A commensal Clostridium bacteria restricts alphavirus dissemination through a bile acid-type I IFN signaling axis

The emerging alphavirus chikungunya virus (CHIKV) has infected millions of people. However, the factors modulating disease outcome remain poorly understood. We show that depletion of the gut microbiota in oral antibiotic-treated or germ-free mice leads to greater CHIKV infection and spread within one day of virus inoculation. Perturbation of the gut microbiota 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 commensal bacterial species, Clostridium scindens, or its derived metabolite, the 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, commensal gut bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects virus dissemination and potentially, epidemic spread 3 biological replicates were processed per time point and group RNA was isolated from sorted splenic plasmacytoid dendritic cells using the MagMAX™ mirVana™ Total RNA Isolation Kit as per manufacturer’s instructions. For RNA analysis, 100 ng total RNA was hybridized to a nCounter® Mouse Immunology Panel (XT-CSO-MIM1-12) according to the manufacturer’s protocol (NanoString Technologies Inc.).