42 results on '"Duhan, Vikas"'
Search Results
2. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury
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Drommelschmidt, Karla, Serdar, Meray, Bendix, Ivo, Herz, Josephine, Bertling, Frederik, Prager, Sebastian, Keller, Matthias, Ludwig, Anna-Kristin, Duhan, Vikas, Radtke, Stefan, de Miroschedji, Kyra, Horn, Peter A., van de Looij, Yohan, Giebel, Bernd, and Felderhoff-Müser, Ursula
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- 2017
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3. Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
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Lang, Judith, Bohn, Patrick, Bhat, Hilal, Jastrow, Holger, Walkenfort, Bernd, Cansiz, Feyza, Fink, Julian, Bauer, Michael, Olszewski, Dominik, Ramos-Nascimento, Ana, Duhan, Vikas, Friedrich, Sarah-Kim, Becker, Katrin Anne, Krawczyk, Adalbert, Edwards, Michael J., Burchert, Andreas, Huber, Magdalena, Friebus-Kardash, Justa, Göthert, Joachim R., Hardt, Cornelia, Probst, Hans Christian, Schumacher, Fabian, Köhrer, Karl, Kleuser, Burkhard, Babiychuk, Eduard B., Sodeik, Beate, Seibel, Jürgen, Greber, Urs F., Lang, Philipp A., Gulbins, Erich, and Lang, Karl S.
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- 2020
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4. Editorial: Natural killer cell plasticity and diversity in antiviral immunity
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Krebs, Philippe, primary, Peng, Hui, additional, and Duhan, Vikas, additional
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- 2023
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5. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity
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Wagner, Johannes M., Jaurich, Henriette, Wallner, Christoph, Abraham, Stephanie, Becerikli, Mustafa, Dadras, Mehran, Harati, Kamran, Duhan, Vikas, Khairnar, Vishal, Lehnhardt, Marcus, and Behr, Björn
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- 2017
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6. Adipose‐Derived Stromal Cells Are Capable of Restoring Bone Regeneration After Post‐Traumatic Osteomyelitis and Modulate B‐Cell Response
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Wagner, Johannes Maximilian, Reinkemeier, Felix, Wallner, Christoph, Dadras, Mehran, Huber, Julika, Schmidt, Sonja Verena, Drysch, Marius, Dittfeld, Stephanie, Jaurich, Henriette, Becerikli, Mustafa, Becker, Kathrin, Rauch, Nicole, Duhan, Vikas, Lehnhardt, Marcus, and Behr, Björn
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Male ,B-Lymphocytes ,Medicine (General) ,QH573-671 ,Cell Differentiation ,Mesenchymal Stem Cells ,Osteomyelitis ,Stem cells ,B‐cells ,Bone regeneration ,Mice ,R5-920 ,Adipose Tissue ,Tissue Engineering and Regenerative Medicine ,Post‐traumatic osteomyelitis ,Osteoimmunology ,Animals ,Humans ,Female ,Cytology - Abstract
Bone infections are a frequent cause for large bony defects with a reduced healing capacity. In previous findings, we could already show diminished healing capacity after bone infections, despite the absence of the causing agent, Staphylococcus aureus. Moreover, these bony defects showed reduced osteoblastogenesis and increased osteoclastogenesis, meaning elevated bone resorption ongoing with an elevated B‐cell activity. To overcome the negative effects of this postinfectious inflammatory state, we tried to use the regenerative capacity of mesenchymal stem cells derived from adipose tissue (adipose‐derived stem cells [ASCs]) to improve bone regeneration and moreover were curious about immunomodulation of applicated stem cells in this setting. Therefore, we used our established murine animal model and applicated ASCs locally after sufficient debridement of infected bones. Bone regeneration and resorption as well as immunological markers were investigated via histology, immunohistochemistry, Western blot, and fluorescence‐activated cell scanning (FACS) analysis and μ‐computed tomography (CT) analysis. Interestingly, ASCs were able to restore bone healing via elevation of osteoblastogenesis and downregulation of osteoclasts. Surprisingly, stem cells showed an impact on the innate immune system, downregulating B‐cell population. In summary, these data provide a fascinating new and innovative approach, supporting bone healing after bacterial infections and moreover gain insights into the complex ceremony of stem cell interaction in terms of bone infection and regeneration. stem cells translational medicine 2019;8:1084–1091
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- 2019
7. Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation
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Friedrich, Sarah-Kim, Schmitz, Rosa, Bergerhausen, Michael, Lang, Judith, Duhan, Vikas, Hardt, Cornelia, Tenbusch, Matthias, Prinz, Marco, Asano, Kenichi, Bhat, Hilal, Hamdan, Thamer A., Lang, Philipp Alexander, and Lang, Karl Sebastian
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enforced viral replication ,Medizinische Fakultät » Universitätsklinikum Essen » Institut für Immunologie ,innate immune activation ,viruses ,Medizin ,Medicine ,ddc:610 ,Influenza virus ,Article - Abstract
The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs, however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 (Usp18). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.
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- 2021
8. Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells
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Duhan, Vikas, Khairnar, Vishal, Kitanovski, Simo, Hamdan, Thamer A, Klein, Andrés D, Lang, Judith, Ali, Murtaza, Adomati, Tom, Bhat, Hilal, Friedrich, Sarah-Kim, Li, Fanghui, Krebs, Philippe, Futerman, Anthony H, Addo, Marylyn M, Hardt, Cornelia, Hoffmann, Daniel, Lang, Philipp A, and Lang, Karl S
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Mice, 129 Strain ,GWAS -- genome wide association screen -- Itgae -- CD103 -- vesicular stomatitis virus -- IFN-I -- AKT -- mTOR ,Medizinische Fakultät » Universitätsklinikum Essen » Institut für Immunologie ,viruses ,Immunology ,Medizin ,chemical and pharmacologic phenomena ,Receptor, Interferon alpha-beta ,Virus Replication ,Mice, Inbred AKR ,Antigens, CD ,Mice, Inbred NOD ,ddc:570 ,Animals ,GWAS ,ddc:610 ,Phosphorylation ,Cells, Cultured ,Itgae ,Original Research ,Mice, Knockout ,Mice, Inbred BALB C ,Mice, Inbred C3H ,genome wide association screen ,TOR Serine-Threonine Kinases ,AKT ,hemic and immune systems ,Dendritic Cells ,Vesiculovirus ,Immunity, Innate ,Mice, Inbred C57BL ,Disease Models, Animal ,Fakultät für Biologie » Bioinformatics and Computational Biophysics ,Mice, Inbred DBA ,Host-Pathogen Interactions ,Interferon Type I ,CD103 ,IFN-I ,mTOR ,570 Life sciences ,biology ,vesicular stomatitis virus ,Vesicular Stomatitis ,Biologie ,Integrin alpha Chains ,Proto-Oncogene Proteins c-akt ,Genome-Wide Association Study ,Signal Transduction - Abstract
Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection. OA Förderung 2021
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- 2021
9. Innate myeloid cells in the tumor microenvironment
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Duhan, Vikas, primary and Smyth, Mark J, additional
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- 2021
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10. Map3k14 as a regulator of innate and adaptive immune response during acute viral infection
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Hamdan, Thamer A., Bhat, Hilal, Cham, Lamin B., Adomati, Tom, Lang, Judith, Li, Fanghui, Murtaza, Ali, Hardt, Cornelia, Lang, Philipp A., Duhan, Vikas, and Lang, Karl S.
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genome-wide association study ,Medizinische Fakultät » Universitätsklinikum Essen » Institut für Immunologie ,animal diseases ,viruses ,lcsh:R ,Medizin ,lcsh:Medicine ,Alymphoplasia mice ,respiratory system ,Article ,respiratory tract diseases ,lymphocytic choriomeningitis virus ,marginal zone ,ddc:610 ,viral infection ,vesicular stomatitis virus - Abstract
The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice (aly/aly, Map3k14aly/aly, or Nikaly/aly), which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169+ macrophages correlated with reduced immune activation in Map3k14aly/aly mice. The transfer of wildtype B cells into Map3k14aly/aly mice repopulated CD169+ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control.
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- 2020
11. Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression
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Bhat, Hilal, primary, Zaun, Gregor, additional, Hamdan, Thamer A., additional, Lang, Judith, additional, Adomati, Tom, additional, Schmitz, Rosa, additional, Friedrich, Sarah-Kim, additional, Bergerhausen, Michael, additional, Cham, Lamin B., additional, Li, Fanghui, additional, Ali, Murtaza, additional, Zhou, Fan, additional, Khairnar, Vishal, additional, Duhan, Vikas, additional, Brandenburg, Tim, additional, Machlah, Yara Maria, additional, Schiller, Maximilian, additional, Berry, Arshia, additional, Xu, Haifeng, additional, Vollmer, Jörg, additional, Häussinger, Dieter, additional, Thier, Beatrice, additional, Pandyra, Aleksandra A., additional, Schadendorf, Dirk, additional, Paschen, Annette, additional, Schuler, Martin, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
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- 2020
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12. Usp18 Expression in CD169+ Macrophages is Important for Strong Immune Response after Vaccination with VSV-EBOV
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Friedrich, Sarah-Kim, primary, Schmitz, Rosa, additional, Bergerhausen, Michael, additional, Lang, Judith, additional, Cham, Lamin B., additional, Duhan, Vikas, additional, Häussinger, Dieter, additional, Hardt, Cornelia, additional, Addo, Marylyn, additional, Prinz, Marco, additional, Asano, Kenichi, additional, Lang, Philipp Alexander, additional, and Lang, Karl Sebastian, additional
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- 2020
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13. Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection
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Adomati, Tom, primary, Cham, Lamin B., additional, Hamdan, Thamer A., additional, Bhat, Hilal, additional, Duhan, Vikas, additional, Li, Fanghui, additional, Ali, Murtaza, additional, Lang, Elisabeth, additional, Huang, Anfei, additional, Naser, Eyad, additional, Khairnar, Vishal, additional, Friedrich, Sarah-Kim, additional, Lang, Judith, additional, Friebus-Kardash, Justa, additional, Bergerhausen, Michael, additional, Schiller, Maximilian, additional, Machlah, Yara Maria, additional, Lang, Florian, additional, Häussinger, Dieter, additional, Ferencik, Stanislav, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
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- 2020
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14. Map3k14 as a Regulator of Innate and Adaptive Immune Response during Acute Viral Infection
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Hamdan, Thamer A., primary, Bhat, Hilal, additional, Cham, Lamin B., additional, Adomati, Tom, additional, Lang, Judith, additional, Li, Fanghui, additional, Murtaza, Ali, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, Duhan, Vikas, additional, and Lang, Karl S., additional
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- 2020
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15. Tamoxifen Protects from Vesicular Stomatitis Virus Infection
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Cham, Lamin B., primary, Friedrich, Sarah-Kim, additional, Adomati, Tom, additional, Bhat, Hilal, additional, Schiller, Maximilian, additional, Bergerhausen, Michael, additional, Hamdan, Thamer, additional, Li, Fanghui, additional, Machlah, Yara Maria, additional, Ali, Murtaza, additional, Duhan, Vikas, additional, Lang, Karl Sebastian, additional, Friebus-Kardash, Justa, additional, and Lang, Judith, additional
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- 2019
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16. NK cell–intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection
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Duhan, Vikas, primary, Hamdan, Thamer A., additional, Xu, Haifeng C., additional, Shinde, Prashant, additional, Bhat, Hilal, additional, Li, Fanghui, additional, Al-Matary, Yahya, additional, Häussinger, Dieter, additional, Bezgovsek, Judith, additional, Friedrich, Sarah-Kim, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
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- 2019
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17. Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity
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Zhou, Fan, primary, Kardash, Justa, additional, Bhat, Hilal, additional, Duhan, Vikas, additional, Friedrich, Sarah-Kim, additional, Bezgovsek, Judith, additional, Kalkavan, Halime, additional, Bergerhausen, Michael, additional, Schiller, Max, additional, Machlah, Yara, additional, Brandenburg, Tim, additional, Hardt, Cornelia, additional, Krolik, Michal, additional, Flatz, Lukas, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
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- 2019
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18. TLR7 Controls VSV Replication in CD169+ SCS Macrophages and Associated Viral Neuroinvasion
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Solmaz, Gülhas, primary, Puttur, Franz, additional, Francozo, Marcela, additional, Lindenberg, Marc, additional, Guderian, Melanie, additional, Swallow, Maxine, additional, Duhan, Vikas, additional, Khairnar, Vishal, additional, Kalinke, Ulrich, additional, Ludewig, Burkhard, additional, Clausen, Björn E., additional, Wagner, Hermann, additional, Lang, Karl S., additional, and Sparwasser, Tim D., additional
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- 2019
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19. Dead Cells Induce Innate Anergy Via Mertk after Acute Viral Infection
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Adomati, Tom, primary, Duhan, Vikas, additional, Hamdan, Thamer A., additional, Cham, Lamin B., additional, Bhat, Hilal, additional, Li, Fangui, additional, Lang, Elisabeth, additional, Khairnar, Vishal, additional, Friedrich, Sarah-Kim, additional, Friebus-Kardash, Justa, additional, Bezgovsek, Judith, additional, Bergerhausen, Michael, additional, Schiller, Maximilian, additional, Maria, Machlah Yara, additional, Ali, Murtaza, additional, Lang, Florian, additional, Häussinger, Dieter, additional, Ferencik, Stanislav, additional, Hardt, Cornelia, additional, Lang, Philipp, additional, and Sebastian Lang, Karl, additional
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- 2019
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20. Crosstalk between Splenic CD169+ Macrophages and Adaptive Immune System
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Duhan, Vikas, Lang, Karl S. (Akademische Betreuung), and Lang, Karl Sebastian
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Medizinische Fakultät » Universitätsklinikum Essen » Institut für Immunologie ,ddc:570 ,viruses ,ddc:572 ,Biologie - Abstract
Krankheiten, die durch Virusinfektionen ausgelöst werden, stellen eine große Besorgnis für die Menschheit dar. Viren wie das humane Immundefizienz-Virus (HIV), Hepatitis B Virus (HBV) und Hepatitis C Virus (HCV), die chronische Infektionen verursachen, sind immer lebensbedrohlich. Die Mechanismen zu verstehen, wie das Immunsystem Virusinfektionen bekämpft, kann helfen bessere Impfstoffe oder Therapien zu entwickeln, um tödlichen Virusinfektionen vorzubeugen. In dieser Studie untersuchten wir die Rolle von CD169+ Makrophagen, die in der Marginalzone der Milz lokalisiert sind, für der adaptiven Immunantwort. Die anfängliche Virus-Replikation in den CD169+ Makrophagen der Milz bei einer systemischen Infektion mit dem vesikulären Stomatitis-Virus (VSV), welche das angeborene und adaptive Immunsystem aktiviert, wurde bereits beschrieben. Indem wir hier das lymphozytäre Choriomeningitis-Virus (LCMV) im Maus-Modell untersuchten, fanden wir, dass die CD169+ Makrophagen in Milz und Lymphknoten Typ-I-Interferon (IFN-I) produzieren. IFN-I agierte antiviral, inhibierte somit die Virus-Replikation in verschiedenen peripheren Organen und stimulierte die Expression von program death ligand 1 (PD-L1) in der Leber. PD-L1 ist ein Ligand für PD1, das auf aktivierten CD8+ T-Zellen exprimiert wird. Die Signale über die PD-L1/PD1-Achse induzieren die Erschöpfung von CD8+ T-Zellen. In Abwesenheit von CD169+ Makrophagen war die IFN-I-Produktion und PD-L1-Expression stark reduziert. Die führte zu einer überwältigenden Virus-Replikation bei fehlender CD8+ T-Zell-Erschöpfung, was in schwerer Immunpathologie und dem Tod der Mäuse endete. Diese Arbeit zeigt klar die Rolle von CD169+ Makrophagen bei der funktionalen Regulierung der CD8+ T-Zellen auf. In einer zweiten Studie beschrieben wir den Einfluss Virus-spezifischer Antikörper oder Virus-spezifischer CD8+ T-Zellen auf die CD169+ Makrophagen der Milz während einer systemischen Zweit-Infektion mit LCMV. Wir berichteten, dass die Anwesenheit von LCMV-spezifischen Antikörpern die intrazelluläre Virus-Replikation in den CD169+ Makrophagen der Marginalzone der Milz zulässt, aber die Virus-Replikation in peripheren Organen unterdrückt. Während einer persistenten Infektion mit LCMV-Docile war die Replikation in den CD169+ Makrophagen der Milz bei Anwesenheit Virus-spezifischer Antikörper essentiell für die Vorbereitung der CD8+ T-Zellen, was zur Beseitung des Virus führte. Parallel zu spezifischen Antikörpern inhibierten CD8+ T-Gedächtnis-Zellen die Virus-Replikation in CD169+ Makrophagen und die systemische IFN-I-Produktion und schafften es nicht eine effective CD8+ T-Zell-Antwort aufzubauen, was in der Persistenz des Virus resultierte. Diese Untersuchung erklärt die Mechanismen der Immun-Aktivierung und des Immun-Schutzes bei Anwesenheit von Virus-spezifischen Antikörpern bei viralen Zweit-Infektionen. Insgesamt kann man aus diesen beiden Studien schlussfolgern, dass CD169+ Makrophagen signifikante Rollen für die Induzierung einer starken antiviralen angeborenen und adaptiven Immunantwort bei viralen Erst- und Zweit-Infektionen einnehmen. Diseases caused by viral infections are major concerns for human being. Viruses like human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) that induce chronic infection, is always a risk for human life. Understanding the mechanisms how immune system combat against viral infection can help to develop better vaccines or treatment therapies to prevent from lethal viral infections. Here in this study, we analyzed the roles of CD169+ macrophages present in splenic marginal zone on adaptive immunity. Initial virus replication in splenic CD169+ macrophages during systemic infection of vesicular stomatitis virus (VSV) was described earlier which activate innate and adaptive immune system. Here using Lymphocytic choriomeningitis virus (LCMV) in mouse model, we found that CD169+ macrophages in spleen and lymph node produce type I interferon (IFN-I). IFN-I acts as antiviral and inhibited virus replication in different peripheral organs, and stimulated program death ligand 1 (PD-L1) expression in liver. PD-L1 is a ligand for PD-1 expressed on activated CD8+ T cells, and PD-L1/PD-1 axis signaling induces CD8+ T cell exhaustion. In absence of CD169+ macrophages, IFN-I production was impaired and PD-L1 expression was highly reduced. This led to overwhelming virus replication in absence of CD8+ T cells exhaustion that resulted in severe immunopathology and death of mice. This study clearly shows the role of CD169+ macrophages in regulating the functions of CD8+ T cells. In another study, we described the influence of virus-specific antibodies or virus-specific memory CD8+ T cells on splenic CD169+ macrophages during systemic recall infection of LCMV. We reported that the presence of LCMV-specific antibodies permit intracellular viral replication in CD169+ macrophages of splenic marginal zone but suppressed viral replication in peripheral organs. During persistent infection with the LCMV-Docile, viral replication in CD169+ macrophages of spleen in presence of virus specific antibodies was found to be essential for priming of CD8+ T cells that led to viral clearance. In parallel to specific antibodies, memory CD8+ T cells inhibited viral replication in CD169+ macrophages and systemic IFN-I production, and failed to mount effective CD8+ T cell response that resulted in viral persistence. This investigation explains the mechanism of immune activation and protection in presence of virus specific antibodies during secondary viral infection. Over all from these two studies we can conclude that CD169+ macrophages play significant roles for inducing strong antiviral innate and adaptive immunity during primary and secondary viral infection. Dissertation, Universität Duisburg-Essen, 2017
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- 2017
21. Sphingolipids in early viral replication and innate immune activation
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Bezgovsek, Judith, primary, Gulbins, Erich, additional, Friedrich, Sarah-Kim, additional, Lang, Karl S., additional, and Duhan, Vikas, additional
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- 2018
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22. CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection
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Khairnar, Vishal, primary, Duhan, Vikas, additional, Patil, Ashwini M., additional, Zhou, Fan, additional, Bhat, Hilal, additional, Thoens, Christine, additional, Sharma, Piyush, additional, Adomati, Tom, additional, Friendrich, Sarah-Kim, additional, Bezgovsek, Judith, additional, Dreesen, Janine D., additional, Wennemuth, Gunther, additional, Westendorf, Astrid M., additional, Zelinskyy, Gennadiy, additional, Dittmer, Ulf, additional, Hardt, Cornelia, additional, Timm, Jörg, additional, Göthert, Joachim R., additional, Lang, Philipp A., additional, Singer, Bernhard B., additional, and Lang, Karl S., additional
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- 2018
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23. CD169+ macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection
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Shaabani, Namir, primary, Duhan, Vikas, additional, Khairnar, Vishal, additional, Gassa, Asmae, additional, Ferrer-Tur, Rita, additional, Häussinger, Dieter, additional, Recher, Mike, additional, Zelinskyy, Gennadiy, additional, Liu, Jia, additional, Dittmer, Ulf, additional, Trilling, Mirko, additional, Scheu, Stefanie, additional, Hardt, Cornelia, additional, Lang, Philipp A, additional, Honke, Nadine, additional, and Lang, Karl S, additional
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- 2016
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24. The uric acid crystal receptor Clec12A potentiates type I interferon responses.
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Kai Li, Neumann, Konstantin, Duhan, Vikas, Namineni, Sukumar, Hansen, Anne Louise, Wartewig, Tim, Kurgyis, Zsuzsanna, Holm, Christian K., Heikenwalder, Mathias, Lang, Karl S., and Ruland, Jürgen
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TYPE I interferons ,URIC acid ,LYMPHOCYTIC choriomeningitis virus ,PROTEIN-tyrosine kinases ,CRYSTALS - Abstract
The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acidinducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I-stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response. [ABSTRACT FROM AUTHOR]
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- 2019
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25. NK cell–intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection.
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Duhan, Vikas, Hamdan, Thamer A., Xu, Haifeng C., Shinde, Prashant, Bhat, Hilal, Li, Fanghui, Al-Matary, Yahya, Häussinger, Dieter, Bezgovsek, Judith, Friedrich, Sarah-Kim, Hardt, Cornelia, Lang, Philipp A., and Lang, Karl S.
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VIRUS diseases , *KILLER cells , *LYMPHOCYTIC choriomeningitis virus , *CELL receptors , *LEUCOCYTES , *T cells - Abstract
During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g–/–mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g–/–mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell–activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection. [ABSTRACT FROM AUTHOR]
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- 2019
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26. TLR7 Controls VSV Replication in CD169+ SCS Macrophages and Associated Viral Neuroinvasion.
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Solmaz, Gülhas, Puttur, Franz, Francozo, Marcela, Lindenberg, Marc, Guderian, Melanie, Swallow, Maxine, Duhan, Vikas, Khairnar, Vishal, Kalinke, Ulrich, Ludewig, Burkhard, Clausen, Björn E., Wagner, Hermann, Lang, Karl S., and Sparwasser, Tim D.
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TOLL-like receptors ,VESICULAR stomatitis ,RHABDOVIRUSES ,SKIN infections ,LYMPH nodes - Abstract
Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169
+ subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7−/− mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7−/− mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7−/− mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
27. Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation
- Author
-
Shaabani, Namir, primary, Khairnar, Vishal, additional, Duhan, Vikas, additional, Zhou, Fan, additional, Tur, Rita Ferrer, additional, Häussinger, Dieter, additional, Recher, Mike, additional, Tumanov, Alexei V., additional, Hardt, Cornelia, additional, Pinschewer, Daniel, additional, Christen, Urs, additional, Lang, Philipp A., additional, Honke, Nadine, additional, and Lang, Karl S., additional
- Published
- 2016
- Full Text
- View/download PDF
28. Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control
- Author
-
Duhan, Vikas, primary, Khairnar, Vishal, additional, Friedrich, Sarah-Kim, additional, Zhou, Fan, additional, Gassa, Asmae, additional, Honke, Nadine, additional, Shaabani, Namir, additional, Gailus, Nicole, additional, Botezatu, Lacramioara, additional, Khandanpour, Cyrus, additional, Dittmer, Ulf, additional, Häussinger, Dieter, additional, Recher, Mike, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
- Published
- 2016
- Full Text
- View/download PDF
29. IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts
- Author
-
Gassa, Asmae, primary, Jian, Fu, additional, Kalkavan, Halime, additional, Duhan, Vikas, additional, Honke, Nadine, additional, Shaabani, Namir, additional, Friedrich, Sarah-Kim, additional, Dolff, Sebastian, additional, Wahlers, Thorsten, additional, Kribben, Andreas, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, Witzke, Oliver, additional, and Lang, Karl S., additional
- Published
- 2016
- Full Text
- View/download PDF
30. High Frequencies of Anti-Host Reactive CD8+ T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model
- Author
-
Gassa, Asmae, primary, Kalkavan, Halime, additional, Jian, Fu, additional, Duhan, Vikas, additional, Khairnar, Vishal, additional, Shaabani, Namir, additional, Honke, Nadine, additional, Carpinteiro, Alexander, additional, Botezatu, Lacramioara, additional, Crivello, Pietro, additional, Dolff, Sebastian, additional, Ferencik, Stanislav, additional, Häussinger, Dieter, additional, Khandanpour, Cyrus, additional, Fleischhauer, Katharina, additional, Witzke, Oliver, additional, Wahlers, Thorsten, additional, Hardt, Cornelia, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
- Published
- 2016
- Full Text
- View/download PDF
31. CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection.
- Author
-
Khairnar, Vishal, Duhan, Vikas, Patil, Ashwini M., Fan Zhou, Bhat, Hilal, Thoens, Christine, Sharma, Piyush, Adomati, Tom, Friendrich, Sarah-Kim, Bezgovsek, Judith, Dreesen, Janine D., Wennemuth, Gunther, Westendorf, Astrid M., Zelinskyy, Gennadiy, Dittmer, Ulf, Hardt, Cornelia, Timm, Jörg, Göthert, Joachim R., Lang, Philipp A., and Singer, Bernhard B.
- Abstract
Dysfunction of CD8
+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus-specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
32. IFN-γ licenses CD11b+ cells to induce progression of systemic lupus erythematosus
- Author
-
Shaabani, Namir, primary, Honke, Nadine, additional, Dolff, Sebastian, additional, Görg, Boris, additional, Khairnar, Vishal, additional, Merches, Katja, additional, Duhan, Vikas, additional, Metzger, Sabine, additional, Recher, Mike, additional, Barthuber, Carmen, additional, Hardt, Cornelia, additional, Proksch, Peter, additional, Häussinger, Dieter, additional, Witzke, Oliver, additional, Lang, Philipp A., additional, and Lang, Karl S., additional
- Published
- 2015
- Full Text
- View/download PDF
33. Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169 + Macrophage Function during Viral Infection
- Author
-
Xu, Haifeng C., primary, Huang, Jun, additional, Khairnar, Vishal, additional, Duhan, Vikas, additional, Pandyra, Aleksandra A., additional, Grusdat, Melanie, additional, Shinde, Prashant, additional, McIlwain, David R., additional, Maney, Sathish Kumar, additional, Gommerman, Jennifer, additional, Löhning, Max, additional, Ohashi, Pamela S., additional, Mak, Tak W., additional, Pieper, Kathrin, additional, Sic, Heiko, additional, Speletas, Matthaios, additional, Eibel, Hermann, additional, Ware, Carl F., additional, Tumanov, Alexei V., additional, Kruglov, Andrey A., additional, Nedospasov, Sergei A., additional, Häussinger, Dieter, additional, Recher, Mike, additional, Lang, Karl S., additional, and Lang, Philipp A., additional
- Published
- 2015
- Full Text
- View/download PDF
34. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production
- Author
-
Khairnar, Vishal, primary, Duhan, Vikas, additional, Maney, Sathish Kumar, additional, Honke, Nadine, additional, Shaabani, Namir, additional, Pandyra, Aleksandra A., additional, Seifert, Marc, additional, Pozdeev, Vitaly, additional, Xu, Haifeng C., additional, Sharma, Piyush, additional, Baldin, Fabian, additional, Marquardsen, Florian, additional, Merches, Katja, additional, Lang, Elisabeth, additional, Kirschning, Carsten, additional, Westendorf, Astrid M., additional, Häussinger, Dieter, additional, Lang, Florian, additional, Dittmer, Ulf, additional, Küppers, Ralf, additional, Recher, Mike, additional, Hardt, Cornelia, additional, Scheffrahn, Inka, additional, Beauchemin, Nicole, additional, Göthert, Joachim R., additional, Singer, Bernhard B., additional, Lang, Philipp A., additional, and Lang, Karl S., additional
- Published
- 2015
- Full Text
- View/download PDF
35. Virus-Induced Type I Interferon Deteriorates Control of Systemic Pseudomonas Aeruginosa Infection
- Author
-
Merches, Katja, primary, Khairnar, Vishal, additional, Knuschke, Torben, additional, Shaabani, Namir, additional, Honke, Nadine, additional, Duhan, Vikas, additional, Recher, Mike, additional, Navarini, Alexander A., additional, Hardt, Cornelia, additional, Häussinger, Dieter, additional, Tümmler, Burkhard, additional, Gulbins, Erich, additional, Futerman, Anthony H., additional, Hoffmann, Daniel, additional, Lang, Florian, additional, Lang, Philipp A., additional, Westendorf, Astrid M., additional, and Lang, Karl S., additional
- Published
- 2015
- Full Text
- View/download PDF
36. High Frequencies of Anti-Host Reactive CD8+ T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model.
- Author
-
Gassa, asmae, Kalkavan, Halime, Jian, Fu, Duhan, Vikas, Khairnar, Vishal, Shaabani, Namir, Honke, Nadine, Carpinteiro, alexander, Botezatu, Lacramioara, Crivello, Pietro, Dolff, Sebastian, Ferencik, Stanislav, Häussinger, Dieter, Khandanpour, Cyrus, Fleischhauer, Katharina, Witzke, Oliver, Wahlers, Thorsten, Hardt, Cornelia, Lang, Philipp a., and Lang, Karl S.
- Subjects
GRAFT versus host disease ,BONE marrow transplant complications ,T cells ,LABORATORY mice ,GLYCOPROTEINS ,LIPOPOLYSACCHARIDES - Abstract
Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied. Methods: Here we used a CD8
+ T cell transgenic mouse line (P14/CD45.1+ ) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8+ T cells after BMT. Results: We found that anti-host reactive CD8+ T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti-host reactive CD8+ T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccharides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8+ T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8+ T cells. Conclusion: We found that after BMT anti-host reactive CD8+ T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, LPS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8+ T cells after BMT. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
37. Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control.
- Author
-
Duhan, Vikas, Khairnar, Vishal, Friedrich, Sarah-Kim, Zhou, Fan, Gassa, Asmae, Honke, Nadine, Shaabani, Namir, Gailus, Nicole, Botezatu, Lacramioara, Khandanpour, Cyrus, Dittmer, Ulf, Häussinger, Dieter, Recher, Mike, Hardt, Cornelia, Lang, Philipp A., and Lang, Karl S.
- Published
- 2016
- Full Text
- View/download PDF
38. Usp18 Expression in CD169 + Macrophages is Important for Strong Immune Response after Vaccination with VSV-EBOV.
- Author
-
Friedrich SK, Schmitz R, Bergerhausen M, Lang J, Cham LB, Duhan V, Häussinger D, Hardt C, Addo M, Prinz M, Asano K, Lang PA, and Lang KS
- Abstract
Ebola virus epidemics can be effectively limited by the VSV-EBOV vaccine (Ervebo) due to its rapid protection abilities; however, side effects prevent the broad use of VSV-EBOV as vaccine. Mechanisms explaining the efficient immune activation after single injection with the VSV-EBOV vaccine remain mainly unknown. Here, using the clinically available VSV-EBOV vaccine (Ervebo), we show that the cell-intrinsic expression of the interferon-inhibitor Usp18 in CD169
+ macrophages is one important factor modulating the anti-Ebola virus immune response. The absence of Usp18 in CD169+ macrophages led to the reduced local replication of VSV-EBOV followed by a diminished innate as well as adaptive immune response. In line, CD169 -Cre+/ki x Usp18fl/fl mice showed reduced innate and adaptive immune responses against the VSV wildtype strain and died quickly after infection, suggesting that a lack of Usp18 makes mice more susceptible to the side effects of the VSV vector. In conclusion, our study shows that Usp18 expression in CD169+ macrophages is one important surrogate marker for effective vaccination against VSV-EBOV, and probably other VSV-based vaccines also.- Published
- 2020
- Full Text
- View/download PDF
39. TLR7 Controls VSV Replication in CD169 + SCS Macrophages and Associated Viral Neuroinvasion.
- Author
-
Solmaz G, Puttur F, Francozo M, Lindenberg M, Guderian M, Swallow M, Duhan V, Khairnar V, Kalinke U, Ludewig B, Clausen BE, Wagner H, Lang KS, and Sparwasser TD
- Subjects
- Animals, Brain immunology, Brain virology, Macrophages virology, Membrane Glycoproteins genetics, Mice, Mice, Knockout, Rhabdoviridae Infections genetics, Rhabdoviridae Infections pathology, Sialic Acid Binding Ig-like Lectin 1 genetics, Signal Transduction genetics, Signal Transduction immunology, Spinal Cord immunology, Spinal Cord virology, Toll-Like Receptor 7 genetics, Virus Replication genetics, Macrophages immunology, Membrane Glycoproteins immunology, Rhabdoviridae Infections immunology, Sialic Acid Binding Ig-like Lectin 1 immunology, Toll-Like Receptor 7 immunology, Vesiculovirus physiology, Virus Replication immunology
- Abstract
Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169
+ subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7-/- mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7-/- mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7-/- mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies.- Published
- 2019
- Full Text
- View/download PDF
40. CEACAM1 promotes CD8 + T cell responses and improves control of a chronic viral infection.
- Author
-
Khairnar V, Duhan V, Patil AM, Zhou F, Bhat H, Thoens C, Sharma P, Adomati T, Friendrich SK, Bezgovsek J, Dreesen JD, Wennemuth G, Westendorf AM, Zelinskyy G, Dittmer U, Hardt C, Timm J, Göthert JR, Lang PA, Singer BB, and Lang KS
- Subjects
- Adoptive Transfer, Animals, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes metabolism, Carcinoembryonic Antigen genetics, Chimera, Chronic Disease, Female, Humans, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus pathogenicity, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Antigens, CD metabolism, CD8-Positive T-Lymphocytes immunology, Carcinoembryonic Antigen metabolism, Cell Adhesion Molecules metabolism, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology
- Abstract
Dysfunction of CD8
+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus-specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells.- Published
- 2018
- Full Text
- View/download PDF
41. CD169 + macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection.
- Author
-
Shaabani N, Duhan V, Khairnar V, Gassa A, Ferrer-Tur R, Häussinger D, Recher M, Zelinskyy G, Liu J, Dittmer U, Trilling M, Scheu S, Hardt C, Lang PA, Honke N, and Lang KS
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Chronic Disease, Cross-Priming immunology, Liver metabolism, Liver pathology, Liver virology, Lymph Nodes metabolism, Lymphocytic Choriomeningitis virology, Mice, Inbred C57BL, Spleen metabolism, B7-H1 Antigen metabolism, Interferon Type I metabolism, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis pathology, Lymphocytic choriomeningitis virus physiology, Macrophages metabolism, Sialic Acid Binding Ig-like Lectin 1 metabolism
- Abstract
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8
+ T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169+ macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169+ macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus. Lack of CD169+ macrophages also limited the IFN-I-dependent expression of PD-L1. Enhanced viral replication in the absence of PD-L1 led to persistence of virus and prevented CD8+ T-cell exhaustion. As a consequence, mice exhibited severe immunopathology and died quickly after infection. Therefore, CD169+ macrophages are important contributors to the IFN-I response and thereby influence antiviral activity, CD8+ T-cell exhaustion and immunopathology.- Published
- 2016
- Full Text
- View/download PDF
42. Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.
- Author
-
Xu HC, Huang J, Khairnar V, Duhan V, Pandyra AA, Grusdat M, Shinde P, McIlwain DR, Maney SK, Gommerman J, Löhning M, Ohashi PS, Mak TW, Pieper K, Sic H, Speletas M, Eibel H, Ware CF, Tumanov AV, Kruglov AA, Nedospasov SA, Häussinger D, Recher M, Lang KS, and Lang PA
- Subjects
- Adaptive Immunity, Animals, Immunity, Innate, Interferon Type I metabolism, Lymphocytic choriomeningitis virus immunology, Mice, Knockout, Signal Transduction, Vesiculovirus immunology, Arenaviridae Infections immunology, Macrophages chemistry, Macrophages immunology, Receptors, Interleukin-4 deficiency, Rhabdoviridae Infections immunology, Sialic Acid Binding Ig-like Lectin 1 analysis
- Abstract
Unlabelled: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections., Importance: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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