RVFV毒力因子NSs形成filament结构及介导毒性效应的机理研究

Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus, with non-structural protein NSs as the major virulence factor. NSs forms a unique filamentous structure in infected cells. The formation and stabilization of filament might be directly related to the toxic effect mediated by NSs, which is regulated by different mechanisms in “dead-end” host and arthropod vector cells. In this project, we plan to employ multiple methods including molecular biology, proteomics and modern imaging technologies together with the established reverse genetic system to 1) identify host factors mediating the toxic effect of NSs through participating in the process of filament formation; 2) investigate the mechanism of key host factors in the regulation of NSs virulence; 3) reveal the dynamic process of key host factor participating in the formation of filament. Taken these results together, we will be able to elucidate the mechanism of filament formation and toxic effect mediated by NSs. This work will not only facilitate the comprehensive understanding of the pathogenic mechanism of RVFV, but also provide specific targets for the design and development of novel anti-viral drugs against the RVFV key virulence factor NSs.

RVFV是一种高致病性蚊传病毒，编码的非结构蛋白NSs是其最关键的毒力因子。NSs在细胞内形成独特的长丝状结构(filament)，这一结构的形成和稳定可能与其介导的毒性效应直接相关，并在中间宿主（传播媒介）和终宿主（哺乳动物）细胞中受不同的机制调控。本项研究拟基于RVFV反向遗传学系统，采用包括分子生物学、蛋白质组学和现代影像学在内的多种技术手段，1)鉴定参与filament形成介导NSs毒性效应的宿主因子；2)阐明关键宿主因子调控NSs毒力的分子机制；3)解析关键宿主因子参与filament形成的动态过程。最终整合上述工作阐明NSs形成filament结构及介导毒性效应的分子机理。这项研究不仅将有助于RVFV致病机制的阐明，也将为针对关键毒力因子NSs的抗病毒药物的研发提供新靶点。

RVFV是一种蚊传的高致病性病毒，其编码的非结构蛋白NSs与致病性密切相关，是其最关键的毒力因子。NSs在细胞内形成的长丝状(filament)结构可能与其介导的毒性效应直接相关，然而具体的作用机制尚不明确。本项目旨在揭示NSs filament结构形成和稳定的机制及其所介导的毒性效应的分子机制。通过本项目的实施，我们取得了以下成果：1）鉴定出决定NSs filament结构形成和稳定的关键氨基酸位点，并明确了决定NSs filament结构形成的关键氨基酸位点与裂谷热病毒毒力相关。2）解析了NSs filament结构介导毒性效应的机制。3）鉴定出具有抑制裂谷热病毒复制活性的天然产物小分子。项目研究进展为深入阐明RVFV致病机制奠定基础，同时为针对关键毒力因子NSs开发的抗病毒药物提供潜在靶点。截至目前，共发表项目标注的SCI论文2篇，获得授权发明专利1项。