Commensal Microbiota Modulation of Natural Resistance to Virus Infection

Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-beta by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-beta was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-beta. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-beta expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-beta. In a murine VSV infection model, commensal-induced IFN-beta regulated natural resistance to virus infection. Due to the physiological importance of IFN-beta, discovery of an IFN-beta-inducing microbial molecule represents a potential approach for the treatment of some human diseases.