PRRSV evades innate immune cGAS-STING antiviral function via its Nsp5 to deter STING translocation and activation

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is an important pathogen that seriously endangers pig breeding, causing significant economic losses to the global swine industry. Our previous study found that the DNA sensing innate cGAS-STING signaling pathway plays an important role in inducing interferon (IFN) upon PRRSV infection and inhibition of PRRSV replication. However, the immune evasion and its mechanism by PRRSV is still unclear. In current study, we found that PRRSV Non-structural protein 5 (Nsp5) strongly inhibits the cGAS-STING-IFN antiviral response. Further, we found that Nsp5 interacts with STING, blocking STING transport from ER to Golgi apparatus and interfering with STING recruitment of TBK1/IKKepsilon/IRF3. Finally, we demonstrated that the Nsp5 36-47 and 58-67 amino acid regions are critical regions for inhibiting STING activity and PRRSV replication. The study describes a novel mechanism by PRRSV for suppression of the host innate antiviral response and have implications for our understanding of PRRSV pathogenesis.