title: Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue.
abstract: Type I interferons (IFN-Is) are fundamental for antiviral immunity, but their role in bacterial infections is contradictory and incompletely described. Streptococcus pyogenes activates IFN-I production in innate immune cells, and IFN-I receptor 1 (Ifnar1)-deficient mice are highly susceptible to S. pyogenes infection. Here we report that IFN-I signaling protects the host against invasive S. pyogenes infection by restricting inflammation-driven damage in distant tissues. Lethality following infection in Ifnar1-deficient mice is caused by systemically exacerbated levels of the proinflammatory cytokine IL-1β. Critical cellular effectors of IFN-I in vivo are LysM+ and CD11c+ myeloid cells, which exhibit suppression of Il1b transcription upon Ifnar1 engagement. These cells are also the major source of IFN-β, which is significantly induced by S. pyogenes 23S rRNA in an Irf5-dependent manner. Our study establishes IL-1β and IFN-I levels as key homeostatic variables of protective, yet tuned, immune responses against severe invasive bacterial infection.
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Virginia
authors.initials: V
authors.lastname: Castiglia
authors.affiliation: Institute of Animal Pathology (COMPATH), University of Bern, 3012 Bern, Switzerland; Life Science Faculty, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Piersigilli
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Ebner
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Marton
authors.initials: M
authors.lastname: Janos
authors.affiliation: Infection Immunology Research Group, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goldmann
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Damböck
authors.affiliation: Institute of Medical Microbiology, Otto-von-Guericke-University, 39106 Magdeburg, Germany; Department of Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Sigfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Jamieson
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kirschning
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover Medical School and Helmholtz Centre for Infection Research, 30625 Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover Medical School and Helmholtz Centre for Infection Research, 30625 Hannover, Germany; Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria. Electronic address: pavel.kovarik@univie.ac.at.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007370:Interferon Type I / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D018461:Soft Tissue Infections / Q000276:immunology* / Q000473:pathology*; D013290:Streptococcal Infections / Q000276:immunology* / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D007370:Interferon Type I; D053583:Interleukin-1beta