# Molecular mechanisms governing chikungunya virus binding, tropism, and pathogenesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $582,578

## Abstract

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes a painful musculoskeletal inflammatory
disease, which can persist for months to years. Chronic CHIKV arthritis is debilitating and produces substantial
social and economic consequences. Despite the burden posed by acute and chronic CHIKV disease, licensed
vaccines and antiviral therapeutics are not available. Virus-host interactions at the cell-surface dictate species
and tissue tropism and are often determinants of virulence. We discovered that multiple pathogenic strains of
CHIKV bind to heparan sulfate (HS), a type of glycosaminoglycan (GAG) that is highly variable in subunits and
modifications, to mediate adhesion to cells. Efficient binding and infection of biologically relevant cell types by
CHIKV depends on cell-surface HS, but little is known about the viral and host determinants that mediate these
initial contacts or how CHIKV-HS interactions influence virulence and disease outcomes. We hypothesize that
CHIKV has evolved an optimum affinity for unique HS structures, including N-sulfation, via specific residues of
CHIKV E2 to mediate efficient CHIKV attachment to target cells, which influences viral disease outcomes. Three
integrated but independent specific aims are proposed. In Specific Aim 1, we will test the hypothesis that CHIKV
binds to specific modifications of HS chains to attach to target cells. A combination of biochemical, biophysical,
genetic, and virological techniques will be used to define specific HS structures required for binding and infection
of target cells, which will be genetically validated in target cells. Binding parameters will be biophysically charac-
terized. In Specific Aim 2, we will test the hypothesis that multiple HS binding sites on CHIKV virions are medi-
ated by specific basic residues in E2. The structural features and specific resides of E2 that facilitate CHIKV-HS
interactions will be defined by cryo-EM, and targeted mutagenesis of HS-binding sites will be used to engineer
mutants with a loss of function in HS binding. Viral mutants will be characterized for E2 functions in vitro and
used to determine the requirement of viral engagement with HS for binding and infection of target cells. In
Specific Aim 3, we will test the hypothesis that decreased attachment to HS will result in attenuation in a mouse
model of disease. We will first elucidate the dependence of CHIKV binding to HS on target cells using mice
harboring conditional knockout of the HS-modifying gene Ndst1 in endothelial and muscle cells. Mice will also
be infected with a panel of viruses that display decreased capacity in binding to HS or entry receptor MXRA8 to
assess the specific function of virus engagement with HS in dissemination, cell tropism, immune responses, and
tissue. Studies in this application will define structural and biophysical parameters of CHIKV-HS binding, eluci-
date the significance of HS-dependent attachment to target cells, and unravel functions o...

## Key facts

- **NIH application ID:** 10801622
- **Project number:** 1R01AI173044-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Laurie A. Silva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,578
- **Award type:** 1
- **Project period:** 2024-07-03 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801622

## Citation

> US National Institutes of Health, RePORTER application 10801622, Molecular mechanisms governing chikungunya virus binding, tropism, and pathogenesis (1R01AI173044-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10801622. Licensed CC0.

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