title: Fas-associated death domain-containing protein-mediated antiviral innate immune signaling involves the regulation of Irf7.
abstract: The induction of type I (alphabeta) IFN following virus infection is necessary for the stimulation of effective antiviral host defense. In fibroblasts, a subset of primary genes (including those encoding IFN-beta and IFN-alpha4) are induced directly by intracellular dsRNA generated by the virus during its replication. These primary type I IFNs induce expression of IFN regulatory factor (IRF)-7, required for production of a second cascade of IFN-alpha subtypes and the further establishment of a complete antiviral state. Previously, we had reported on a role for Fas-associated death domain-containing protein (FADD) in the control of TLR-independent innate immune responses to virus infection. Our data in this study demonstrate that FADD is not only required for efficient primary gene induction, but is also essential for induction of Irf7 and effective expression of secondary IFN-alphas and other antiviral genes. Ectopic overexpression of IRF-7 partially rescued dsRNA responsiveness and IFN-alpha production, and a constitutively active variant of IRF-7 displayed normal activity in Fadd(-/-) murine embryonic fibroblasts. MC159, a FADD-interacting viral protein encoded by the molluscum contagiosum poxvirus was found to inhibit dsRNA-activated signaling events upstream of IRF-7. These data indicate that FADD's antiviral activity involves regulation of IRF-7-dependent production of IFN-alpha subtypes and consequent induction of secondary antiviral genes.
authors.affiliation: Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Venkataraman
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
mesh_terms: D000818:Animals; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D011212:Poxviridae / Q000276:immunology*; D011213:Poxviridae Infections / Q000276:immunology* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D015533:Transcriptional Activation; D014779:Virus Replication / Q000276:immunology
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D012330:RNA, Double-Stranded