The Roles of IRF-3 and IRF-7 in Innate Antiviral Immunity against Dengue Virus

摘要

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.