of T cell-derived IFN-γ. Additionally, LIP of lymphopenia-insensitive CD4+ T cells requires an intact microflora and is accompanied by the massive accumulation of IL-6 and dendritic cells (DCs). Consistent with these results, IL-6 neutralization and the DC-specific restoration of IFN-γR expression are both sufficient to restrict LIP. Hence, the insensitivity of CD4+ T cells to lymphopenia relies on cell-intrinsic properties and a complex interplay between the commensal microflora, IL-6, IFN-γR+ DCs, and T cell-derived IFN-γ.
2019-03-06
2019-03-06
2019-01-01
Article
Front Immunol. 2019 Feb 7;10:140. doi: 10.3389/fimmu.2019.00140. eCollection 2019.
1664-3224
30792713
10.3389/fimmu.2019.00140
http://hdl.handle.net/10033/621715
Frontiers in Immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Frontiers
oai:repository.helmholtz-hzi.de:10033/6217202019-03-20T01:24:51Zcom_10033_620601col_10033_620602
Interferon-γ Receptor Signaling in Dendritic Cells Restrains Spontaneous Proliferation of CD4 T Cells in Chronic Lymphopenic Mice.
Knop, Laura
Frommer, Charlotte
Stoycheva, Diana
Deiser, Katrin
Kalinke, Ulrich
Blankenstein, Thomas
Kammertoens, Thomas
Dunay, Ildiko Rita
Schüler, Thomas
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
CD4+ T cells
dendritic cells
interferon-γ
lymphopenia
lymphopenia-induced proliferation (LIP)
In lymphopenic mice, T cells become activated and undergo lymphopenia-induced proliferation (LIP). However, not all T cells are equally sensitive to lymphopenia. Several lymphopenia-insensitive T cell clones were described and their non-responsiveness was mainly attributed to clone-specific properties. Here, we provide evidence for an additional, host-dependent mechanism restraining LIP of lymphopenia-insensitive CD4
2019-03-12
2019-03-12
2019-01-01
Article
1664-3224
30792713
10.3389/fimmu.2019.00140
http://hdl.handle.net/10033/621720
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
oai:repository.helmholtz-hzi.de:10033/6217322019-08-30T11:32:40Zcom_10033_620601col_10033_620602
RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade.
Heidegger, Simon
Kreppel, Diana
Bscheider, Michael
Stritzke, Florian
Nedelko, Tatiana
Wintges, Alexander
Bek, Sarah
Fischer, Julius C
Graalmann, Theresa
Kalinke, Ulrich
Bassermann, Florian
Haas, Tobias
Poeck, Hendrik
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
Anti-cancer vaccine
Dendritic cells
Immune checkpoint inhibitors
Immuno-oncology
Innate immunity
RIG-I
Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Here we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5'-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models. We found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8 Overall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation.
2019-03-28
2019-03-28
2019-03-06
Article
2352-3964
30852164
10.1016/j.ebiom.2019.02.056
http://hdl.handle.net/10033/621732
EBIO Medicine
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
oai:repository.helmholtz-hzi.de:10033/6217572019-08-30T11:32:36Zcom_10033_620601com_10033_311308col_10033_620721col_10033_620602
Modulation of TAP-dependent antigen compartmentalization during human monocyte-to-DC differentiation.
Döring, Marius
Blees, Hanna
Koller, Nicole
Tischer-Zimmermann, Sabine
Müsken, Mathias
Henrich, Frederik
Becker, Jennifer
Grabski, Elena
Wang, Junxi
Janssen, Hans
Zuschratter, Werner
Neefjes, Jacques
Klawonn, Frank
Eiz-Vesper, Britta
Tampé, Robert
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7,30625 Hannover, Germany.
Dendritic cells (DCs) take up antigen in the periphery, migrate to secondary lymphoid organs, and present processed antigen fragments to adaptive immune cells and thus prime antigen-specific immunity. During local inflammation, recirculating monocytes are recruited from blood to the inflamed tissue, where they differentiate to macrophages and DCs. In this study, we found that monocytes showed high transporter associated with antigen processing (TAP)–dependent peptide compartmentalization and that after antigen pulsing, they were not able to efficiently stimulate antigen-specific T lymphocytes. Nevertheless, upon in vitro differentiation to monocyte-derived DCs, TAP-dependent peptide compartmentalization as well as surface major histocompatibility complex I turnover decreased and the cells efficiently restimulated T lymphocytes. Although TAP-dependent peptide compartmentalization decreased during DC differentiation, TAP expression levels increased. Furthermore, TAP relocated from early endosomes in monocytes to the endoplasmic reticulum (ER) and lysosomal compartments in DCs. Collectively, these data are compatible with the model that during monocyte-to-DC differentiation, the subcellular relocation of TAP and the regulation of its activity assure spatiotemporal separation of local antigen uptake and processing by monocytes and efficient T-lymphocyte stimulation by DCs.
2019-04-29
2019-04-29
2019-03-26
Article
Blood Adv. 2019 Mar 26;3(6):839-850. doi: 10.1182/bloodadvances.2018027268.
2473-9537
30867143
10.1182/bloodadvances.2018027268
http://hdl.handle.net/10033/621757
Blood Advances
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
American Society of Hematology
oai:repository.helmholtz-hzi.de:10033/6218752019-08-30T11:26:40Zcom_10033_620601col_10033_620602
STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus.
Tegtmeyer, Pia-Katharina
Spanier, Julia
Borst, Katharina
Becker, Jennifer
Riedl, André
Hirche, Christoph
Ghita, Luca
Skerra, Jennifer
Baumann, Kira
Lienenklaus, Stefan
Doering, Marius
Ruzsics, Zsolt
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Cytomegalovirus is a DNA-encoded β-herpesvirus that induces STING-dependent type 1 interferon responses in macrophages and uses myeloid cells as a vehicle for dissemination. Here we report that STING knockout mice are as resistant to murine cytomegalovirus (MCMV) infection as wild-type controls, whereas mice with a combined Toll-like receptor/RIG-I-like receptor/STING signaling deficiency do not mount type 1 interferon responses and succumb to the infection. Although STING alone is dispensable for survival, early IFN-β induction in Kupffer cells is STING-dependent and controls early hepatic virus propagation. Infection experiments with an inducible reporter MCMV show that STING constrains MCMV replication in myeloid cells and limits viral dissemination via these cells. By contrast, restriction of viral dissemination from hepatocytes to other organs is independent of STING. Thus, during MCMV infection STING is involved in early IFN-β induction in Kupffer cells and the restriction of viral dissemination via myeloid cells, whereas it is dispensable for survival.
2019-07-15
2019-07-15
2019-06-27
Article
Nat Commun. 2019 Jun 27;10(1):2830. doi: 10.1038/s41467-019-10863-0.
2041-1723
31249303
10.1038/s41467-019-10863-0
http://hdl.handle.net/10033/621875
Nature Communications
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Springer-Nature
oai:repository.helmholtz-hzi.de:10033/6219422019-09-17T02:31:02Zcom_10033_620613com_10033_620601col_10033_620614col_10033_620602
Preferential uptake of chitosan-coated PLGA nanoparticles by primary human antigen presenting cells.
Durán, Verónica
Yasar, Hanzey
Becker, Jennifer
Thiyagarajan, Durairaj
Loretz, Brigitta
Kalinke, Ulrich
Lehr, Claus-Michael
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Chitosan-PLGA NP
Intracellular trafficking
Monocyte-derived DC
Nanoparticles
PBMC
PLGA NP
Biodegradable polymeric nanoparticles (NP) made from poly (lactid-co-glycolide) acid (PLGA) and chitosan (CS) hold promise as innovative formulations for targeted delivery. Since interactions of such NP with primary human immune cells have not been characterized, yet, here we assessed the effect of PLGA or CS-PLGA NP treatment on human peripheral blood mononuclear cells (PBMC), as well as on monocyte-derived DC (moDC). Amongst PBMC, antigen presenting cells (APC) showed higher uptake of both NP preparations than lymphocytes. Furthermore, moDC internalized CS-PLGA NP more efficiently than PLGA NP, presumably because of receptor-mediated endocytosis. Consequently, CS-PLGA NP were delivered mostly to endosomal compartments, whereas PLGA NP primarily ended up in lysosomes. Thus, CS-PLGA NP confer enhanced delivery to endosomal compartments of APC, offering new therapeutic options to either induce or modulate APC function and to inhibit pathogens that preferentially infect APC.
2019-09-16
2019-09-16
2019-07-31
Article
Nanomedicine. 2019 Jul 31;21:102073. doi: 10.1016/j.nano.2019.102073.
1549-9642
31376570
10.1016/j.nano.2019.102073
http://hdl.handle.net/10033/621942
Nanomedicine: Nanotechnology, Biology, and Medicine
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
oai:repository.helmholtz-hzi.de:10033/6219442019-09-18T03:36:38Zcom_10033_620613com_10033_620601col_10033_620614col_10033_620602
OCTN2-mediated acetyl-l-carnitine transport in human pulmonary epithelial cells in vitro
Salomon, Johanna J.
Gausterer, Julia C.
Selo, Mohammed Ali
Hosoya, Ken Ichi
Huwer, Hanno
Schneider-Daum, Nicole
Lehr, Claus Michael
Ehrhardt, Carsten
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Acetyl-l-carnitine
Asthma
Epithelial transport
In vitro models
Lung epithelium
OCTN2
Organic cation transporter
The carnitine transporter OCTN2 is associated with asthma and other inflammatory diseases. The aims of this work were (i) to determine carnitine uptake into freshly isolated human alveolar type I (ATI)-like epithelial cells in primary culture, (ii) to compare the kinetics of carnitine uptake between respiratory epithelial in vitro cell models, and (iii) to establish whether any cell line was a suitable model for studies of carnitine transport at the air-blood barrier. Levels of time-dependent [3H]-acetyl-l-carnitine uptake were similar in ATI-like, NCl-H441, and Calu-3 epithelial cells, whereas uptake into A549 cells was ~5 times higher. Uptake inhibition was more pronounced by OCTN2 modulators, such as l-Carnitine and verapamil, in ATI-like primary epithelial cells compared to NCl-H441 and Calu-3 epithelial cells. Our findings suggest that OCTN2 is involved in the cellular uptake of acetyl-l-carnitine at the alveolar epithelium and that none of the tested cell lines are optimal surrogates for primary cells.
2019-09-17
2019-09-17
2019-08-01
Article
Pharmaceutics. 2019 Aug 7;11(8). pii: pharmaceutics11080396. doi: 10.3390/pharmaceutics11080396.
31394757
10.3390/pharmaceutics11080396
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071193528&origin=inward
http://hdl.handle.net/10033/621944
Pharmaceutics
2-s2.0-85071193528
SCOPUS_ID:85071193528
en
Pharmaceutics
8
11
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MPDI
oai:repository.helmholtz-hzi.de:10033/6220532019-12-20T01:59:26Zcom_10033_620601col_10033_620602
HSV-1 triggers paracrine fibroblast growth factor response from cortical brain cells via immediate-early protein ICP0.
Hensel, Niko
Raker, Verena
Förthmann, Benjamin
Detering, Nora Tula
Kubinski, Sabrina
Buch, Anna
Katzilieris-Petras, Georgios
Spanier, Julia
Gudi, Viktoria
Wagenknecht, Sylvia
Kopfnagel, Verena
Werfel, Thomas Andreas
Stangel, Martin
Beineke, Andreas
Kalinke, Ulrich
Paludan, Søren Riis
Sodeik, Beate
Claus, Peter
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Akt
Cortex
ERK
FGF
Fibroblast growth factors
HSV-1
ICP0
Neurotrophic factors
Signaling
BACKGROUND:
Herpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells.
METHOD:
We employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells.
RESULTS:
Astrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism.
CONCLUSIONS:
HSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.
2019-12-19
2019-12-19
2019-12-02
Article
J Neuroinflammation. 2019 Dec 2;16(1):248. doi: 10.1186/s12974-019-1647-5.
1742-2094
31791351
10.1186/s12974-019-1647-5
http://hdl.handle.net/10033/622053
Journal of Neuroinflammation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BMC
oai:repository.helmholtz-hzi.de:10033/6220622020-01-07T02:02:39Zcom_10033_620601col_10033_620602
Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function.
Lercher, Alexander
Bhattacharya, Anannya
Popa, Alexandra M
Caldera, Michael
Schlapansky, Moritz F
Baazim, Hatoon
Agerer, Benedikt
Gürtl, Bettina
Kosack, Lindsay
Májek, Peter
Brunner, Julia S
Vitko, Dijana
Pinter, Theresa
Genger, Jakob-Wendelin
Orlova, Anna
Pikor, Natalia
Reil, Daniela
Ozsvár-Kozma, Maria
Kalinke, Ulrich
Ludewig, Burkhard
Moriggl, Richard
Bennett, Keiryn L
Menche, Jörg
Cheng, Paul N
Schabbauer, Gernot
Trauner, Michael
Klavins, Kristaps
Bergthaler, Andreas
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CD8 T cells
hepatitis
hepatocyte
immunometabolism
infection
inflammation
interferons
liver
urea cycle
virus
Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.
2020-01-06
2020-01-06
2019-12-17
Article
Immunity. 2019 Dec 17;51(6):1074-1087.e9. doi: 10.1016/j.immuni.2019.10.014. Epub 2019 Nov 26.
1097-4180
31784108
10.1016/j.immuni.2019.10.014
http://hdl.handle.net/10033/622062
Immunity
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier/ Cel Press
oai:repository.helmholtz-hzi.de:10033/6220812020-01-15T02:19:34Zcom_10033_620601col_10033_620602
A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice.
Kalodimou, Georgia
Veit, Svenja
Jany, Sylvia
Kalinke, Ulrich
Broder, Christopher C
Sutter, Gerd
Volz, Asisa
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
MVA vector vaccines
T cell responses
emerging viruses
vaccination
Nipah virus (NiV) is an emerging zoonotic virus that is transmitted by bats to humans and to pigs, causing severe respiratory disease and often fatal encephalitis. Antibodies directed against the NiV-glycoprotein (G) protein are known to play a major role in clearing NiV infection and in providing vaccine-induced protective immunity. More recently, T cells have been also shown to be involved in recovery from NiV infection. So far, relatively little is known about the role of T cell responses and the antigenic targets of NiV-G that are recognized by CD8 T cells. In this study, NiV-G protein served as the target immunogen to activate NiV-specific cellular immune responses. Modified Vaccinia virus Ankara (MVA), a safety-tested strain of vaccinia virus for preclinical and clinical vaccine research, was used for the generation of MVA-NiV-G candidate vaccines expressing different versions of recombinant NiV-G. Overlapping peptides covering the entire NiV-G protein were used to identify major histocompatibility complex class I/II-restricted T cell responses in type I interferon receptor-deficient (IFNAR-/-) mice after vaccination with the MVA-NiV-G candidate vaccines. We have identified an H2-b-restricted nonamer peptide epitope with CD8 T cell antigenicity and a H2-b 15mer with CD4 T cell antigenicity in the NiV-G protein. The identification of this epitope and the availability of the MVA-NiV-G candidate vaccines will help to evaluate NiV-G-specific immune responses and the potential immune correlates of vaccine-mediated protection in the appropriate murine models of NiV-G infection. Of note, a soluble version of NiV-G was advantageous in activating NiV-G-specific cellular immune responses using these peptides
2020-01-14
2020-01-14
2019-12-24
Article
Viruses. 2019 Dec 24;12(1). pii: v12010026. doi: 10.3390/v12010026.
1999-4915
31878180
10.3390/v12010026
http://hdl.handle.net/10033/622081
Viruses
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MDPI
oai:repository.helmholtz-hzi.de:10033/6221152020-02-04T02:37:11Zcom_10033_620601col_10033_620602
Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88).
Iampietro, Mathieu
Aurine, Noemie
Dhondt, Kevin P
Dumont, Claire
Pelissier, Rodolphe
Spanier, Julia
Vallve, Audrey
Raoul, Herve
Kalinke, Ulrich
Horvat, Branka
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
MAVS
MyD88
Nipah virus
TLR
TRIF
innate immunity
interferon
mice
Interferon (IFN) type I plays a critical role in the protection of mice from lethal Nipah virus (NiV) infection, but mechanisms responsible for IFN-I induction remain unknown. In the current study, we demonstrated the critical role of the mitochondrial antiviral signaling protein signaling pathway in IFN-I production and NiV replication in murine embryonic fibroblasts in vitro, and the redundant but essential roles of both mitochondrial antiviral signaling protein and myeloid differentiation primary response 88 adaptors, but not TRIF (Toll/Interleukin-1 receptor/Resistance [TIR] domain-containing adaptor-inducing IFN-β), in the control of NiV infection in mice. These results reveal potential novel targets for antiviral intervention and help in understanding NiV immunopathogenesis.
2020-02-03
2020-02-03
2019-12-19
Article
J Infect Dis. 2019 Dec 19. pii: 5680630. doi: 10.1093/infdis/jiz602.
1537-6613
31853535
10.1093/infdis/jiz602
http://hdl.handle.net/10033/622115
Journal of Infectious Diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Oxford Academic
oai:repository.helmholtz-hzi.de:10033/6221252021-08-13T11:16:16Zcom_10033_620601col_10033_620602
A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control.
Namineni, Sukumar
O'Connor, Tracy
Faure-Dupuy, Suzanne
Johansen, Pål
Riedl, Tobias
Liu, Kaijing
Xu, Haifeng
Singh, Indrabahadur
Shinde, Prashant
Li, Fanghui
Pandyra, Aleksandra
Sharma, Piyush
Ringelhan, Marc
Muschaweckh, Andreas
Borst, Katharina
Blank, Patrick
Lampl, Sandra
Durantel, David
Farhat, Rayan
Weber, Achim
Lenggenhager, Daniela
Kündig, Thomas M
Staeheli, Peter
Protzer, Ulrike
Wohlleber, Dirk
Holzmann, Bernhard
Binder, Marco
Breuhahn, Kai
Assmus, Lisa Mareike
Nattermann, Jacob
Abdullah, Zeinab
Rolland, Maude
Dejardin, Emmanuel
Lang, Philipp A
Lang, Karl S
Karin, Michael
Lucifora, Julie
Kalinke, Ulrich
Knolle, Percy A
Heikenwalder, Mathias
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Cytotoxic T cells
Hepatocytes
Innate Immune responses
Interferon Stimulated Genes
NF-kB signaling
PRRs
Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (IKKβΔHep) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IFNARΔHep), or interferon-α/β signaling in myeloid cells-(IFNARΔMyel) were infected.
2020-02-10
2020-02-10
2020-01-15
Article
J Hepatol. 2020 Jan 15. pii: S0168-8278(20)30010-6. doi: 10.1016/j.jhep.2019.12.019.
1600-0641
31954207
10.1016/j.jhep.2019.12.019
http://hdl.handle.net/10033/622125
Journal of Hepatology
http://creativecommons.org/licenses/by-nc-nd/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
oai:repository.helmholtz-hzi.de:10033/6221452020-02-19T02:01:09Zcom_10033_620601col_10033_620602
Obstetric Ultrasonography to Detect Fetal Abnormalities in a Mouse Model for Zika Virus Infection.
Forster, Dominik
Schwarz, Jan Hendrik
Brosinski, Katrin
Kalinke, Ulrich
Sutter, Gerd
Volz, Asisa
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Zika virus
pregnancy
ultrasound
uteroplacental infection
viral pathogenesis
In 2015 Zika virus (ZIKV) emerged for the first time in South America. The following ZIKV epidemic resulted in the appearance of a clinical phenotype with microcephaly and other severe malformations in newborns. So far, mechanisms of ZIKV induced damage to the fetus are not completely understood. Previous data suggest that ZIKV may bypass the placenta to reach the fetus. Thus, animal models for ZIKV infection are important to facilitate studies about ZIKV infection during pregnancy. Here, we used ultrasound based imaging (USI) to characterize ZIKV induced pathogenesis in the pregnant Type I interferon receptor-deficient (IFNAR-/-) mouse model. Based on USI we suggest the placenta to be a primary target organ of ZIKV infection enabling ZIKV spreading to the fetus. Moreover, in addition to direct infection of the fetus, the placental ZIKV infection may cause an indirect damage to the fetus through reduced uteroplacental perfusion leading to intrauterine growth retardation (IUGR) and fetal complications as early as embryonic day (ED) 12.5. Our data confirmed the capability of USI to characterize ZIKV induced modifications in mouse fetuses. Data from further studies using USI to monitor ZIKV infections will contribute to a better understanding of ZIKV infection in pregnant IFNAR-/- mice.
2020-02-18
2020-02-18
2020-01-07
Article
Viruses. 2020 Jan 7;12(1). pii: v12010072. doi: 10.3390/v12010072.
1999-4915
31936159
10.3390/v12010072
http://hdl.handle.net/10033/622145
Viruses
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MDPI
oai:repository.helmholtz-hzi.de:10033/6221652020-02-25T02:04:40Zcom_10033_620601col_10033_620602
The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13.
Mulas, Floriana
Wang, Xu
Song, Shanshan
Nishanth, Gopala
Yi, Wenjing
Brunn, Anna
Larsen, Pia-Katharina
Isermann, Berend
Kalinke, Ulrich
Barragan, Antonio
Naumann, Michael
Deckert, Martina
Schlüter, Dirk
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
OTUB1
dendritic cell
innate immunity
signal transduction
ubiquitination
Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.
2020-02-24
2020-02-24
2020-02-05
Article
Cell Mol Immunol. 2020 Feb 5. pii: 10.1038/s41423-020-0362-6. doi: 10.1038/s41423-020-0362-6.
2042-0226
32024978
10.1038/s41423-020-0362-6
http://hdl.handle.net/10033/622165
Cellular and Molecular Immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Springer Nature
oai:repository.helmholtz-hzi.de:10033/6221802020-03-06T04:09:33Zcom_10033_620601col_10033_620602
IL-7 derived from lymph node fibroblastic reticular cells is dispensable for naive T cell homeostasis but crucial for central memory T cell survival.
Knop, Laura
Deiser, Katrin
Bank, Ute
Witte, Amelie
Mohr, Juliane
Philipsen, Lars
Fehling, Hans J
Müller, Andreas J
Kalinke, Ulrich
Schüler, Thomas
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
T cell homeostasis
central memory T cells
fibroblastic reticular cells
interleukin-7
naive T cells
The survival of peripheral T cells is dependent on their access to peripheral lymph nodes (pLNs) and stimulation by Interleukin-7 (IL-7). In pLNs fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) produce IL-7 suggesting their contribution to the IL-7-dependent survival of T cells. However, IL-7 production is detectable in multiple organs and is not restricted to pLNs. This raises the question whether pLN-derived IL-7 is required for the maintenance of peripheral T cell homeostasis. Here, we show that numbers of naive T cells (TN ) remain unaffected in pLNs and spleen of mice lacking Il7 gene activity in pLN FRCs, LECs or both. In contrast, frequencies of central memory T cells (TCM ) are reduced in FRC-specific IL-7 knockout mice. Thus, steady state IL-7 production by pLN FRCs is critical for the maintenance of TCM , but not TN , indicating that both T cell subsets colonize different ecological niches in vivo. This article is protected by copyright. All rights reserved.
2020-02-27
2020-02-27
2020-02-11
Article
Eur J Immunol. 2020 Feb 11. doi: 10.1002/eji.201948368.
1521-4141
32043573
10.1002/eji.201948368
http://hdl.handle.net/10033/622180
European journal of immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Wiley Online Open
oai:repository.helmholtz-hzi.de:10033/6221812020-03-06T04:09:39Zcom_10033_620601col_10033_620602
Selective reconstitution of IFN‑γ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection.
Borst, Katharina
Flindt, Sven
Blank, Patrick
Larsen, Pia-Katharina
Chhatbar, Chintan
Skerra, Jennifer
Spanier, Julia
Hirche, Christoph
König, Martin
Alanentalo, Tomas
Hafner, Martin
Waibler, Zoe
Pfeffer, Klaus
Sexl, Veronika
Sutter, Gerd
Müller, Werner
Graalmann, Theresa
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity.
2020-02-27
2020-02-27
2020-02-01
Article
PLoS Pathog. 2020 Feb 5;16(2):e1008279. doi: 10.1371/journal.ppat.1008279. eCollection 2020 Feb.
1553-7374
32023327
10.1371/journal.ppat.1008279
http://hdl.handle.net/10033/622181
PLOS pathogens
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
PLOS
oai:repository.helmholtz-hzi.de:10033/6222042020-03-14T01:59:31Zcom_10033_620601col_10033_620602
Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway.
Haake, Kathrin
Neehus, Anna-Lena
Buchegger, Theresa
Kühnel, Mark Philipp
Blank, Patrick
Philipp, Friederike
Oleaga-Quintas, Carmen
Schulz, Ansgar
Grimley, Michael
Goethe, Ralph
Jonigk, Danny
Kalinke, Ulrich
Boisson-Dupuis, Stéphanie
Casanova, Jean-Laurent
Bustamante, Jacinta
Lachmann, Nico
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
MSMD
hematopoiesis
induced pluripotent stem cells
interferon γ
macrophages
mycobacteria
nterferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-γ related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-γR1 and IFN-γR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-γ immunity.
2020-03-13
2020-03-13
2020-02-19
Article
Cells. 2020 Feb 19;9(2). pii: cells9020483. doi: 10.3390/cells9020483.
32093117
10.3390/cells9020483
http://hdl.handle.net/10033/622204
2073-4409
Cells
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
MDPI
oai:repository.helmholtz-hzi.de:10033/6222852020-06-10T01:29:38Zcom_10033_620722com_10033_620601col_10033_620723col_10033_620602
Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS.
Hosseini, Shirin
Michaelsen-Preusse, Kristin
Grigoryan, Gayane
Chhatbar, Chintan
Kalinke, Ulrich
Korte, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-β-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-β has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-β treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade.
2020-06-09
2020-06-09
Article
Cell Rep. 2020;31(7):107666. doi:10.1016/j.celrep.2020.107666.
32433975
10.1016/j.celrep.2020.107666
http://hdl.handle.net/10033/622285
2211-1247
Cell reports
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier (Cell Press)
oai:repository.helmholtz-hzi.de:10033/6224612020-09-26T02:53:40Zcom_10033_620601col_10033_620602
Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease.
Vardi, Ayelet
Ben-Dor, Shifra
Cho, Soo Min
Kalinke, Ulrich
Spanier, Julia
Futerman, Anthony H
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Gaucher disease
Lipid metabolism
Lysosomal storage diseases
Neurodegenerative diseases
Pathogen recognition receptors
Type 1 interferon
Epstein-Barr virus (EBV) is a latent and oncogenic human herpesvirus. Lytic viral protein expression plays an important role in EBV-associated malignancies. The EBV envelope glycoprotein 350 (gp350) is expressed abundantly during EBV lytic reactivation and sporadically on the surface of latently infected cells. Here we tested T cells expressing gp350-specific chimeric antigen receptors (CARs) containing scFvs derived from two novel gp350-binding, highly neutralizing monoclonal antibodies. The scFvs were fused to CD28/CD3ζ signaling domains in a retroviral vector. The produced gp350CAR-T cells specifically recognized and killed gp350+ 293T cells in vitro. The best-performing 7A1-gp350CAR-T cells were cytotoxic against the EBV+ B95-8 cell line, showing selectivity against gp350+ cells. Fully humanized Nod.Rag.Gamma mice transplanted with cord blood CD34+ cells and infected with the EBV/M81/fLuc lytic strain were monitored dynamically for viral spread. Infected mice recapitulated EBV-induced lymphoproliferation, tumor development, and systemic inflammation. We tested adoptive transfer of autologous CD8+gp350CAR-T cells administered protectively or therapeutically. After gp350CAR-T cell therapy, 75% of mice controlled or reduced EBV spread and showed lower frequencies of EBER+ B cell malignant lymphoproliferation, lack of tumor development, and reduced inflammation. In summary, CD8+gp350CAR-T cells showed proof-of-concept preclinical efficacy against impending EBV+ lymphoproliferation and lymphomagenesis.
2020-09-25
2020-09-25
2020-09-07
Article
J Neuroinflammation. 2020 Sep 7;17(1):265. doi: 10.1186/s12974-020-01934-x.
32892753
10.1186/s12974-020-01934-x
http://hdl.handle.net/10033/622461
1742-2094
Journal of neuroinflammation
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
BMC
oai:repository.helmholtz-hzi.de:10033/6226362020-12-09T01:38:51Zcom_10033_620652com_10033_620968com_10033_620601col_10033_620969col_10033_620673col_10033_620602
Triple RNA-Seq Reveals Synergy in a Human Virus-Fungus Co-infection Model.
Seelbinder, Bastian
Wallstabe, Julia
Marischen, Lothar
Weiss, Esther
Wurster, Sebastian
Page, Lukas
Löffler, Claudia
Bussemer, Lydia
Schmitt, Anna-Lena
Wolf, Thomas
Linde, Jörg
Cicin-Sain, Luka
Becker, Jennifer
Kalinke, Ulrich
Vogel, Jörg
Panagiotou, Gianni
Einsele, Hermann
Westermann, Alexander J
Schäuble, Sascha
Loeffler, Juergen
HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Aspergillus
cross-species interaction
cytomegalovirus
dendritic cells
host response
pulmonary infections
synergy
transcriptional networks
triple RNA-seq
High-throughput RNA sequencing (RNA-seq) is routinely applied to study diverse biological processes; however, when performed separately on interacting organisms, systemic noise intrinsic to RNA extraction, library preparation, and sequencing hampers the identification of cross-species interaction nodes. Here, we develop triple RNA-seq to simultaneously detect transcriptomes of monocyte-derived dendritic cells (moDCs) infected with the frequently co-occurring pulmonary pathogens Aspergillus fumigatus and human cytomegalovirus (CMV). Comparing expression patterns after co-infection with those after single infections, our data reveal synergistic effects and mutual interferences between host responses to the two pathogens. For example, CMV attenuates the fungus-mediated activation of pro-inflammatory cytokines through NF-κB (nuclear factor κB) and NFAT (nuclear factor of activated T cells) cascades, while A. fumigatus impairs viral clearance by counteracting viral nucleic acid-induced activation of type I interferon signaling. Together, the analytical power of triple RNA-seq proposes molecular hubs in the differential moDC response to fungal/viral single infection or co-infection that contribute to our understanding of the etiology and, potentially, clearance of post-transplant infections.
2020-12-08
2020-12-08
2020-11-17
Article
Cell Rep. 2020 Nov 17;33(7):108389. doi: 10.1016/j.celrep.2020.108389.
33207195
10.1016/j.celrep.2020.108389
http://hdl.handle.net/10033/622636
2211-1247
Cell reports
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Elsevier (Cell Press)
oai:repository.helmholtz-hzi.de:10033/6227102021-02-02T03:34:53Zcom_10033_620613com_10033_620601col_10033_620614col_10033_620602
Redispersible Spray-Dried Powder Containing Nanoencapsulated Curcumin: the Drying Process Does Not Affect Neuroprotection In vitro.
de Andrade, Diego Fontana
Vukosavljevic, Branko
Hoppe, Juliana Bender
Pohlmann, Adriana Raffin
Guterres, Sílvia Stanisçuaski
Windbergs, Maike
Külkamp-Guerreiro, Irene
Salbego, Christianne Gazzana
Beck, Ruy Carlos Ruver
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.;TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
curcumin
nanocapsules
neuroinflammation
powders
spray-drying
A redispersible spray-dried formulation containing curcumin-loaded, lipid-core nanocapsules (LNC-C) was developed for oral administration. The neuroprotective activity of curcumin after the spray-drying process was evaluated in vitro. The spray-dried powder (SD-LNC-C) was produced using a drying adjuvant composed of a blend of maltodextrin and L-leucine (90:10 w/w). Acceptable process yield (~ 70%) and drug content (6.5 ± 0.2 mg g-1) were obtained. SD-LNC-C was formed by smooth, spherical-shaped particles, and confocal Raman analysis indicated the distribution of the LNC-C on the surface of the leucine/maltodextrin agglomerates. The surface of the agglomerates was formed by a combination of LNC-C and adjuvants, and laser diffraction showed that SD-LNC-C had adequate aqueous redispersion, with no loss of controlled drug release behaviour of LNC-C. The in vitro curcumin activity against the lipopolysaccharide (LPS)-induced proinflammatory response in organotypic hippocampal slice cultures was evaluated. Both formulations (LNC-C and SD-LNC-C) reduced TNF-α to similar levels. Therefore, neuroprotection of curcumin in vitro may be improved by nanoencapsulation followed by spray-drying, with no loss of this superior performance. Hence, the redispersible spray-dried powder proposed here represents a suitable approach for the development of innovative nanomedicines containing curcumin for the prevention/treatment of neurodegenerative diseases.
2021-02-01
2021-02-01
2019-08-12
Article
AAPS PharmSciTech. 2019 Aug 12;20(7):283. doi: 10.1208/s12249-019-1501-1.
31407115
10.1208/s12249-019-1501-1
http://hdl.handle.net/10033/622710
1530-9932
AAPS PharmSciTech
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Springer
oai:repository.helmholtz-hzi.de:10033/6229042021-06-15T01:41:01Zcom_10033_620613com_10033_620601col_10033_620614col_10033_620602
Fucosylated lipid nanocarriers loaded with antibiotics efficiently inhibit mycobacterial propagation in human myeloid cells.
Durán, Verónica
Grabski, Elena
Hozsa, Constantin
Becker, Jennifer
Yasar, Hanzey
Monteiro, João T
Costa, Bibiana
Koller, Nicole
Lueder, Yvonne
Wiegmann, Bettina
Brandes, Gudrun
Kaever, Volkhard
Lehr, Claus-Michael
Lepenies, Bernd
Tampé, Robert
Förster, Reinhold
Bošnjak, Berislav
Furch, Marcus
Graalmann, Theresa
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.;HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Alveolar macrophages
Liposomes
Nanomedicine
Targeted drug delivery
Tuberculosis
Antibiotic treatment of tuberculosis (TB) is complex, lengthy, and can be associated with various adverse effects. As a result, patient compliance often is poor, thus further enhancing the risk of selecting multi-drug resistant bacteria. Macrophage mannose receptor (MMR)-positive alveolar macrophages (AM) constitute a niche in which Mycobacterium tuberculosis replicates and survives. Therefore, we encapsulated levofloxacin in lipid nanocarriers functionalized with fucosyl residues that interact with the MMR. Indeed, such nanocarriers preferentially targeted MMR-positive myeloid cells, and in particular, AM. Intracellularly, fucosylated lipid nanocarriers favorably delivered their payload into endosomal compartments, where mycobacteria reside. In an in vitro setting using infected human primary macrophages as well as dendritic cells, the encapsulated antibiotic cleared the pathogen more efficiently than free levofloxacin. In conclusion, our results point towards carbohydrate-functionalized nanocarriers as a promising tool for improving TB treatment by targeted delivery of antibiotics.
2021-06-14
2021-06-14
2021-04-16
Article
J Control Release. 2021 Jun 10;334:201-212. doi: 10.1016/j.jconrel.2021.04.012. Epub 2021 Apr 16.
33865899
10.1016/j.jconrel.2021.04.012
http://hdl.handle.net/10033/622904
1873-4995
Journal of controlled release : official journal of the Controlled Release Society
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Elsevier
oai:repository.helmholtz-hzi.de:10033/6229742021-07-31T02:37:58Zcom_10033_620652com_10033_620601col_10033_620666col_10033_620672col_10033_620602
B cell depletion impairs vaccination-induced CD8 T cell responses in a type I interferon-dependent manner.
Graalmann, Theresa
Borst, Katharina
Manchanda, Himanshu
Vaas, Lea
Bruhn, Matthias
Graalmann, Lukas
Koster, Mario
Verboom, Murielle
Hallensleben, Michael
Guzmán, Carlos Alberto
Sutter, Gerd
Schmidt, Reinhold E
Witte, Torsten
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, Germany.
Arthritis
B-Lymphocytes
Rheumatoid
Rituximab
T-Lymphocyte subsets
Vaccination
Objectives: The monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.
Methods: CD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.
Results: Rituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.
Conclusions: Depending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.
2021-07-30
2021-07-30
2021-07-05
Article
Ann Rheum Dis. 2021 Jul 5:annrheumdis-2021-220435. doi: 10.1136/annrheumdis-2021-220435. Epub ahead of print.
34226189
10.1136/annrheumdis-2021-220435
http://hdl.handle.net/10033/622974
1468-2060
Annals of the rheumatic diseases
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
BMJ Publishing Group
oai:repository.helmholtz-hzi.de:10033/6230752021-10-19T01:51:36Zcom_10033_620601col_10033_620602
Sequential MAVS and MyD88/TRIF signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes.
Ghita, Luca
Breitkopf, Veronika
Mulenge, Felix
Pavlou, Andreas
Gern, Olivia Luise
Durán, Verónica
Prajeeth, Chittappen Kandiyil
Kohls, Moritz
Jung, Klaus
Stangel, Martin
Steffen, Imke
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
MAVS signaling
astrocytic anti-viral response
flaviviruses
innate immunity
neurotropic infection
tick-borne encephalitis virus
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV-infected mice, mitochondrial antiviral-signaling protein (MAVS), the downstream adaptor of retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To characterize the brain-resident cell subset that produces protective IFN-β in TBEV-infected mice, we isolated neurons, astrocytes, and microglia from mice and exposed these cell types to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-β was not detectable, while infected astrocytes showed high and microglia low IFN-β expression. Transcriptome analyses of astrocytes implied that MAVS signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-β responses. Nevertheless, at later time points, moderate amounts of IFN-β were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced only late IFN-β responses of TBEV-infected WT astrocytes and blocked entirely IFN-β responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-β producers showing biphasic IFN-β induction that initially depends on MAVS and later on MyD88/TRIF signaling.
2021-10-18
2021-10-18
2021-07-23
Article
J Neurosci Res. 2021 Jul 23. doi: 10.1002/jnr.24923. Epub ahead of print.
34296786
10.1002/jnr.24923
http://hdl.handle.net/10033/623075
1097-4547
Journal of neuroscience research
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Wiley
oai:repository.helmholtz-hzi.de:10033/6231342022-01-11T03:46:51Zcom_10033_620601col_10033_620602
Long-Lasting Immunity Against SARS-CoV-2: Dream or Reality?
Gussarow, Daniel
Bonifacius, Agnes
Cossmann, Anne
Stankov, Metodi V
Mausberg, Philip
Tischer-Zimmermann, Sabine
Gödecke, Nina
Kalinke, Ulrich
Behrens, Georg M N
Blasczyk, Rainer
Eiz-Vesper, Britta
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
SARS-CoV-2
antiviral T cells
cellular immunity
humoral immunity
immune protection
Since its declaration as a pandemic in March 2020, SARS-CoV-2 has infected more than 217 million people worldwide and despite mild disease in the majority of the cases, more than 4.5 million cases of COVID-19-associated death have been reported as of September 2021. The question whether recovery from COVID-19 results in prevention of reinfection can be answered with a "no" since cases of reinfections have been reported. The more important question is whether during SARS-CoV-2 infection, a protective immunity is built and maintained afterwards in a way which protects from possibly severe courses of disease in case of a reinfection. A similar question arises with respect to vaccination: as of September 2021, globally, more than 5.2 billion doses of vaccines have been administered. Therefore, it is of utmost importance to study the cellular and humoral immunity toward SARS-CoV-2 in a longitudinal manner. In this study, reconvalescent COVID-19 patients have been followed up for more than 1 year after SARS-CoV-2 infection to characterize in detail the long-term humoral as well as cellular immunity. Both SARS-CoV-2-specific T cells and antibodies could be detected for a period of more than 1 year after infection, indicating that the immune protection established during initial infection is maintained and might possibly protect from severe disease in case of reinfection or infection with novel emerging variants. Moreover, these data demonstrate the opportunity for immunotherapy of hospitalized COVID-19 patients via adoptive transfer of functional antiviral T cells isolated from reconvalescent individuals.
2022-01-10
2022-01-10
2021-11-25
Article
Front Med (Lausanne). 2021 Nov 25;8:770381. doi: 10.3389/fmed.2021.770381.
2296-858X
34901085
10.3389/fmed.2021.770381
http://hdl.handle.net/10033/623134
Frontiers in medicine
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Frontiers
oai:repository.helmholtz-hzi.de:10033/6231562022-02-02T02:04:24Zcom_10033_620601col_10033_620602
Toll-like Receptors in Viral Encephalitis.
Gern, Olivia Luise
Mulenge, Felix
Pavlou, Andreas
Ghita, Luca
Steffen, Imke
Stangel, Martin
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CNS
Toll-like receptors
astrocytes
microglia
neurons
viral encephalitis
viruses
Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
2022-02-01
2022-02-01
2021-10-14
Review
Viruses. 2021 Oct 14;13(10):2065. doi: 10.3390/v13102065.
34696494
10.3390/v13102065
http://hdl.handle.net/10033/623156
1999-4915
Viruses
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
MDPI
oai:repository.helmholtz-hzi.de:10033/6231582022-02-04T01:56:49Zcom_10033_620601col_10033_620602
Beneficial and detrimental functions of microglia during viral encephalitis.
Waltl, Inken
Kalinke, Ulrich
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
CNS infection
antiviral defence
brain immune response
cellular crosstalk
microglia
icroglia are resident immune cells of the central nervous system (CNS) with multiple functions in health and disease. Their response during encephalitis depends on whether inflammation is triggered in a sterile or infectious manner, and in the latter case on the type of the infecting pathogen. Even though recent technological innovations advanced the understanding of the broad spectrum of microglia responses during viral encephalitis (VE), it is not entirely clear which microglia gene expression profiles are associated with antiviral and detrimental activities. Here, we review novel approaches to study microglia and the latest concepts of their function in VE. Improved understanding of microglial functions will be essential for the development of new therapeutic interventions for VE.
2022-02-03
2022-02-03
2021-12-11
Article
Trends Neurosci. 2022 Feb;45(2):158-170. doi: 10.1016/j.tins.2021.11.004. Epub 2021 Dec 11.
34906391
10.1016/j.tins.2021.11.004
http://hdl.handle.net/10033/623158
1878-108X
Trends in neurosciences
en
http://creativecommons.org/licenses/by-nc-nd/4.0/
Attribution-NonCommercial-NoDerivatives 4.0 International
Elsevier (Cell Press)