Chacterization of Structure-based Targets for Vaccines Against Respiratory Syncytial Virus

Principal Investigator(s):

Gaya Amarasinghe, Ph.D. - Pathology and Immunology

Status: Completed

Center(s): Center for Pediatric Pulmonary Disease

Award Mechanism: Interdisciplinary Research Initiative

Project Period: 2/1/2013 - 1/31/2015

Total Amount: $300,000

Collaborators: Daisy Leung, Michael J. Holtzman

Project Summary:

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections, morbidity, and mortality in pediatric populations worldwide. Despite decades of intensive research, treatment and vaccine options are limited and need to be improved. RSV produces two important proteins called NS1 and NS2, which antagonize the host interferon (IFN) response and are required for RSV to cause disease.  In this proposal, we will develop a mechanistic understanding of how these proteins function in RSV pathogenesis by defining how their structural dynamics contribute to IFN antagonism. This information will be used to develop modified viruses with impaired IFN antagonism that may be useful in future vaccines.

Aims: 1) Use nuclear magnetic resonance (NMR)-based dynamics studies to identify structural “hot spots” in RSV NS1 and NS2  that contribute to IFN antagonism and viral pathogenesis; 2) Determine the impact of these hot spots on interactions between NS1/ NS2 and host factors in airway cells; 3) Develop viruses with attenuated IFN antagonism based on structural studies for use as vaccine candidates

Potential Impact:  We anticipate that our research, aimed at delineating the molecular mechanisms of immune antagonism of a key virus that impacts the pediatric population, will lead to vaccines that limit RSV infections and prevent long-term potentiation of other illnesses, such as asthma.