The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis.

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. • Perturbation of the intestinal microbiome results in enhanced alphavirus infection • An altered microbiome diminishes type I IFN responses in monocytes and pDCs • Recolonization with a single Clostridium symbiont restores antiviral immunity • Secondary bile acids restore pDC and IFN responses to restrict CHIKV dissemination Winkler et al. demonstrate that the intestinal microbiome modulates innate immunity to control alphavirus infection of circulating monocytes. Microbiome perturbation dampens TLR7-MyD88 responses in pDCs, blunting type I IFN production and monocyte ISG expression. A single Clostridium species or its associated secondary bile acid restores antiviral responses to inhibit CHIKV infection. [ABSTRACT FROM AUTHOR]