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Abstract
The type I interferon (IFN) response is a crucial innate immune signalling pathway required for defense against viral infection. Accordingly, the great majority of mammalian viruses possess means to inhibit this important host immune response. Here we show that vaccinia virus (VACV) strain Western Reserve protein C6, is a dual function protein that inhibits the cellular response to type I IFNs in addition to its published function as an inhibitor of IRF-3 activation, thereby restricting type I IFN production from infected cells. Ectopic expression of C6 inhibits the induction of interferon stimulated genes (ISGs) in response to IFNα treatment at both the mRNA and protein level. C6 inhibits the IFNα-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway at a late stage, downstream of STAT1 and STAT2 phosphorylation, nuclear translocation and binding of the interferon stimulated gene factor 3 (ISGF3) complex to the interferon stimulated response element (ISRE). Mechanistically, C6 associates with the transactivation domain of STAT2 and this might explain how C6 inhibits the type I IFN signalling very late in the pathway. During virus infection C6 reduces ISRE-dependent gene expression despite the presence of the viral protein phosphatase VH1 that dephosphorylates STAT1 and STAT2. The ability of a cytoplasmic replicating virus to dampen the immune response within the nucleus, and the ability of viral immunomodulators such as C6 to inhibit multiple stages of the innate immune response by distinct mechanisms, emphasizes the intricacies of host-pathogen interactions and viral immune evasion.
Highlights
The innate immune response is the first line of defense against invading pathogens
IFNs are released from the infected cell and can act on the infected cell itself or neighbouring cells to initiate a signalling pathway that results in the production of hundreds of anti-viral proteins
Given many vaccinia virus (VACV) proteins have been shown to have multiple functions, for example N1 that inhibits both NF-κB signalling [29] and apoptosis [23,30], and the observation that the hitherto only known function of C6 occurs in the cytoplasm of infected cells despite C6 being present in the nucleus and cytoplasm, we investigated whether C6 may have additional immunomodulatory functions
Summary
The innate immune response is the first line of defense against invading pathogens. Interferons (IFNs) are one of the key players in this early response to infection and are important to protect against viruses, as can be seen by the increased susceptibility of IFNα/β receptor (IFNAR) knock out mice to viral infections [1]. Type I IFNs, which include IFNβ, several IFNα variants and other tissue or species-specific members, are produced directly in response to virus detection by cellular pattern recognition receptors (PRRs). Upon recognition of pathogen associated molecular patterns (PAMPs) such as viral DNA or RNA, PRRs activate several signalling pathways many of which converge on the kinases TANK-binding kinase (TBK1) and IκB kinase-ε (IKKε). These kinases, in complex with adaptor proteins such as TANK, NAK-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD), phosphorylate the transcription factor IFN regulatory factor 3 (IRF-3). IRF-3 dimerises and translocates into the nucleus and, in combination with other transcription factors, drives transcription from promoters containing cognate binding sites, including the IFNβ promoter [2]
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