Chikungunya virus non-structural protein 2 (nsP2) inhibits RIG-I and TLR-mediated immune response

Chikungunya virus (CHIKV) is a single-stranded positive-sense RNA virus that employs various strategies to evade the host immune response. CHIKV non-structural protein 2 (nsP2) is one of the viral-encoded proteins essential for viral replication as well as modulation of the immune response. In this study, we demonstrated that CHIKV nsP2 suppresses both Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and Toll-like receptors (TLRs) signaling pathways. Domain mapping of nsP2 identified that the N-terminal region encompassing the N-terminal domain and the helicase domain (NH) is responsible for the inhibition. Furthermore, site-directed mutagenesis experiments showed that a functional helicase is necessary for inhibiting interferon production, but the C-terminal VLoop region, previously implicated in host transcriptional shutoff is not. Lastly, we demonstrated that nsP2 disrupts two key immune RLRs and TLRs mediated signaling pathways by interfering with the common proteins TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), which are involved in both signaling pathways. These findings enhance our understanding of CHIKV immune evasion strategies and offer potential targets for the development of antiviral therapeutics.