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 hosts immune response. The 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 demonstrate that CHIKV nsP2 suppresses both RIG-I-like receptors (RLR) and Toll-like receptors (TLR) signaling pathways. Domain mapping of the nsP2 identified 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 functional helicase is necessary for inhibiting interferon production, but the C-terminal V-Loop region, previously implicated in host transcriptional shutoff is not. Lastly, we demonstrate that nsP2 disrupts two key immune signaling pathways, RLR and TLRs, by interfering with common proteins, TBK1 and IRF3, 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.