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  • 1.
    Bavdek, Andrej
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Gekara, Nelson O
    Priselac, Dragan
    Gutiérrez Aguirre, Ion
    Darji, Ayub
    Chakraborty, Trinad
    Macek, Peter
    Lakey, Jeremy H
    Weiss, Siegfried
    Anderluh, Gregor
    Sterol and pH interdependence in the binding, oligomerization, and pore formation of Listeriolysin O.2007In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 14, 4425-4437 p.Article in journal (Refereed)
    Abstract [en]

    Listeriolysin O (LLO) is the most important virulence factor of the intracellular pathogen Listeria monocytogenes. Its main task is to enable escape of bacteria from the phagosomal vacuole into the cytoplasm. LLO belongs to the cholesterol-dependent cytolysin (CDC) family but differs from other members, as it exhibits optimal activity at low pH. Its pore forming ability at higher pH values has been largely disregarded in Listeria pathogenesis. Here we show that high cholesterol concentrations in the membrane restore the low activity of LLO at high pH values. LLO binds to lipid membranes, at physiological or even slightly basic pH values, in a cholesterol-dependent fashion. Binding, insertion into lipid monolayers, and permeabilization of calcein-loaded liposomes are maximal above approximately 35 mol % cholesterol, a concentration range typically found in lipid rafts. The narrow transition region of cholesterol concentration separating low and high activity indicates that cholesterol not only allows the binding of LLO to membranes but also affects other steps in pore formation. We were able to detect some of these by surface plasmon resonance-based assays. In particular, we show that LLO recognition of cholesterol is determined by the most exposed 3beta-hydroxy group of cholesterol. In addition, LLO binds and permeabilizes J774 cells and human erythrocytes in a cholesterol-dependent fashion at physiological or slightly basic pH values. The results clearly show that LLO activity at physiological pH cannot be neglected and that its action at sites distal to cell entry may have important physiological consequences for Listeria pathogenesis.

  • 2. Dietrich, Nicole
    et al.
    Lienenklaus, Stefan
    Weiss, Siegfried
    Gekara, Nelson O
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Murine toll-like receptor 2 activation induces type I interferon responses from endolysosomal compartments.2010In: PloS one, ISSN 1932-6203, Vol. 5, no 4, e10250- p.Article in journal (Refereed)
    Abstract [en]

    The results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.

  • 3. Dietrich, Nicole
    et al.
    Rohde, Manfred
    Geffers, Robert
    Kröger, Andrea
    Hauser, Hansjörg
    Weiss, Siegfried
    Gekara, Nelson O
    Helmholtz-Centre for Infection Research, 38124 Braunschweig, Germany.
    Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria.2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 19, 8748-8753 p.Article in journal (Refereed)
    Abstract [en]

    Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes. Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-beta. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses.

  • 4.
    Erttmann, Saskia F.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bacteria Induce Prolonged PMN Survival via a Phosphatidylcholine-Specific Phospholipase C- and Protein Kinase C-Dependent Mechanism2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, e87859- p.Article in journal (Refereed)
    Abstract [en]

    Polymorphonuclear leukocytes (PMNs) are essential for the human innate immune defense, limiting expansion of invading microorganisms. PMN turnover is controlled by apoptosis, but the regulating signaling pathways remain elusive, largely due to inherent differences between mice and humans that undermine use of mouse models for understanding human PMN biology. Here, we aim to elucidate signal transduction mediating survival of human peripheral blood PMNs in response to bacteria, such as Yersinia pseudotuberculosis, an enteropathogen that causes the gastro-intestinal disease yersiniosis, as well as Escherichia coli and Staphylococcus aureus. Determinations of cell death reveal that uninfected control cells undergo apoptosis, while PMNs infected with either Gram-positive or -negative bacteria show profoundly increased survival. Infected cells exhibit decreased caspase 3 and 8 activities, increased mitochondrial integrity and are resistant to apoptosis induced by a death receptor ligand. This bacteria-induced response is accompanied by pro-inflammatory cytokine production including interleukin-8 and tumor necrosis factor-a competent to attract additional PMNs. Using agonists and pharmacological inhibitors, we show participation of Toll-like receptor 2 and 4, and interestingly, that protein kinase C (PKC) and phosphatidylcholine-specific phospholipase C (PC-PLC), but not tyrosine kinases or phosphatidylinositol-specific phospholipase C (PI-PLC) are key players in this dual PMN response. Our findings indicate the importance of prolonged PMN survival in response to bacteria, where general signaling pathways ensure complete exploitation of PMN anti-microbial capacity.

  • 5.
    Gekara, N O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Weiss, S
    Lipid rafts clustering and signalling by listeriolysin O.2004In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 32, no Pt 5, 712-714 p.Article in journal (Refereed)
    Abstract [en]

    Listeriolysin O, the major virulent determinant of Listeria monocytogenes, is known for forming pores on cholesterol-rich membranes. In the present study, we reveal its other facet, rafts clustering. By immunofluorescence microscopy, we show that the glycosylphosphatidylinositol-anchored proteins CD14 and CD24, which normally exhibit uniform distribution on J774 cells, undergo clustering upon treatment with LLO. The non-raft marker transferrin receptor is unaffected by such treatment. Rafts clustering might explain the induction of tyrosine phosphorylation observed on LLO-treated cells.

  • 6.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Dietrich, Nicole
    Lyszkiewicz, Marcin
    Lienenklaus, Stefan
    Weiss, Siegfried
    Signals triggered by a bacterial pore-forming toxin contribute to toll-like receptor redundancy in gram-positive bacterial recognition.2009In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 199, no 1, 124-33 p.Article in journal (Refereed)
    Abstract [en]

    The results illustrate that signals triggered by LLO contribute to TLR2 redundancy in recognition of L. monocytogenes. Under normal conditions, multiple and, sometimes, redundant pathways cooperate to induce a rapid antimicrobial defense. When one signaling pathway-in this case, TLR2-is removed from the system, the other pathways are still capable of mounting a sufficient response to ensure survival of the host.

  • 7.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Groebe, Lothar
    Viegas, Nuno
    Weiss, Siegfried
    Listeria monocytogenes desensitizes immune cells to subsequent Ca2+ signaling via listeriolysin O-induced depletion of intracellular Ca2+ stores.2008In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 2, 857-862 p.Article in journal (Refereed)
    Abstract [en]

    Listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, is a prototype of the cholesterol-dependent cytolysins (CDCs) secreted by several pathogenic and nonpathogenic gram-positive bacteria. In addition to mediating the escape of the bacterium into the cytosol, this toxin is generally believed to be a central player in host-pathogen interactions during L. monocytogenes infection. LLO triggers the influx of Ca(2+) into host cells as well as the release of Ca(2+) from intracellular stores. Thus, many of the cellular responses induced by LLO are related to calcium signaling. Interestingly, in this study, we report that prolonged exposure to LLO desensitizes cells to Ca(2+) mobilization upon subsequent stimulations with LLO. Cells preexposed to LLO-positive L. monocytogenes but not to the LLO-deficient Deltahly mutant were found to be highly refractory to Ca(2+) induction in response to receptor-mediated stimulation. Such cells also exhibited diminished Ca(2+) signals in response to stimulation with LLO and thapsigargin. The presented results suggest that this phenomenon is due to the depletion of intracellular Ca(2+) stores. The ability of LLO to desensitize immune cells provides a significant hint about the possible role played by CDCs in the evasion of the immune system by bacterial pathogens.

  • 8.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Jacobs, Thomas
    Chakraborty, Trinad
    Weiss, Siegfried
    The cholesterol-dependent cytolysin listeriolysin O aggregates rafts via oligomerization.2005In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 7, no 9, 1345-1356 p.Article in journal (Refereed)
    Abstract [en]

    The pore-forming toxin listeriolysin O (LLO) is the main virulence factor of Listeria monocytogenes. LLO is known to act as a pseudo cytokine/chemokine, which induces a broad spectrum of host responses that ultimately influences the outcome of listeriosis. In the present study we demonstrate that LLO is a potent aggregator of lipid rafts. LLO was found to aggregate the raft associated molecules GM1, the GPI-anchored proteins CD14 and CD16 as well as the tyrosine kinase Lyn. Abrogation of the cytolytic activity of LLO by cholesterol pretreatment was found not to interfere with LLO's ability to aggregate rafts or trigger tyrosine phosphorylation in cells. However, a monoclonal antibody that blocks the oligomerization of LLO was found to inhibit rafts' aggregation as well as the induction of tyrosine phosphorylation. This implies that rafts aggregation by LLO which is independent of cytolytic activity, is due to the oligomerization of its membrane bound toxin monomers. Thus, LLO most likely induces signalling through the coaggregation of rafts' associated receptors, kinases and adaptors.

  • 9.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Weiss, Siegfried
    Mast cells initiate early anti-Listeria host defences.2008In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, no 1, 225-236 p.Article in journal (Refereed)
    Abstract [en]

    The Gram-positive bacterium Listeria monocytogenes (L. m.) is the aetiological agent of listeriosis. The early phase listeriosis is characterized by strong innate host responses that play a major role in bacterial clearance. This is emphasized by the fact that mice deficient in T and B cells have a remarkable ability to control infection. Mast cells, among the principal effectors of innate immunity, have largely been studied in the context of hyper-reactive conditions such as allergy and autoimmune diseases. In the present study, we evaluated the significance of mast cells during the early phase of listeriosis. Compared with controls, mice depleted of mast cells showed hundred-fold higher bacterial burden in spleen and liver and were significantly impaired in neutrophil mobilization. Although L. m. interacts with and triggers mast cell degranulation, bacteria were hardly found within such cells. Mainly neutrophils and macrophages phagozytosed L. m. Thus, mast cells control infection not via direct bacterial uptake, but by initiating neutrophils influx to the site of infection. We show that this is initiated by pre-synthesized TNF-alpha, rapidly secreted by mast cell upon activation by L. m. We also show that upon recruitment, neutrophils also become activated and additionally secrete TNF-alpha thus amplifying the anti-L. m. inflammatory response.

  • 10.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Westphal, Kathrin
    Ma, Bin
    Rohde, Manfred
    Groebe, Lothar
    Weiss, Siegfried
    The multiple mechanisms of Ca2+ signalling by listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes.2007In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 9, no 8, 2008-2021 p.Article in journal (Refereed)
    Abstract [en]

    Cholesterol-dependent cytolysins (CDCs) represent a large family of conserved pore-forming toxins produced by several Gram-positive bacteria such as Listeria monocytogenes, Streptococcus pyrogenes and Bacillus anthracis. These toxins trigger a broad range of cellular responses that greatly influence pathogenesis. Using mast cells, we demonstrate that listeriolysin O (LLO), a prototype of CDCs produced by L. monocytogenes, triggers cellular responses such as degranulation and cytokine synthesis in a Ca(2+)-dependent manner. Ca(2+) signalling by LLO is due to Ca(2+) influx from extracellular milieu and release of from intracellular stores. We show that LLO-induced release of Ca(2+) from intracellular stores occurs via at least two mechanisms: (i) activation of intracellular Ca(2+) channels and (ii) a Ca(2+) channels independent mechanism. The former involves PLC-IP(3)R operated Ca(2+) channels activated via G-proteins and protein tyrosine kinases. For the latter, we propose a novel mechanism of intracellular Ca(2+) release involving injury of intracellular Ca(2+) stores such as the endoplasmic reticulum. In addition to Ca(2+) signalling, the discovery that LLO causes damage to an intracellular organelle provides a new perspective in our understanding of how CDCs affect target cells during infection by the respective bacterial pathogens.

  • 11.
    Gekara, Nelson O
    et al.
    Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Zietara, Natalia
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Geffers, Robert
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Weiss, Siegfried
    Molecular Immunology and 2Department of Cell Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Listeria monocytogenes induces T cell receptor unresponsiveness through pore-forming toxin listeriolysin O2010In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 202, no 11, 1698-1707 p.Article in journal (Refereed)
    Abstract [en]

    Background.  The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert adaptive immune defenses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins that are produced by more than 20 gram-positive bacterial species. Listeriolysin O (LLO), a prototype CDC, is the main virulence factor of Listeria monocytogenes. Methods.  We employed flow cytometric and microarray techniques to analyze the effect of LLO on T cell activation in vitro and in vivo. Results.  In vivo and in vitro proliferation of CD4(+) T cells upon T cell receptor (TCR) activation was highly diminished in the presence of LLO or wild-type L. monocytogenes but not in the presence of LLO-deficient L. monocytogenes. This block in T cell proliferation was specific to T cell activation via the TCR and not by phorbol 12-myristate 13-acetate-ionomycin, which bypasses the proximal TCR signaling event. The results of microarray analysis suggest that LLO-induced T cell unresponsiveness is due to the induction of a calcium-nuclear factor of activated T cells-dependent transcriptional program that drives the expression of negative regulators of TCR signaling. Conclusion. These findings provide important insights into how bacterial toxins silence adaptive immune responses and thus enable prolonged survival of the pathogen in the host.

  • 12.
    Härtlova, Anetta
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Erttmann, Saskia F.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Raffi, Faizal A. M.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schmalz, Anja M.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Resch, Ulrike
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Anugula, Sharath
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lienenklaus, Stefan
    Nilsson, Lisa M.
    Kroeger, Andrea
    Nilsson, Jonas A.
    Ek, Torben
    Weiss, Siegfried
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity2015In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 42, no 2, 332-343 p.Article in journal (Refereed)
    Abstract [en]

    Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

  • 13.
    Härtlova, Anetta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Link, Marek
    Balounova, Jana
    Benesova, Martina
    Resch, Ulrike
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Straskova, Adela
    Sobol, Margarita
    Philimonenko, Anatoly
    Hozak, Pavel
    Krocova, Zuzana
    Gekara, Nelson
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Filipp, Dominik
    Stulik, Jiri
    Quantitative proteomics analysis of macrophage-derived lipid rafts reveals induction of autophagy pathway at the early time of Francisella tularensis LVS infection2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 2, 796-804 p.Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis is a highly infectious intracellular pathogen that has evolved an efficient strategy to subvert host defense response to survive inside the host. The molecular mechanisms regulating these host-pathogen interactions and especially those that are initiated at the time of the bacterial entry via its attachment to the host plasma membrane likely predetermine the intracellular fate of pathogen. Here, we provide the evidence that infection of macrophages with F. tularensis leads to changes in protein composition of macrophage-derived lipid rafts, isolated as detergent-resistant membranes (DRMs). Using SILAC-based quantitative proteomic approach, we observed the accumulation of autophagic adaptor protein p62 at the early, stages of microbe-host cell interaction. We confirmed the colocalization of the p62 with ubiquitinated and LC3-decorated intracellular F. tularensis microbes with its maximum at 1 h postinfection. Furthermore, the infection of p62-knockdown host cells led to the transient increase in the intracellular number of microbes up to 4 h after in vitro infection. Together, these data suggest that the activation of the autophagy pathway in F. tularensis infected macrophages, which impacts the early phase of microbial proliferation, is subsequently circumvented by ongoing infection.

  • 14.
    Kurhade, Chaitanya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Zegenhagen, Loreen
    Weber, Elvira
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Michaelsen-Preusse, Kristin
    Spanier, Julia
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kroeger, Andrea
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-12016In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 13, 22Article in journal (Refereed)
    Abstract [en]

    Background: Although type I interferons (IFNs)—key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.

    Methods: IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed.

    Results: We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-β levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS.

    Conclusions: We show that LGTV replication is restricted to the olfactory bulb and that IPS-1 is a very important player in the olfactory bulb in shaping the innate immune response by inhibiting early viral replication and viral spread throughout the central nervous system. In the absence of IPS-1, higher viral replication leads to the evasion of antiviral response by inhibiting interferon signaling. Our data suggest that the local microenvironment of distinct brain regions is critical to determine virus permissiveness.

  • 15. Leschner, Sara
    et al.
    Westphal, Kathrin
    Dietrich, Nicole
    Viegas, Nuno
    Jablonska, Jadwiga
    Lyszkiewicz, Marcin
    Lienenklaus, Stefan
    Falk, Werner
    Gekara, Nelson
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Loessner, Holger
    Weiss, Siegfried
    Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.2009In: PloS one, ISSN 1932-6203, Vol. 4, no 8, e6692- p.Article in journal (Refereed)
    Abstract [en]

    Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria.

  • 16. Lienenklaus, Stefan
    et al.
    Cornitescu, Marius
    Zietara, Natalia
    Łyszkiewicz, Marcin
    Gekara, Nelson
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Jabłónska, Jadwiga
    Edenhofer, Frank
    Rajewsky, Klaus
    Bruder, Dunja
    Hafner, Martin
    Staeheli, Peter
    Weiss, Siegfried
    Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo.2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 5, 3229-3236 p.Article in journal (Refereed)
    Abstract [en]

    Type I IFN is a major player in innate and adaptive immune responses. Besides, it is involved in organogenesis and tumor development. Generally, IFN responses are amplified by an autocrine loop with IFN-beta as the priming cytokine. However, due to the lack of sensitive detection systems, where and how type I IFN is produced in vivo is still poorly understood. In this study, we describe a luciferase reporter mouse, which allows tracking of IFN-beta gene induction in vivo. Using this reporter mouse, we reveal strong tissue-specific induction of IFN-beta following infection with influenza or La Crosse virus. Importantly, this reporter mouse also allowed us to visualize that IFN-beta is expressed constitutively in several tissues. As suggested before, low amounts of constitutively produced IFN might maintain immune cells in an activated state ready for a timely response to pathogens. Interestingly, thymic epithelial cells were the major source of IFN-beta under noninflammatory conditions. This relatively high constitutive expression was controlled by the NF Aire and might influence induction of tolerance or T cell development.

  • 17.
    Panda, Swarupa
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Jonas A.
    Gothenburg, Sweden.
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes2015In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 43, no 4, 647-659 p.Article in journal (Refereed)
    Abstract [en]

    Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.

  • 18.
    Weber, Elvira
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Finsterbusch, Katja
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lienenklaus, Stefan
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Gekara, Nelson O
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Janik, Dirk
    Institute of Pathology, Helmholtz Center Munich, Neuherberg, Germany.
    Weiss, Siegfried
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Kalinke, Ulrich
    Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.
    Överby, Anna K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kröger, Andrea
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses2014In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 89, no 21, 12202-12212 p.Article in journal (Refereed)
    Abstract [en]

    Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE: The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.

  • 19. Zietara, Natalia
    et al.
    Łyszkiewicz, Marcin
    Gekara, Nelson
    Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Puchałka, Jacek
    Dos Santos, Vitor A P Martins
    Hunt, Clayton R
    Pandita, Tej K
    Lienenklaus, Stefan
    Weiss, Siegfried
    Absence of IFN-beta impairs antigen presentation capacity of splenic dendritic cells via down-regulation of heat shock protein 70.2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 2, 1099-1109 p.Article in journal (Refereed)
    Abstract [en]

    Type I IFNs play a key role in linking the innate and adaptive arms of the immune system. Although produced rapidly in response to pathogens, IFNs are also produced at low levels in the absence of infection. In the present study, we demonstrate that constitutively produced IFNs are necessary in vivo to maintain dendritic cells in an "Ag presentation-competent" state. Conventional dendritic cells (cDCs) isolated from spleens of IFN-beta or IFNAR-deficient mice exhibit a highly impaired ability to present Ag and activate naive T cells. Microarray analysis of mRNA isolated from IFN-beta(-/-) and IFNAR(-/-) cDCs revealed diminished expression of two genes that encoded members of the heat shock protein 70 (Hsp70) family. Consistent with this observation, pharmacological inhibition of Hsp70 in cDCs from wild-type mice impaired their T cell stimulatory capacity. Similarly, the Ag presentation ability of splenic cDCs isolated from Hsp70.1/3(-/-) mice was also severely impaired in comparison to wild-type cDCs. Thus, constitutive IFN-beta expression regulates Hsp70 levels to help maintain dendritic cells in a competent state for efficient priming of effector T cells in vivo.

  • 20. Łyszkiewicz, Marcin
    et al.
    Zietara, Natalia
    Rohde, Manfred
    Gekara, Nelson O
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Jabłońska, Jadwiga
    Dittmar, Kurt E
    Weiss, Siegfried
    SIGN-R1+MHC II+ cells of the splenic marginal zone: a novel type of resident dendritic cells2011In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 89, no 4, 607-615 p.Article in journal (Refereed)
    Abstract [en]

    In the spleen, the MZ forms an interface between red and white pulp. Its major function is to trap blood-borne antigens and to reorient them to APCs and lymphocytes. SIGN-R1(+) cells are of the MZ inherent cell population, which for a long time, have been considered as macrophages. We now show that one subpopulation of SIGN-R1(+) cells that express MHC II molecules should be considered as a resident DC. Histological analysis indicated that SIGN-R1(+) cells have dendritic-like protrusions extending into T and B cell areas. Flow cytometry analysis revealed an expression profile of adhesion, costimulatory, and MHC molecules similar to cDCs but distinct from macrophages. Most importantly, SIGN-R1(+)MHC(+) cells were able to present antigen to naïve CD4 T cells, as well as to cross-present soluble, particulate antigens secreted by Listeria monocytogenes to CD8 T cells in vitro and in vivo. Our experiments identified SIGN-R1(+)MHC II(+) cells as professional APCs and indicate their nature as splenic resident DCs.

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