title: Deficient IFN signaling by myeloid cells leads to MAVS-dependent virus-induced sepsis.
abstract: The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar-/- mice completely lacking type I IFN signaling. In Mavs-/-×Ifnar-/- myeloid cells and mice lacking both Ifnar and the RIG-I-like receptor adaptor gene Mavs, cytokine production was muted despite high levels of WNV infection. Thus, in myeloid cells, viral infection triggers signaling through MAVS to induce proinflammatory cytokines that can result in sepsis and organ damage. Viral pathogenesis was caused in part by massive complement activation, as liver damage was minimized in animals lacking complement components C3 or factor B or treated with neutralizing anti-C5 antibodies. Disease in Ifnar-/- and CD11c Cre+Ifnarf/f mice also was facilitated by the proinflammatory cytokine TNF-α, as blocking antibodies diminished complement activation and prolonged survival without altering viral burden. Collectively, our findings establish the dominant role of type I IFN signaling in myeloid cells in restricting virus infection and controlling pathological inflammation and tissue injury.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Pinto
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Hilario J
authors.initials: HJ
authors.lastname: Ramos
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gorman
authors.affiliation: Department of Pediatrics, Emory Vaccine Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Kristin Y
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Emory Vaccine Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America; Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D014901:West Nile Fever / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014902:West Nile virus / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003176:Complement C3; D011415:Complement Factor B; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; C512612:MAVS protein, mouse; C508032:Ifnar1 protein, mouse
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