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The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis.
Metadata
Journalcell38.637Date
2020 Jul 08
a month ago
Publication Type
Journal Article
Volume
2020-Jul-08 / :
Author
Winkler ES 1, Shrihari S 2, Hykes BL 3, Handley SA 3, Andhey PS 4, Huang YS 5, Swain A 4, Droit L 3, Chebrolu KK 6, Mack M 7, Vanlandingham DL 5, Thackray LB 2, Cella M 4, Colonna M 4, Artyomov MN 4, Stappenbeck TS 8, Diamond MS 9
Affiliation
  • 2. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5. Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Biosecurity Research Institute, Kansas State University, Manhattan, KS 66506, USA.
  • 6. Proteomics and Mass Spectrometry Facility, Donald Danforth Plant Science Center, St. Louis, MO 63132, USA.
  • 7. Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
  • 8. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 9. Department 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; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected]
Doi
PMIDMESH
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.
Keywords: Clostridium alphavirus bile acid chikungunya interferon microbiome monocyte pathogenesis plasmacytoid dendritic cell
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