Abstract
Abstract Vaccinia virus C7 protein is an important host-range factor for vaccinia virus life cycle in mammalian cells. C7L homologs are present in almost all of the poxviruses that infect mammalian hosts. Type I IFN plays an important role in host defense of viral infection, and yet, the role of C7 in immune modulation of the IFN pathway is unclear. We have previously reported that the highly attenuated modified vaccinia virus Ankara (MVA) infection of conventional dendritic cells (cDCs) induces type I IFN via the cGAS/STING/TBK1/IRF3 pathway. In this study, we find that ectopic C7 expression blocks STING, TBK1, or IRF3-induced IFNB and ISRE (interferon stimulated response element) promoter activation. Murine or human macrophage cell lines that overexpress C7 have blunted innate immune responses to DNA or RNA stimuli, or the infection of DNA or RNA viruses. Overexpression of C7 also attenuates ISG gene expression induced by IFN-b treatment. MVA with deletion of C7L (MVAΔC7L) infection of cDCs induces higher levels of type I IFN than MVA. C7 blocks IFN-b-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway via preventing Stat2 phosphorylation. C7 directly interacts with stat2 as demonstrated by co-immunoprecipitation studies. Taken together, our results provide evidence that C7 has dual inhibitory roles in type I IFN production and signaling.
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