STRUCTURAL BASIS FOR IMMUNE EVASION BY RSV NON-STRUCTURAL PROTEINS

描述（由申请人提供）：呼吸道合胞病毒（RSV）是全球婴幼儿、老年人和免疫功能低下个体严重下呼吸道感染、发病率和死亡率的主要原因。尽管经过数十年的深入研究，治疗方案仍然有限，而且还需要改进。非结构蛋白1 （NS1）和非结构蛋白2 （NS2）是在RSV毒力和发病机制中起关键作用的多功能蛋白。NS1/2参与宿主免疫抑制，包括抑制I型干扰素（IFN）的诱导和信号传导，以及抑制

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections, morbidity, and mortality in infants and young children, the elderly, and immunocompromised individuals worldwide. Despite decades of intensive research, treatment options are limited and in need of improvement. Non-structural proteins 1 (NS1) and 2 (NS2) are multifunctional proteins that play critical roles in RSV virulence and pathogenesis. NS1/2 are involved in host immune suppression, including inhibition of Type I interferon (IFN) induction and signaling, as well as inhibition of the NF-κB pathway and apoptosis. Although many host factors are thought to be targeted by RSV NS1/2 protein, currently no structures of NS1 or NS2 are available. The lack of structural studies limits our knowledge and corresponding mechanistic insights into immune evasion facilitated by these non-structural proteins. Moreover, this gap in knowledge also restricts our ability to develop countermeasures. In order to address this gap, we will (a) develop a structural and mechanistic understanding of viral immune antagonists NS1/2 proteins and (b) characterize their interactions with IFN production and response signaling pathways, including IRF3, STAT1, and STAT2 using biochemical and structural methods. Findings from these studies will be tested in vivo to identify residues critical for immune antagonist function. Through these studies, we expect to define the molecular basis for how RSV NS1/2 contributes to immune evasion and identify new targets for therapeutic and antiviral development.