Perfusable Brain Microvascular Network-On-Chip Model to Study Flavivirus NS1-Induced Endothelial Dysfunction

Flaviviruses can lead to severe neurotropic-encephalitic pathology, for which the viral nonstructural protein 1 (NS1) plays a major role. 2D in vitro cellular systems and animal models are currently used to investigate the effects of flavivirus NS1 in the brain-blood barrier do not fully capture pathogenesis and drug responses seen in humans. Here is reported the development of a perfusable human brain microvascular network-on-a-chip (BMVasChip) model which incorporates brain endothelial cells and pericytes and recapitulates the cellular organization and expression of brain blood barrier-specific markers, including intracellular junction proteins. This BMVasChip model is used to investigate vasculopathy caused by exposure to a panel of flavivirus NS1 proteins, including Japanese encephalitis (JEV), West Nile (WNV), and dengue virus (DENV) NS1 proteins. The BMVasChip platform is able to demonstrate flavivirus NS1-induced pathophysiological phenotypes in the BMVasChip, including early and late endothelial activation and dysfunction features such as loss of barrier integrity, morphological features, and production of pro-inflammatory markers in a virus, dose, and time-dependent manner. In summary, the BMVasChip model recapitulates key features of endothelial dysfunction, potentially reflecting NS1's role in viral pathogenesis and providing targets for antiviral therapeutics and vaccine development.