ยฉ 2015, American Society for Microbiology. Infection with the murine coronavirus mouse hepatitis virus (MHV) activates the pattern recognition receptors melanoma differentiation-associated gene 5 (MDA5) and Toll-like receptor 7 (TLR7) to induce transcription of type I interferon. Type I interferon is crucial for control of viral replication and spread in the natural host, but the specific contributions of MDA5 signaling to this pathway as well as to pathogenesis and subsequent immune responses are largely unknown. In this study, we use MHV infection of the liver as a model to demonstrate that MDA5 signaling is critically important for controlling MHV-induced pathology and regulation of the immune response. Mice deficient in MDA5 expression (MDA5-/- mice) experienced more severe disease following MHV infection, with reduced survival, increased spread of virus to additional sites of infection, and more extensive liver damage than did wild-type mice. Although type I interferon transcription decreased in MDA5-/- mice, the interferon- stimulated gene response remained intact. Cytokine production by innate and adaptive immune cells was largely intact in MDA5-/- mice, but perforin induction by natural killer cells and levels of interferon gamma, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-ฮฑ) in serum were elevated. These data suggest that MDA5 signaling reduces the severity of MHVinduced disease, at least in part by reducing the intensity of the proinflammatory cytokine response.
year โฐ 2015
issn ๐Ÿ—„ 10985514 0022538X
volume 89
number 24
page 12330-12340
citedbycount 12