title: The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus.
abstract: We investigated the roles of IFN regulatory factor (IRF)-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3(-/-)7(-/-) mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 h postinfection (hpi); however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3(-/-) mice post-DENV infection, whereas in the Irf-7(-/-) and Irf-3(-/-)7(-/-) mice, significantly low levels of IFN-α/β expression was observed within 24 hpi. IFN-stimulated gene induction was also delayed in Irf-3(-/-)7(-/-) mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3(-/-)7(-/-) mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3(-/-)7(-/-) mice 24 hpi, at which time point viral titers peaked and started to be cleared. Ab-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3(-/-)7(-/-) mice. Additionally, the IFN-stimulated genes Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Kevin
authors.initials: K
authors.lastname: King
authors.forename: Jui
authors.initials: J
authors.lastname: Tu
authors.forename: Marisa
authors.initials: M
authors.lastname: Sanchez
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000330:Aedes; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000097:blood*; D016899:Interferon-beta / Q000097:blood*; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D016601:RNA-Binding Proteins; D054367:Receptors, CXCR3 / Q000276:immunology; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000097:blood; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; C092573:Ifit1 protein, mouse; C087697:Ifit3 protein, mouse; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C579067:Mx2 protein, mouse; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D054367:Receptors, CXCR3; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma
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