Evan Juan Rose Hills
Investigating the role of dengue virus nonstructural protein 1-induced NLRP3 inflammasome activation in dengue pathogenesis
With an estimated 105 million infections globally, dengue virus (DENV), the causative agent of dengue fever, places a severe burden upon global public health. Severe manifestations of dengue fever are characterized by leak of plasma from the vascular system; these symptoms can develop into hypovolemic shock and organ failure if left untreated. The Harris laboratory and others have discovered that DENV non-structural protein 1 (NS1) is critical to dengue pathogenesis and can directly trigger vascular leak. The exact mechanism of NS1-induced vascular leak is still unknown, but recent work has shown that the DENV NS1 can activate inflammasomes, an innate immune sensor within cells. Inflammasome activation causes the release of inflammatory mediators which can lead to the disruption of the endothelium. However, it is currently unknown how NS1 activates the inflammasome. My project will focus on investigating this mechanism and its importance in causing vascular leak. Thus, I aim to investigate the genetic and molecular determinants governing NS1-induced NLRP3 inflammasome activation. The discoveries from this work may reveal potential therapeutics for the treatment of severe dengue.