Jasmine Larrick L&S Sciences
Molecular Determinants and Mechanism of Flavivirus NS1-Induced Endothelial Permeability
A hallmark of severe dengue virus (DENV) infection is vascular leak. DENV non-structural protein 1 (NS1) directly triggers endothelial hyperpermeability and vascular leak via disruption of the endothelial glycocalyx layer (EGL). The EGL is a matrix of glycoproteins and membrane-bound proteoglycans lining the vascular endothelium, playing a protective role in maintaining endothelial barrier integrity. DENV NS1 binds to the endothelial cell surface through interactions with surface glycosaminoglycans (GAGs), such as heparan sulfate or chondroitin sulfate. However, the specific amino acid residues responsible for conferring cell binding specificity of various flavivirus NS1 proteins are not known. My project aims to investigate the molecular determinants behind NS1 recognition of endothelial GAGs by producing and evaluating NS1 chimeric proteins, which contain regions or specific amino acids of different flavivirus NS1 proteins into the backbone of DENV NS1. This summer, I will express and purify a panel of mutant NS1 proteins and evaluate their ability to bind to endothelial cells and lead to disruption of the EGL. Our findings may illuminate new paths to therapeutics for DENV or other flaviviruses.