2025-09-23 カリフォルニア大学ロサンゼルス校(UCLA)
<関連情報>
- https://newsroom.ucla.edu/releases/how-mosquito-borne-viruses-breach-brain-defenses
- https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01076-9
旧世界のアルファウイルスは神経侵襲のために脳微小血管内皮細胞を感染させる際、異なるメカニズムを用いる Old World alphaviruses use distinct mechanisms to infect brain microvascular endothelial cells for neuroinvasion
Pablo A. Alvarez ∙ Ashley Tang ∙ Declan M. Winters ∙ … ∙ Mehdi Bouhaddou ∙ Hengli Tang ∙ Melody M.H. Li
Cell Reports Published:September 22, 2025
DOI:https://doi.org/10.1016/j.celrep.2025.116305
Graphical abstract
Highlights
- Neuroinvasive SINV robustly infects brain endothelial cells and pericytes
- Efficient infection is conferred by viral E2 glycoprotein mutations at the step of viral entry
- Neuroinvasive SINV specializes in PCDH10-dependent entry while non-neuroinvasive virus uses multiple receptors
- BBB infection is conserved in neuroinvasive alphaviruses, including the widespread CHIKV
Summary
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.
