# Regulation of Antiviral Responses in Plasmacytoid Dendritic Cells to Chikungunya Virus by the Gut Microbiota

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2022 · $51,752

## Abstract

Project Summary
 Chikungunya virus (CHIKV) is a re-emerging mosquito-transmitted alphavirus in the Togaviridae family
that causes severe acute and chronic polyarthritis and affects millions of people globally. Despite the morbidity
associated with CHIKV infection and the large population at risk, no approved vaccines or therapeutics are
available to prevent or treat CHIKV infection. Moreover, the acquired factors that dictate the severity of symptoms
or progression from acute to chronic disease are poorly understood. Mouse models of CHIKV pathogenesis have
highlighted a critical role of type I interferon (IFN) signaling in limiting viral dissemination and preventing fatal
CHIKV infection. Recently, several studies have implicated the gut microbiota in priming systemic IFN responses
or modulating viral pathogenesis at sites distant from the gastrointestinal tract. Despite the growing evidence
that the gut microbiota shapes antiviral responses at extra-intestinal sites, its role in influencing host immunity to
alphavirus infections has not been explored.
 The proposed project builds upon extensive preliminary data suggesting that the gut microbiota
modulates systemic innate antiviral responses to limit CHIKV dissemination. Subcutaneous CHIKV infection of
either oral antibiotic (Abx)-treated or germ-free (GF) mice results in increased viral burden in the blood and in
tissues distant from the inoculation site. This enhanced viral dissemination is due to increased viral replication
in monocytes of the blood or spleen. Furthermore, upon CHIKV infection, microbiota-depleted mice demonstrate
a blunted systemic type I IFN response that normally is promoted by circulating plasmacytoid dendritic cells
(pDCs). Re-colonization of either Abx-treated or GF mice with fecal microbiota transfers derived from untreated
Abx-naïve controls restores type I IFN responses and decreases viral burden in the blood. Notably, the
introduction of a single bacterial species (e.g., Clostridium) or its derived metabolite, the secondary bile acid
(BA), deoxycholic acid, into Abx-treated or GF mice also can restrict viral dissemination in the blood.
 I hypothesize that specific BA-transforming bacterial species instruct type I IFN responses in pDCs. In
the absence of these microbial factors, pDCs cannot respond rapidly enough to produce IFNs and restrict
monocytes in circulation from CHIKV infection, leading to enhanced viral dissemination. Aim 1 of this proposal
focuses on characterizing immune pathways by which the gut microbiota instructs pDC function in response to
CHIKV infection. Aim 2 focuses on identifying the molecular components, specifically BAs, generated by
specific Clostridium species that restrict CHIKV infection of monocytes and dissemination. Together, these
results will enhance our understanding of how the gut microbiota shapes the innate immune response to limit
infection and pathogenesis of alphaviruses, and potentially other viruses with a tropism for monocyte...

## Key facts

- **NIH application ID:** 10328491
- **Project number:** 5F30AI152327-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Emma Suening Winkler
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328491

## Citation

> US National Institutes of Health, RePORTER application 10328491, Regulation of Antiviral Responses in Plasmacytoid Dendritic Cells to Chikungunya Virus by the Gut Microbiota (5F30AI152327-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328491. Licensed CC0.

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