Old World alphaviruses use distinct mechanisms to infect brain microvascular endothelial cells for neuroinvasion
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.
Authors
- Pablo Álvarez (ORCID: https://orcid.org/0000-0002-0079-3392)
- Frédéric Amant (ORCID: https://orcid.org/0000-0002-5452-4905)
- Doug Winters
- Robyn M. Kaake (ORCID: https://orcid.org/0000-0002-8341-3067)
- Prashant Kaushal
- Hengli Tang (ORCID: https://orcid.org/0000-0002-9358-410X)
- Marta Nieto (ORCID: https://orcid.org/0000-0002-8349-8435)
- Melody M. H. Li (ORCID: https://orcid.org/0000-0002-6905-7940)
- Mehdi Bouhaddou (ORCID: https://orcid.org/0000-0002-9526-1427)
- Oliver I. Fregoso (ORCID: https://orcid.org/0000-0003-3087-3374)
- Ashley Tang
- Karolina Elżbieta Kaczor‐Urbanowicz (ORCID: https://orcid.org/0000-0001-9243-3652)
- April D. Pyle (ORCID: https://orcid.org/0000-0001-6122-1649)
- Angélica Medina
- Bryan Ramirez Reyes
Institutions
- Florida State University (US)
- QB3 (US)
- Gladstone Institutes (US)
- University of California, Los Angeles (US)
- University of California, Santa Cruz (US)
- Broad Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116305
- Citations
- 1
- Primary Topic
- Neonatal and fetal brain pathology
- Type
- article
- Field-Weighted Citation Impact
- 3.49
Funders
- W. M. Keck Foundation
- Washington State University
- James B. Pendleton Charitable Trust
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of Allergy and Infectious Diseases
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
- David Geffen School of Medicine, University of California, Los Angeles
- UCLA AIDS Institute