STRUCTURAL BASIS FOR IMMUNE EVASION BY RSV NON-STRUCTURAL PROTEINS

描述(申请人提供)：呼吸道合胞病毒(RSV)是世界各地婴幼儿、老年人和免疫功能低下的人严重下呼吸道感染、发病率和死亡率的主要原因。尽管进行了数十年的密集研究，但治疗选择有限，需要改进。非结构蛋白1(NS1)和非结构蛋白2(NS2)是在RSV毒力和致病过程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型干扰素的诱导和信号转导，以及抑制 核因子-κB通路与细胞凋亡虽然许多宿主因子被认为是RSV NS1/2蛋白的靶标，但目前还没有可用的NS1或NS2结构。缺乏结构研究限制了我们对这些非结构蛋白促进免疫逃避的知识和相应的机制洞察。此外，这种知识差距也制约了我们制定对策的能力。为了弥补这一差距，我们将(A)建立对病毒免疫拮抗剂NS1/2蛋白的结构和机制的理解，并(B)使用生化和结构方法表征它们与干扰素产生和反应信号通路的相互作用，包括IRF3、STAT1和STAT2。这些研究的结果将在体内进行测试，以确定对免疫拮抗剂功能至关重要的残基。通过这些研究，我们期望确定RSV NS1/2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.