IKKϵ is targeted by pathogenic West Nile virus to evade host immune control (P1387)

Abstract Innate antiviral immunity and interferon (IFN) defenses are essential for the control of West Nile virus (WNV) infection. A pathogenic strain of the virus (WNV-TX) can suppress IFN actions by blocking JAK-STAT signaling, thus evading host IFN defenses. It was recently shown that IKKϵ directly regulates STAT1 activity by phosphorylating STAT1 on S708 to enhance IFIT2 expression and suppress WNV infection. However, the spectrum of interferon-stimulated gene (ISG) expression that is regulated by IKKϵ/STAT1 S708 signaling undergoing WNV infection and IFN signaling is not defined nor is it known if pathogenic WNV can evade these actions as a basis of disease. Here, we compared the transcriptomes of cells infected with pathogenic (WNV-TX) and non-pathogenic (WNV-MAD) strains of WNV to identify the genes specifically regulated by pathogenic WNV. Further, we compared the transcriptomes of IFN treated WT and IKKϵ KO cells to identify IKKϵ-dependent ISGs. These analyses allow us to identify genes that are shut down by pathogenic WNV in an IKKϵ-dependent manner to evade host immune response. Importantly, we also found IKKϵ-mediated induction of ISGs to be blocked by the anchored capsid portion of WNV-TX but not WNV-MAD. The anchored capsid of WNV-TX physically interacts with IKKϵ to mediate kinase suppression and a block in STAT1 S708 phosphorylation. Thus, IKKϵ is preferentially targeted by the anchored capsid of the pathogenic WNV to evade antiviral innate immunity and IFN actions.