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Published on: March 2, 2014
The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling
Emma S Winkler1, Swathi Shrihari2, Barry L Hykes3
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
Insights
The gut microbiome influences Chikungunya virus (CHIKV) infection severity. Restoring specific gut bacteria or their metabolites enhances antiviral immunity, reducing CHIKV spread and transmission.
Area of Science:
- Virology
- Immunology
- Microbiome Research
Background:
- Chikungunya virus (CHIKV) is an emerging alphavirus causing widespread infections.
- Factors influencing CHIKV disease severity are not fully understood.
- The role of the gut microbiome in CHIKV pathogenesis is largely unexplored.
Purpose of the Study:
- To investigate the impact of the intestinal microbiome on CHIKV infection and disease outcome.
- To elucidate the mechanisms by which the microbiome modulates antiviral immunity against CHIKV.
Main Methods:
- Experiments were conducted in germ-free mice and antibiotic-treated mice with depleted gut microbiomes.
- Chikungunya virus (CHIKV) infection and spread were monitored.
- Toll-like receptor 7 (TLR7)-MyD88 signaling, type I interferon (IFN) production, and IFN-stimulated gene expression in monocytes were analyzed.
- Microbiome reconstitution was performed using Clostridium scindens or deoxycholic acid.
Main Results:
- Depletion of the gut microbiome led to increased CHIKV infection and spread within 24 hours.
- Altered microbiomes impaired TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs), reducing type I IFN production.
- Circulating monocytes became permissive to CHIKV infection due to reduced IFN-stimulated gene expression.
- Reconstitution with Clostridium scindens or deoxycholic acid restored pDC- and MyD88-dependent type I IFN responses, restricting CHIKV infection and transmission.
Conclusions:
- Symbiotic intestinal bacteria play a crucial role in modulating antiviral immunity against CHIKV.
- A bile acid-pDC-IFN signaling axis, influenced by gut bacteria, controls viremia, dissemination, and transmission of CHIKV.
- Targeting the gut microbiome or its metabolites represents a potential strategy for managing CHIKV infections.
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