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.

Public Health Relevance

Respiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections in infants and young children worldwide. There are major gaps in our understanding as to the mechanisms by which these viruses interact with host factors and evade immune responses. We will study interaction of the RSV non-structural proteins, NS1 and NS2, with cellular proteins, including RIG-I, IRF3, and STAT2, in order to shed light on these interactions and identify novel antiviral approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI107056-02
Application #
8662195
Study Section
Virology - A Study Section (VIRA)
Program Officer
Kim, Sonnie
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$387,000
Indirect Cost
$109,200
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130