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/IKKε/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.

猪繁殖与呼吸综合征病毒（Porcine Reproductive and Respiratory Syndrome Virus, PRRSV）是严重危害养猪产业的重要病原，给全球养猪业造成了巨额经济损失。本课题组前期研究发现，DNA感知天然免疫cGAS-STING信号通路在PRRSV感染诱导干扰素（Interferon, IFN）产生以及抑制PRRSV复制过程中发挥关键作用。然而，PRRSV的免疫逃逸机制目前仍不明确。本研究发现，PRRSV非结构蛋白5（Non-structural protein 5, Nsp5）可强效抑制cGAS-STING-IFN抗病毒信号通路。进一步机制研究显示，Nsp5可与STING发生相互作用，阻断STING从内质网（Endoplasmic Reticulum, ER）向高尔基体的转运过程，并干扰STING对TBK1/IKKε/IRF3的招募。本研究进一步证实，Nsp5的36-47位与58-67位氨基酸区域是其抑制STING活性以及PRRSV复制的关键功能区域。本研究揭示了PRRSV抑制宿主天然抗病毒免疫应答的全新机制，为深入理解PRRSV的致病机理提供了新的理论参考。