Old World alphaviruses use distinct mechanisms to infect brain microvascular endothelial cells for neuroinvasion

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Several alphaviruses bypass the blood-brain barrier (BBB), causing debilitating or fatal encephalitis. Sindbis virus (SINV) has been extensively studied in vivo to understand alphavirus neuropathogenesis, yet the molecular details of neuroinvasion remain poorly understood. We investigated alphavirus-BBB interactions by pairing a physiologically relevant, human pluripotent stem cell-derived model of brain microvascular endothelial-like cells with SINV strains of opposite neuroinvasiveness. Our system demonstrates that SINV neuroinvasion correlates with robust BBB infection. Specifically, SINV genetic determinants of neuroinvasion enhance viral entry into human pluripotent stem cell-derived brain microvascular endothelial-like cells. We also demonstrate that neuroinvasive SINV relies primarily on PCDH10, while non-neuroinvasive SINV relies on multiple entry factors, including LRP1. This specialist-versus-generalist strategy is what ultimately modulates neuroinvasion. Strikingly, efficient BBB infection is a conserved phenotype that correlates with the neuroinvasive capacity of several Old World alphaviruses, including chikungunya virus. We reveal BBB infection as a shared pathway for alphavirus neuroinvasion that can be targeted to prevent alphavirus-induced encephalitis.

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