Ebola virus sequesters IRF3 in viral inclusion bodies to evade host antiviral immunity

Abstract

Viral inclusion bodies (IBs) are commonly formed during the replication of Ebola virus (EBOV) in infected cells, but their role in viral immune evasion has rarely been explored. Here, we found that interferon regulatory factor 3 (IRF3), but not TANK-binding kinase 1 (TBK-1) or IκB kinase epsilon (IKKε), was recruited and sequestered in viral IBs when the cells were infected by EBOV transcription- and replication-competent virus-like particles (trVLPs). NP/VP35-induced IBs formation was critical for IRF3 recruitment and sequestration, probably through STING interaction. Consequently, the association of TBK1 and IRF3, which plays a vital role in type I interferon (IFN-I) induction, was blocked by EBOV trVLPs infection. Additionally, IRF3 phosphorylation and nuclear translocation induced by Sendai virus (SeV) or poly(I:C) stimulation were also suppressed by EBOV trVLPs. Furthermore, downregulation of STING significantly attenuated VP35-promoted IRF3 accumulation in IBs. Viral proteins by which IBs-like structures could be formed were demonstrated to be much more potent in IFN-I antagonism than the expression of the IFN-I antagonist VP35 only. These results suggested a novel immune evasion mechanism by which EBOV evades host innate immunity. Ebola virus VP35 protein evades host antiviral immunity by interacting with STING to sequester IRF3 into inclusion bodies and inhibit type-I interferon production.