旧大陆甲病毒利用不同机制感染脑微血管内皮细胞以实现神经侵袭。

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

作者信息

Alvarez Pablo A, Tang Ashley, Winters Declan M, Kaushal Prashant, Medina Angelica, Kaczor-Urbanowicz Karolina E, Reyes Bryan Ramirez, Kaake Robyn M, Fregoso Oliver I, Pyle April D, Bouhaddou Mehdi, Tang Hengli, Li Melody M H

机构信息

Department of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.

出版信息

bioRxiv. 2025 Jan 24:2025.01.22.634395. doi: 10.1101/2025.01.22.634395.

DOI:10.1101/2025.01.22.634395

PMID:39896450

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11785202/

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.

摘要

几种甲病毒可突破血脑屏障（BBB），引发使人衰弱或致命的脑炎。辛德毕斯病毒（SINV）已被广泛研究以了解甲病毒的神经发病机制；然而，血脑屏障处神经侵袭的分子细节仍知之甚少。我们通过将具有生理相关性的、源自人多能干细胞的脑微血管内皮细胞（BMECs）模型与具有相反神经侵袭性的SINV毒株配对，研究了甲病毒与血脑屏障的相互作用。我们的系统表明，SINV神经侵袭与血脑屏障的强烈感染相关。具体而言，SINV神经侵袭的遗传决定因素增强了病毒进入BMECs的能力。我们还确定溶质载体家族2成员3（SLC2A3，也称为GLUT3）是一种潜在的BMEC特异性进入因子，被用于神经侵袭。引人注目的是，高效的血脑屏障感染是一种保守的表型，与包括基孔肯雅病毒在内的几种旧世界甲病毒的神经侵袭能力相关。在这里，我们揭示血脑屏障感染是甲病毒神经侵袭的共同途径，可作为预防甲病毒诱导脑炎的靶点。