Phoebe Wang Rose Hills
Uncovering Functional Domains of Dengue Virus Non-Structural Protein 1
Dengue virus (DENV) infects an estimated 105 million people every year. More than 500,000 of these cases develop into a severe form of disease characterized by leakage of plasma from the vasculature. If left untreated, these symptoms may progress to fatal outcomes such as hemorrhage, hypovolemic shock, and organ failure. Studies have suggested that DENV non-structural protein 1 (NS1) plays an important role in the pathogenesis of severe dengue through interactions with endothelial and immune cells. In addition, the Harris Lab has recently shown in vitro and in vivo that DENV NS1 activates the inflammasome, a family of cytosolic innate immune sensors, leading to a protective immune response to DENV in a murine model of DENV infection. However, the molecular mechanisms behind DENV NS1-induced inflammasome activation remain unknown. For my project, I plan to identify the functional protein domains of NS1 involved in inflammasome activation by using NS1 chimeras containing protein domain swaps between DENV NS1 and the related West Nile virus NS1. Results from this project will clarify the poorly understood role that inflammasome activation plays during the innate immune response to DENV and deepen mechanistic understanding of DENV NS1 biology.