[en] Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169+ cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169+ cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b+ Ly6C+ Ly6G+ cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169+ cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169+ cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169+ cells and innate and adaptive immune activation during VSV infection.IMPORTANCE Over the last decade, strategically placed CD169+ metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169+ macrophages have been shown to activate innate and adaptive immunity via "enforced virus replication," a controlled amplification of virus particles. However, the factors regulating the CD169+ macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169+ macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.
Disciplines :
Immunology & infectious disease
Author, co-author :
Shinde, Prashant V; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Xu, Haifeng C; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Maney, Sathish Kumar; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Kloetgen, Andreas; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany ; Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany
Namineni, Sukumar; Institute of Virology, TU Munich, Munich, Germany ; Institute of Molecular Immunology, Technische Universität Munich and Helmholtz Zentrum Munich, Munich, Germany
Zhuang, Yuan; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Honke, Nadine; Department of Rheumatology, Hiller Research Center Rheumatology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Shaabani, Namir; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA
Bellora, Nicolas; Instituto Andino Patagónico de Tecnologías Biológicas y Geoambientales (IPATEC), Universidad Nacional del Comahue-CONICET, Bariloche, Argentina
Doerrenberg, Mareike; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Trilling, Mirko; Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Pozdeev, Vitaly I; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany ; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
van Rooijen, Nico; Department of Cell Biology, Vrije University Medical Center, Amsterdam, Netherlands
Scheu, Stefanie; Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Pfeffer, Klaus; Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Crocker, Paul R; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
Tanaka, Masato; Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
Duggimpudi, Sujitha; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Knolle, Percy; Institute of Molecular Immunology, Technische Universität Munich and Helmholtz Zentrum Munich, Munich, Germany
Heikenwalder, Mathias; Institute of Virology, TU Munich, Munich, Germany ; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
Ruland, Jürgen; Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität Munich, Munich, Germany ; German Cancer Consortium (DKTK), partner site Munich, Germany ; German Center for Infection Research (DZIF), partner site Munich, Germany ; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
Mak, Tak W; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Pandyra, Aleksandra A; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Hoell, Jessica I; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Borkhardt, Arndt; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany
Häussinger, Dieter; Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
Lang, Karl S; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Lang, Philipp A; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany langp@uni-duesseldorf.de
Jürgen Manchot Graduate School ATTRACT German Research Council Alexander von Humboldt-Stiftung Core
Funding text :
This study was supported by the Alexander von Humboldt Foundation (SKA2010), the German Research Council (SFB974, LA2558/3-1, LA2558/5-1, GRK1949, and TRR60), Jürgen Manchot Graduate School MOI II, and the NIH tetramer facility. D.B. is funded by the ATTRACT Programme (A14/BM/7632103/DBRRIL) and a CORE grant (C15/BM/ 10355103) from the National Research Fund Luxembourg (FNR). J.R. is funded by the DFG (SFB 1054/B01) and the ERC (FP7; grant agreement no. 322865).
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