Critical Role for Interferon Regulatory Factor 3 (IRF-3) and IRF-7 in Type I Interferon-Mediated Control of Murine Norovirus Replication

Human noroviruses (HuNoV) are the major cause of epidemic, nonbacterial gastroenteritis in the world. The short course of HuNoV-induced symptoms has implicated innate immunity in control of norovirus (NoV) infection. Studies using murine norovirus (MNV) confirm the importance of innate immune responses during NoV infection. Type I alpha and beta interferons (IFN-alpha/beta) limit HuNoV replicon function, restrict MNV replication in cultured cells, and control MNV replication in vivo. Therefore, the cell types and transcription factors involved in antiviral immune responses and IFN-alpha/beta-mediated control of NoV infection are important to define. We used mice with floxed alleles of the IFNAR1 chain of the IFN-alpha/beta receptor to identify cells expressing lysozymeMor CD11c as cells that respond to IFN-alpha/beta to restrict MNV replication in vivo. Furthermore, we show that the transcription factors IRF-3 and IRF-7 work in concert to initiate unique and overlapping antiviral responses to restrict MNV replication in vivo. IRF-3 and IRF-7 restrict MNV replication in both cultured macrophages and dendritic cells, are required for induction of IFN-alpha/beta in macrophages but not dendritic cells, and are dispensable for the antiviral effects of IFN-alpha/beta that block MNV replication. These studies suggest that expression of the IFN-alpha/beta receptor on macrophages/neutrophils and dendritic cells, as well as of IRF-3 and IRF-7, is critical for innate immune responses to NoV infection.