title: IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.
abstract: Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3(-/-)×Irf7(-/-) double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3(-/-)×Irf5(-/-)×Irf7(-/-) triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar(-/-)). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar(-/-) mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs(-/-) mDC. The relative equivalence of TKO and Mavs(-/-) responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.forename: Alissa
authors.initials: A
authors.lastname: Lancaster
authors.forename: Courtney
authors.initials: C
authors.lastname: Wilkins
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.forename: Albert
authors.initials: A
authors.lastname: Huang
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Vick
authors.forename: Lisa
authors.initials: L
authors.lastname: Clepper
authors.forename: Larissa
authors.initials: L
authors.lastname: Thackray
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Brassil
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Zugich
authors.forename: Ashlee V
authors.initials: AV
authors.lastname: Moses
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology; D019562:Viral Load; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology / Q000821:virology; D014902:West Nile virus / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D053633:Receptor, Interferon alpha-beta; D051193:Toll-Like Receptors; C512612:MAVS protein, mouse; C498178:Irf5 protein, mouse