# Mechanisms of alphavirus infectivity and adaptation - Resubmission - 1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $532,388

## Abstract

PROJECT SUMMARY
Arboviruses are transmitted from insect vectors to humans, yet the molecular mechanisms that govern this
critical step in the viral life cycle are not completely understood. Chikungunya virus (CHIKV) has undergone
several natural adaptation events, acquiring mutations in the viral glycoproteins that have increased its
infectivity and transmission, yet how the glycoproteins promote infectivity, spread, and disease in vivo is
unclear. We harnessed the power of in vivo viral evolution and identified a new evolutionary intermediate in β-
strand c of the CHIKV E1 glycoprotein that led to increased transmission in mosquitoes and increased
replication and pathogenesis in mice, indicating that these glycoprotein regions are crucial for promoting viral
infectivity and disease. Preliminary studies from our lab show that E1 β-strand c plays essential roles in virion
thermostability, fusion, and cholesterol-dependent entry. Moreover, using viral evolution we have identified
host-specific genetic interactions between CHIKV E1 and E2. Based on these preliminary studies, we
hypothesize that CHIKV E1 and E2 drive distinct mechanisms of entry into insects and mammals and that
temperature and lipid composition in mosquitoes drives viral adaptation. Our overall goal is to understand the
fundamental mechanisms by which the CHIKV structural proteins regulate alphavirus infectivity and
dissemination in insects and mammals, and to elucidate what drives the adaptation of the glycoprotein in
insects. Here, we use complementary biochemical, genetic, in vitro and in vivo approaches coupled with deep
sequencing technologies to establish how the CHIKV structural proteins function to promote entry and CHIKV
pathogenesis and transmission in vivo (Aim 1), and to establish how temperature and host lipids impact
CHIKV-vector interactions in mosquitoes (Aim 2). Understanding the discrete mechanisms of how the viral
structural proteins regulate infectivity in insects and mammals, and how host lipids impact adaptation is
essential to understanding how arboviruses are transmitted, spread, and cause disease.

## Key facts

- **NIH application ID:** 10444392
- **Project number:** 1R01AI162774-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kenneth Stapleford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $532,388
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444392

## Citation

> US National Institutes of Health, RePORTER application 10444392, Mechanisms of alphavirus infectivity and adaptation - Resubmission - 1 (1R01AI162774-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10444392. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*