Interactions of the murine coronavirus mouse hepatitis virus (MHV) with the type I IFN response

Mouse hepatitis virus (MHV) is a member of the coronavirus family of large, positive-sense RNA viruses. While the adaptive immune response to infection has been well characterized, the complex interactions with MHV and the type I interferon (IFN) response have only recently begun to be appreciated. Infection of L2 murine fibroblasts with MHV resulted in delayed induction of IFN-β mRNA as compared to Sendai virus (SeV), with the absence of IFN-β protein. Interestingly, while co-infection with MHV and SeV did not alter SeV-induced IFN-β mRNA production or stability, IFN-β protein was significantly reduced compared to SeV-infected cells. While these data indicate that MHV blocks IFN-β production at a post-transcriptional step, studies showed that MHV did not block general protein synthesis, secretion of the protein, nor did it target IFN-β for proteasomal degradation. Therefore, the mechanism by which MHV blocks IFN-β production in vitro is unclear. In addition, MHV is resistant to the antiviral effects of IFN-β in vitro and downregulates a subset of IFN-stimulated genes (ISGs), elucidating yet another mechanism by which MHV modulates the type I IFN response. Interestingly, the type I IFN response is crucial for containing MHV replication in vivo. During MHV infection of the central nervous system (CNS), both resident microglia and infiltrating macrophages produce IFN-β. In macrophages, MHV is recognized by MDA5, a cytoplasmic receptor thought to primarily recognize picornaviruses, resulting in type I IFN production. In addition, MDA5 mRNA levels appear to correlate with the ability of a particular cell type to produce IFN-β in response to MHV. Studies aimed at identifying the protein(s) responsible for modulating the type I IFN response showed that although the nonstructural ORF2a protein is a virulence factor with putative cyclic phosphodiesterase activity, it does not play a role in blocking the type I IFN response. Together, these studies have helped define the increasingly complex interactions between MHV, and possibly other coronaviruses, and the type I IFN response