title: Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.
abstract: The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system.
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany; Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Vishal
authors.initials: V
authors.lastname: Khairnar
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Vikas
authors.initials: V
authors.lastname: Duhan
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Rita Ferrer
authors.initials: RF
authors.lastname: Tur
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Clinic for Primary Immunodeficiencies, Medical Outpatient Unit, and Immunodeficiency Laboratory, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.affiliation: Trudeau Institute, Saranac Lake, NY, USA.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tumanov
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hardt
authors.affiliation: Department of Biomedicine, Haus Petersplatz, Division of Experimental Virology, University of Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinschewer
authors.affiliation: Clinic of Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany; Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Honke
authors.affiliation: Institute of Immunology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany; Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Electronic address: karlsebastian.lang@uk-essen.de.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D053308:Lymphotoxin-beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D053308:Lymphotoxin-beta; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase
keywords: Enforced viral replication; Immunopathology; Lymphocytic choriomeningitis virus (LCMV)