title: Critical role for interferon regulatory factor 3 (IRF-3) and IRF-7 in type I interferon-mediated control of murine norovirus replication.
abstract: Human noroviruses (HuNoV) are the major cause of epidemic, nonbacterial gastroenteritis in the world. The short course of HuNoV-induced symptoms has implicated innate immunity in control of norovirus (NoV) infection. Studies using murine norovirus (MNV) confirm the importance of innate immune responses during NoV infection. Type I alpha and beta interferons (IFN-α/β) limit HuNoV replicon function, restrict MNV replication in cultured cells, and control MNV replication in vivo. Therefore, the cell types and transcription factors involved in antiviral immune responses and IFN-α/β-mediated control of NoV infection are important to define. We used mice with floxed alleles of the IFNAR1 chain of the IFN-α/β receptor to identify cells expressing lysozyme M or CD11c as cells that respond to IFN-α/β to restrict MNV replication in vivo. Furthermore, we show that the transcription factors IRF-3 and IRF-7 work in concert to initiate unique and overlapping antiviral responses to restrict MNV replication in vivo. IRF-3 and IRF-7 restrict MNV replication in both cultured macrophages and dendritic cells, are required for induction of IFN-α/β in macrophages but not dendritic cells, and are dispensable for the antiviral effects of IFN-α/β that block MNV replication. These studies suggest that expression of the IFN-α/β receptor on macrophages/neutrophils and dendritic cells, as well as of IRF-3 and IRF-7, is critical for innate immune responses to NoV infection.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Larissa B
authors.initials: LB
authors.lastname: Thackray
authors.forename: Erning
authors.initials: E
authors.lastname: Duan
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D007370:Interferon Type I / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D029322:Norovirus / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014779:Virus Replication / Q000502:physiology*
chemical_list: D017931:DNA Primers; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse