The intestinal microbiome and Cetobacterium somerae inhibit viral infection through TLR2-type I IFN signaling axis in zebrafish

Accumulated evidences demonstrate that intestinal microbiome can inhibit viral infection. However, our knowledge of the signaling pathways and specific commensal microbes that mediate the antiviral response is limited. Here, a rhabdoviral infection model in zebrafish allows us to investigate the modes of action of microbiome-mediated antiviral effect. We observed that antibiotics-treated and germ-free zebrafish exhibited greater viral infection. Mechanistically, depletion of the intestinal microbiome alters TLR2-Myd88 signaling, and blunts neutrophil response and type I interferon (IFN) production. Moreover, a single commensal bacterium, Cetobacterium somerae, recapitulated TLR2- and type I IFN-dependent antiviral effect of the microbiome in gnotobiotic zebrafish, and C. somerae exopolysaccharides (CsEPS) was the effector molecule that engaged TLR2 to mediate antiviral function. Together, our results suggest a conserved role of intestinal microbiome in regulating type I IFN response among vertebrates, and reveal that the intestinal microbiome inhibits viral infection through a CsEPS-TLR2-type I IFN signaling axis in zebrafish.