# Evolution and pathogenesis of Usutu virus, an emerging arbovirus

> **NIH NIH R21** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $191,210

## Abstract

Project Summary
West Nile virus (WNV) and Usutu virus (USUV) are closely-related mosquito-borne viruses that cause
neuroinvasive disease in humans. WNV emerged from African and Europe into the U.S. in 1999, and it is now
the most common mosquito-borne disease in the continental U.S.; however, no vaccines or therapeutics are
available. USUV is emerging in Europe, where it has been introduced at least three times from Africa by
migratory birds, and human disease cases are increasing. The viral factors that lead to increases in flavivirus
pathogenesis include naturally-occurring viral genetic mutations and cross-reactive antibodies from co-
circulating heterologous flaviviruses. We have found that African and European strains of USUV differ
drastically in the level of disease generated in a wild-type mouse model, with differences in viremia of up to
100-fold between USUV strains. We have also found that human WNV convalescent sera partially cross-
neutralizes USUV in vitro. The long-term goal of this project is to understand the effect of viral evolution and
antibody cross-reactivity on flavivirus emergence and disease. The objectives of this study are to identify the
genetic mutations in USUV that dictate differences in pathogenesis and to determine whether WNV cross-
reactive antibodies alter USUV disease. The hypothesis is that viral mutations acquired during emergence
increase USUV pathogenesis and that heterologous WNV antibodies decrease USUV pathogenesis. Two
specific aims will address this hypothesis: 1) Identify viral genetic determinants of USUV disease; and 2)
Determine the impact of WNV antibodies on USUV disease. In the first aim, a reverse genetics system that we
recently developed will be used to identify mutations in USUV that alter viremia and disease in mice. In the
second aim, the effect of IgG purified from human WNV convalescent sera on USUV disease will be evaluated
in vivo. The research proposed here is innovative because it investigates significant differences in
pathogenesis caused by contemporary strains of an emerging, neglected virus using a novel reverse genetics
system. Upon successful completion of the proposed research, the anticipated contribution of this work will be
the identification of viral factors that affect USUV pathogenesis and host immune correlates of USUV disease.
This contribution is expected to be significant because it will lead to the ability to develop therapeutics and
vaccines to reduce flavivirus transmission and disease.

## Key facts

- **NIH application ID:** 10471848
- **Project number:** 5R21AI153988-02
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Nisha Duggal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $191,210
- **Award type:** 5
- **Project period:** 2021-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471848

## Citation

> US National Institutes of Health, RePORTER application 10471848, Evolution and pathogenesis of Usutu virus, an emerging arbovirus (5R21AI153988-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10471848. Licensed CC0.

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