# Unraveling alphavirus neuroinvasion: Molecular insights from a stem cell based blood-brain barrier model

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $44,671

## Abstract

PROJECT SUMMARY
Alphaviruses are mosquito-borne viruses that can cause arthritis and fatal encephalitis in humans with no
approved therapeutics. Encephalitic alphaviruses, like Sindbis (SINV) and chikungunya (CHIKV) viruses, must
cross the barriers protecting the central nervous system and therefore are neuroinvasive. The central nervous
system is primarily protected by tightly connected brain microvascular endothelial cells (BMECs), pericytes, and
astrocytes, which together constitute the blood-brain barrier (BBB). Genetic determinants of neuroinvasion reside
in the alphavirus E2 glycoprotein and host factors that interact with the E2 glycoprotein have been identified.
However, the relationship between neuroinvasive residues on E2 and the cell-specific expression of host
interactors are not well characterized in the context of neuroinvasion. Our lab models the BBB by using
pluripotent stem cell derived BMECs (iBMECs) that recapitulate the in vivo neuroinvasive phenotypes of
alphaviruses and flaviviruses. Using this model, we have demonstrated that alphavirus neuroinvasion correlates
with the ability to efficiently infect BMECs. Therefore, we hypothesize that the alphavirus E2 glycoprotein must
interact with a BMEC-specific host factor to efficiently infect BMECs and cross the BBB. We will first determine
how previously identified neuroinvasive E2 residues on SINV and CHIKV confer the ability to efficiently infect
BMECs. Furthermore, we will identify the host factor that neuroinvasive alphaviruses hijack for efficient BMEC
infection and characterize its interactions with E2. This work will elucidate virus-BBB interactions that
facilitate neuropathogenesis, providing a foundation for therapeutic research.
Under the fellowship training plan, I will advance my abilities in experimental design and science communication
by executing, presenting, and publishing the results of this project, as well as through coursework and teaching
as required by my doctoral program. My research training will take place in a rigorous and multidisciplinary
scientific environment at the University of California, Los Angeles, where I have access to all the materials and
expertise necessary for the completion of this project.

## Key facts

- **NIH application ID:** 10903622
- **Project number:** 1F31AI179235-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Pablo Alvarez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,671
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903622

## Citation

> US National Institutes of Health, RePORTER application 10903622, Unraveling alphavirus neuroinvasion: Molecular insights from a stem cell based blood-brain barrier model (1F31AI179235-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903622. Licensed CC0.

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