伪狂犬病病毒利用NMHC-IIA拮抗cGAS-STING介导天然免疫应答的分子机制研究

猪伪狂犬（PR）是由伪狂犬病病毒（PRV）引起的急性接触性动物疫病，对全球特别是我国生猪产业造成重大经济损失。PRV抑制宿主天然免疫的特性是其难以防控的重要原因。申请人前期证实多功能骨架蛋白-非肌肉肌球蛋白II型重链A（NMHC-IIA）具有免疫负调控作用，近期研究发现该蛋白在PRV感染中可以拮抗cGAS-STING介导I型干扰素和促炎性细胞因子产生，但分子机制尚不清楚。针对这一科学问题，本项目首先明确NMHC-IIA对PRV诱导cGAS-STING通路活化的拮抗作用，随后筛选其靶向该通路的关键节点分子并揭示调控机制，最后阐明PRV调节NMHC-IIA介导免疫抑制功能的分子机理。本项目将揭示PRV利用NMHC-IIA抑制cGAS-STING介导天然免疫应答的作用机制，有助于深入理解PRV免疫抑制和致病机理。

Pseudorabies (PR), caused by PR virus (PRV), has led to severe economic losses in global pig-breeding industry, especially in China. PRV is characterized by immunosuppression, which makes it hard to prevent and control. The applicant has revealed that non-muscle myosin heavy chain IIA (NMHC-IIA), a multi-functional cytoskeleton protein, plays an inhibitory role in innate immune responses. NMHC-IIA has been recently demonstrated to suppress cGAS-STING-mediated production of type I interferons and pro-inflammatory cytokines during PRV infection. However, the underlying mechanisms remain to be elucidated. This project will firstly corroborate that NMHC-IIA antagonizes activation of cGAS-STING signaling transduction. Subsequently, the project will identify the signaling molecules of cGAS-STING pathway targeted by NMHC-IIA, and explore the involved mechanisms. Finally, the project will clarify how PRV modulates the immunosuppressive function of NMHC-IIA. This project will reveal the molecular mechanisms by which NMHC-IIA is utilized by PRV to inhibit cGAS-STING pathway-mediated innate immune responses, and deepen the understanding of PRV immunosuppression and pathogenesis.