(1074-C) 3D Brain Perfusable Vascularized Model to Study Neurotropic Flavivirus Recombinant NS1 Induced Endothelial Dysfunction
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: Several flaviviruses, such as JEV, can invade the peripheral and central nervous system and lead to severe encephalitic and hemorrhagic diseases, including blood-brain barrier disruption, vascular damage, hypovolemic shock, and excessive immune cell activation. While some vaccines are available for use, no direct-acting antivirals are available for flaviviruses, and vaccine adoption in highly affected areas is poor. High flavivirus non-structural protein NS1 levels are secreted and circulated in the bloodstream during severe infection. Given its known role in flavivirus-induced pathogenesis, NS1 may be a promising therapeutic candidate against severe flavivirus-induced disease. In order to accelerate the development of anti-NS1 therapeutics, we aimed to model neurotropic flavivirus recombinant NS1-induced pathogenesis using a hydrogel-based vascularized model to screen potential therapeutics. We developed a reproducible, perfusable brain vascular on-chip model using a 64-chip Mimetas Organograft plate platform by combining different cell types, human primary brain microvascular primary endothelial cells, and brain pericytes, in a fibrinogen hydrogel. Then, we exposed the brain vascular-on-chip model to recombinant NS1 proteins from JEV and WNV virus in a dose-dependent and time-dependent manner on a 3D vascularized model and documented vascular damage using live imaging. We observed that JEV NS1 induces significant vascular damage, which we observed through a decrease in vessel density, branching index, vessel length, and vessel intensity and expression of endothelial glycocalyx components and vascular-related genes compared to control. The results suggested the potentiality of secreted viral protein to modulate the endothelial barrier and can provide potential targets for antiviral therapies and vaccine development.