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.

The brain parenchyma has a type I interferon response that can limit virus spread

“…The choroid plexuses are located within the ventricles and have a rich blood supply, located between the blood-brain and blood-ventricle barriers (1). The presence of these tissues within the brain prevents evaluation of virus spread among neurons and glia using methods such as titration of virus from homogenized tissue or qPCR for viral genes (14,43,49) because such methods cannot differentiate between virus load in CNS and non-CNS tissues. The presence of these structures also prevents conclusions regarding CNS innate immunity following peripheral infections, because peripheral infections can pass through both the brain's vasculature and lymphatics, and these structures can mount innate immune responses (1).…”

“…To further investigate the induction of the type I IFN response, the expression of several known ISGs-Rsad2, Cxcl10, and Oas1α-was assayed (43). Compared with PBS injection, DIPs led to an induction in Rsad2 (Fig.…”

Dendritic cell subsets involved in type I IFN induction in mouse measles virus infection models

“…A pharmacological study indicated that MV-derived IFN- expression partially depended on NF-B (Takaki et al, 2014). A recent study using West Nile virus showed that IRF3/IRF7 and IRF5 coordinately regulate the type I IFN response in DCs (Lazear et al, 2013). For MV, IRF5 might be a transcription factor for MAVS-dependent and IRF3/IRF7-independent type I IFN induction in BMDCs (Figure 2).…”

Zebrafish IRF1 Regulates IFN Antiviral Response through Binding to IFNϕ1 and IFNϕ3 Promoters Downstream of MyD88 Signaling

“…In addition to IRF3/7, accumulating evidence suggests that IRF1, IRF5, and IRF8 trigger IFN responses in cell-specific fashions (5)(6)(7)(8). IRF1 is the founder member of the IRF family and initially was identified as a positive regulator directly binding to type I IFN gene promoters (9).…”