STRUCTURAL BASIS FOR IMMUNE EVASION BY RSV NON-STRUCTURAL PROTEINS

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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-?B 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.