Institute for Experimental Infection Research

Hannover, Germany

Institute for Experimental Infection Research

Hannover, Germany
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Dann A.,Albert Ludwigs University of Freiburg | Poeck H.,University of Bonn | Poeck H.,TU Munich | Croxford A.L.,Johannes Gutenberg University Mainz | And 16 more authors.
Nature Neuroscience | Year: 2012

The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5-2-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T H 1 and T H 17 cells, whereas T-cell differentiation was not altered. Notably, T H 1 and T H 17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T H 1 and T H 17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis. © 2012 Nature America, Inc. All rights reserved.

Lebel M.-E.,INRS - Institute National de la Recherche Scientifique | Daudelin J.-F.,University of Montréal | Chartrand K.,INRS - Institute National de la Recherche Scientifique | Tarrab E.,INRS - Institute National de la Recherche Scientifique | And 5 more authors.
Journal of Immunology | Year: 2014

Developing new adjuvants and vaccination strategies is of paramount importance to successfully fight against many life-threatening infectious diseases and cancer. Very few adjuvants are currently authorized for human use, and these mainly stimulate a humoral response. However, specific Abs are not sufficient to confer protection against persisting infections or cancer. Therefore, development of adjuvants and immunomodulators able to enhance cell-mediated immune responses represents a major medical need. We recently showed that papaya mosaic virus nanoparticles (PapMV), self-Assembled from the coat protein of a plant virus and a noncoding ssRNA molecule, are highly immunogenic in mice. PapMV can be used either as a vaccine delivery platform, through fusion of various epitopes to the coat protein or as adjuvant to enhance humoral immune responses against coadministered Ags or vaccines. However, the mechanisms that confer these immunomodulatory properties to PapMV and its ability to enhance T cell vaccines remain unknown. Using immunization studies in mice, we demonstrate in this paper that PapMV represents a novel TLR7 agonist with strong immunostimulatory properties. More importantly, pretreatment with PapMV significantly improves effector and memory CD8+ T cell responses generated through dendritic cell vaccination increasing protection against a Listeria monocytogenes challenge. Copyright © 2014 by The American Association of Immunologists, Inc.

Hogner K.,Justus Liebig University | Wolff T.,Robert Koch Institute | Pleschka S.,Justus Liebig University | Plog S.,Free University of Berlin | And 10 more authors.
PLoS Pathogens | Year: 2013

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury. © 2013 Högner et al.

Zust R.,Agency for Science, Technology and Research Singapore | Toh Y.-X.,Agency for Science, Technology and Research Singapore | Valdes I.,Center for Genetic Engineering and Biotechnology | Cerny D.,Agency for Science, Technology and Research Singapore | And 8 more authors.
Journal of Virology | Year: 2014

Dengue virus (DENV) infects an estimated 400 million people every year, causing prolonged morbidity and sometimes mortality. Development of an effective vaccine has been hampered by the lack of appropriate small animal models; mice are naturally not susceptible to DENV and only become infected if highly immunocompromised. Mouse models lacking both type I and type II interferon (IFN) receptors (AG129 mice) or the type I IFN receptor (IFNAR-/- mice) are susceptible to infection with mouseadapted DENV strains but are severely impaired in mounting functional immune responses to the virus and thus are of limited use for study. Here we used conditional deletion of the type IIFN receptor (IFNAR) on individual immune cell subtypes to generate a minimally manipulated mouse model that is susceptible to DENV while retaining global immune competence. Mice lacking IFNAR expression on CD11c+ dendritic cells and LysM+ macrophages succumbed completely to DENV infection, while mice deficient in the receptor on either CD11c+ or LysM+ cells were susceptible to infection but often resolved viremia and recovered fully from infection. Conditional IFNAR mice responded with a swift and strong CD8+ T-cell response to viral infection, compared to a weak response in IFNAR-/- mice. Furthermore, mice lacking IFNAR on either CD11c+ or LysM+ cells were also sufficiently immunocompetent to raise a protective immune response to a candidate subunit vaccine against DENV-2. These data demonstrate that mice with conditional deficiencies in expression of the IFNAR represent improved models for the study of DENV immunology and screening of vaccine candidates. © 2014, American Society for Microbiology.

Prinz M.,Albert Ludwigs University of Freiburg | Kalinke U.,Institute for Experimental Infection Research
Trends in Molecular Medicine | Year: 2010

Type I interferons (IFN-α and IFN-β) were discovered more than five decades ago and are widely used for the treatment of human autoimmune diseases such as multiple sclerosis (MS). Despite their highly beneficial features, the precise mechanism of action remains speculative. Given the frequent side effects of IFN-α/β therapy, understanding its action in an in vivo setting is vital to further improve this therapeutic approach. Major advances in our understanding of the IFN biology have recently been made and are particularly based on the combination of powerful genome-wide expression analysis in humans with gene-targeting techniques available for basic research. The recent discovery of a novel T-cell subset, Th17 cells, sheds new light on type I IFNs in MS. © 2010 Elsevier Ltd.

Al Moussawi K.,Aix - Marseille University | Ghigo E.,Aix - Marseille University | Kalinke U.,Paul Ehrlich Institute | Kalinke U.,Institute for Experimental Infection Research | And 3 more authors.
PLoS Pathogens | Year: 2010

Macrophages are the first line of defense against pathogens. Upon infection macrophages usually produce high levels of proinflammatory mediators. However, macrophages can undergo an alternate polarization leading to a permissive state. In assessing global macrophage responses to the bacterial agent of Whipple's disease, Tropheryma whipplei, we found that T. whipplei induced M2 macrophage polarization which was compatible with bacterial replication. Surprisingly, this M2 polarization of infected macrophages was associated with apoptosis induction and a functional type I interferon (IFN) response, through IRF3 activation and STAT1 phosphorylation. Using macrophages from mice deficient for the type I IFN receptor, we found that this type I IFN response was required for T. whipplei-induced macrophage apoptosis in a JNKdependent manner and was associated with the intracellular replication of T. whipplei independently of JNK. This study underscores the role of macrophage polarization in host responses and highlights the detrimental role of type I IFN during T. whipplei infection. © 2010 Al Moussawi et al.

Goossens P.,Maastricht University | Gijbels M.J.J.,Maastricht University | Zernecke A.,RWTH Aachen | Eijgelaar W.,Maastricht University | And 13 more authors.
Cell Metabolism | Year: 2010

Inflammatory cytokines are well-recognized mediators of atherosclerosis. Depending on the pathological context, type I interferons (IFNs; IFNα and IFNβ) exert either pro-or anti-inflammatory immune functions, but their exact role in atherogenesis has not been clarified. Here, we demonstrate that IFNβ enhances macrophage-endothelial cell adhesion and promotes leukocyte attraction to atherosclerosis-prone sites in mice in a chemokine-dependent manner. Moreover, IFNβ treatment accelerateslesion formation in two different mouse models of atherosclerosis and increases macrophage accumulation in the plaques. Concomitantly, absence of endogenous type I IFN signaling in myeloid cells inhibits lesion development, protects against lesional accumulation of macrophages, and prevents necrotic core formation. Finally, we show that type I IFN signaling is upregulated in ruptured human atherosclerotic plaques. Hereby, we identify type I IFNs as proatherosclerotic cytokines that may serve as additional targets for prevention or treatment. © 2010 Elsevier Inc.

Volz A.,Ludwig Maximilians University of Munich | Langenmayer M.,Ludwig Maximilians University of Munich | Jany S.,Ludwig Maximilians University of Munich | Jany S.,German Center for Infection Research | And 3 more authors.
Journal of Virology | Year: 2014

Immunization with modified vaccinia virus Ankara (MVA) can rapidly protect mice against lethal ectromelia virus (ECTV) infection, serving as an experimental model for severe systemic infections. Importantly, this early protective capacity of MVA vaccination completely depends on virus-specific cytotoxic CD8+ T cell responses. We used MVA vaccination in the mousepox challenge model using ECTV infection to investigate the previously unknown factors required to elicit rapid protective T cell immunity in normal C57BL/6 mice and in mice lacking the interferon alpha/beta receptor (IFNAR-/-). We found a minimal dose of 105 PFU of MVA vaccine fully sufficient to allow robust protection against lethal mousepox, as assessed by the absence of disease symptoms and failure to detect ECTV in organs from vaccinated animals. Moreover, MVA immunization at low dosage also protected IFNAR-/- mice, indicating efficient activation of cellular immunity even in the absence of type I interferon signaling. When monitoring for virus-specific CD8+ T cell responses in mice vaccinated with the minimal protective dose of MVA, we found significantly enhanced levels of antigen-specific T cells in animals that were MVA vaccinated and ECTV challenged compared to mice that were only vaccinated. The initial priming of naive CD8+ T cells by MVA immunization appears to be highly efficient and, even at low doses, mediates a rapid in vivo burst of pathogen-specific T cells upon challenge. Our findings define striking requirements for protective emergency immunization against severe systemic infections with orthopoxviruses. © 2014, American Society for Microbiology.

Kalinke U.,Institute for Experimental Infection Research
Virulence | Year: 2011

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.

Frenz T.,Institute for Experimental Infection Research | Graalmann L.,Institute for Experimental Infection Research | Detje C.N.,Institute for Experimental Infection Research | Doring M.,Institute for Experimental Infection Research | And 3 more authors.
Journal of Immunology | Year: 2014

Upon treatment with vesicular stomatitis virus (VSV) particles, plasmacytoid dendritic cells (pDC) are triggered to mount substantial type I IFN responses, whereas myeloid DC (mDC) are only minor producers. Interestingly, bone marrow-derived (BM-) mDC were more vulnerable to infection with enhanced GFP (eGFP)-expressing VSV (VSVeGFP) than BM-pDC. BM-pDC stimulated with wild-type VSV mounted TLR-dependent IFN responses that were independent of RIG-I-like helicase (RLH) signaling. In contrast, in BM-pDC the VSV variant M2 induced particularly high IFN responses triggered in a TLR-and RLHdependent manner, whereas BM-mDC stimulation was solely RLH-dependent. Importantly, VSVeGFP treatment of BM-pDC derived from IFN-β yellow fluorescent protein (YFP) reporter mice (messenger of IFN-β) resulted in YFP+and eGFP+singlepositive cells, whereas among messenger of IFN-β-BM-mDC most YFP+cells were also eGFP+. This observation indicated that unlike mDC, direct virus infection was not required to trigger IFN responses of pDC. VSV-infected BM-mDC triggered BM-pDC to mount significantly higher IFN responses than free virus particles. Stimulation with infected cells enhanced the percentages of pDC subsets expressing either IFN-β+or IFN-α6+plus IFN-β+. Irrespective of whether stimulated with free virus or infected cells, IFN induction was dependent on autophagy of pDC, whereas autophagy of the infected mDC was dispensable. Collectively, these results indicated that productive VSV infection was needed to trigger IFN responses of mDC, but not of pDC, and that IFN responses were primarily induced by virus-infected cells that stimulated pDC in a TLR-dependent manner. Copyright © 2014 by The American Association of Immunologists, Inc.

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