NIH Research Festival
Flaviviruses are a family of positive, single stranded RNA viruses, infect approximately 400 million people worldwide each year. Certain Flaviviruses, such as Japanese encephalitis virus, West Nile virus, and dengue virus can lead to severe disease involving but not limited to endothelial dysfunction and vascular damage. While it is known that dengue virus non-structural protein 1 (NS1) is secreted and circulated in blood stream during infection and its amount is linked to disease severity, the role of other related flavivirus NS1s are less well-defined. In addition, there is no current 3D model which fully recapitulate flavivirus NS1 pathogenesis to understand the pathophysiology for personalized medicine. In this study, we aimed to model diverse flavivirus induced pathogenesis using a hydrogel based vascularized model to develop potential therapeutics. We first developed a reproducible, perfusable vascular-on-chip model by combining different cell types in a fibrinogen hydrogel. We then tested effect of recombinant NS1 protein from JEV, WNV, or DENV in a dose and time dependent manner on the vascular-on-chip system and documented vascular damage by different assay read outs. Our findings reveal that flavivirus NS1 alters the permeability and morphometric parameters of vascular network in a time and dose-dependent manner, and this leads to differential disruption of endothelial glycocalyx layer components such as sialic acid and heparan sulfate and upregulation of vascular damage related genes. The results suggests that the vascular-on-chip model may recapitulate tissue- and flavivirus specific pathogenesis of vascular dysfunction. In addition, this model may provide potential targets for antiviral therapies.
Scientific Focus Area: Virology
This page was last updated on Monday, September 25, 2023