STRUCTURAL BASIS FOR IMMUNE EVASION BY RSV NON-STRUCTURAL PROTEINS

描述（由申请方提供）：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。尽管进行了数十年的深入研究，但治疗选择有限，需要改进。非结构蛋白1（NS 1）和2（NS 2）是在RSV毒力和发病机制中起关键作用的多功能蛋白。NS 1/2参与宿主免疫抑制，包括抑制I型干扰素（IFN）诱导和信号传导，以及抑制免疫应答。 NF-κB通路与细胞凋亡尽管许多宿主因子被认为是RSV NS 1/2蛋白的靶向，但目前没有NS 1或NS 2的结构可用。结构研究的缺乏限制了我们对这些非结构蛋白促进的免疫逃避的知识和相应的机制见解。此外，这种知识差距也限制了我们制定对策的能力。为了解决这一差距，我们将（a）开发病毒免疫拮抗剂NS 1/2蛋白的结构和机制的理解和（B）表征其与IFN的生产和响应信号通路，包括IRF 3，STAT 1，和STAT 2使用生物化学和结构的方法相互作用。将对这些研究的结果进行体内检测，以确定对免疫拮抗剂功能至关重要的残留物。通过这些研究，我们希望确定RSV NS 1/2如何促进免疫逃避的分子基础，并确定治疗和抗病毒开发的新靶点。

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.