IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

• DOI: 10.1371/journal.ppat.1003118
• Publication Date: 2013-01-04T00:49:52Z
• Authors: Helen M. Lazear; Alissa Lancaster; Courtney Wilkins; Mehul S. Suthar; Albert Huang; Sarah C. Vick; Lisa Clepper; Larissa Thackray; Margaret M. Brassil; Herbert W. Virgin; Janko Nikolich-Zu...; Ashlee V. Moses; Michael Gale; Klaus Früh; Michael S. Diamond
• Keywords: IRF7; IRF3; Interferon type I; TLR7

Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction IFN stimulated gene (ISG) expression, Irf3−/−×Irf7−/− double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels IFN-β after viral infection. We generated Irf3−/−×Irf5−/−×Irf7−/− triple (TKO) mice to test whether IRF-5 was source residual ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) murine norovirus), TKO succumbed at rates greater than DKO equal or approaching those lacking receptor (Ifnar−/−). ex vivo studies, WNV infection exposure Toll-like agonists, mDCs failed express ISGs. contrast, this response sustained macrophages following To define IRF-regulated signatures, we performed microarray analysis on WNV-infected mDC from wild (WT), DKO, TKO, Ifnar−/− mice, as well RIG-I like adaptor protein MAVS. Whereas pattern similar WT cells, remarkably, almost no ISG detected Mavs−/− mDC. The relative equivalence responses suggested that MAVS dominantly regulates Moreover, showed MAVS-dependent can occur through an IRF-5-dependent yet IRF-7-independent pathway. Our results establish IRF-3, -5, -7 key responsible for mediating during suggest a novel signaling link between IRF-5.