Old World Alphaviruses Use Distinct Mechanisms to Infect Brain Microvascular Endothelial Cells for Neuroinvasion

Overview

Journal bioRxiv

Date 2025 Feb 3

PMID 39896450

Authors

Pablo A Alvarez

Ashley Tang

Declan M Winters

Prashant Kaushal

Angelica Medina

Karolina E Kaczor-Urbanowicz

Bryan Ramirez Reyes

Robyn M Kaake

Oliver I Fregoso

April D Pyle

Mehdi Bouhaddou

Hengli Tang

Melody M H Li

Affiliations

Soon will be listed here.

Abstract

Several alphaviruses bypass the blood-brain barrier (BBB), causing debilitating or fatal encephalitis. Sindbis virus (SINV) has been extensively studied to understand alphavirus neuropathogenesis; yet the molecular details of neuroinvasion at the BBB remain poorly understood. We investigated alphavirus-BBB interactions by pairing a physiologically relevant, human pluripotent stem cell derived model of brain microvascular endothelial cells (BMECs) with SINV strains of opposite neuroinvasiveness. Our system demonstrates that SINV neuroinvasion correlates with robust infection of the BBB. Specifically, SINV genetic determinants of neuroinvasion enhance viral entry into BMECs. We also identify solute carrier family 2 member 3 (SLC2A3, also named GLUT3) as a potential BMEC-specific entry factor exploited for neuroinvasion. Strikingly, efficient BBB infection is a conserved phenotype that correlates with the neuroinvasive capacity of several Old World alphaviruses, including chikungunya virus. Here, we reveal BBB infection as a shared pathway for alphavirus neuroinvasion that can be targeted for preventing alphavirus-induced encephalitis.

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