Resident Viruses in the Gut Control Inflammation Through TLR3/7-Mediated cAMP Activation

Metagenomic analysis has shown that resident viruses inhabit in the healthy gut; however, little is known about how resident viruses are involved in the maintenance of gut homeostasis. Here we have tried to clarify how resident viruses control gut homeostasis in mice with DSS-induced experimental colitis and patients with colitis. We analyzed inflammation in TLR3/7 double knockout mice and wild-type mice after treatment with agonists for TLR3 and TLR7 or inactivated rotavirus. We investigated the associations of human Tlr3 and Tlr7 variants and susceptibility to the colitis using direct sequencing and subsequent genotying of the two gene variants. Mice deficient in both TLR3 and TLR7, which lack the ability to recognize viral single- and double-stranded RNAs, were more susceptible to DSS-induced experimental colitis. Conversely, when WT mice were reconstituted with TLR3/7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Furthermore, cAMP was accumulated after ligation of resident viruses to TLR3/7 and this accumulated cAMP regulated DSS-induced colitis by inhibiting NF-kB activation. Importantly, combined TLR3/7 genetic variations significantly influenced the severity of ulcerative colitis in humans. These results imply that the recognition of resident viruses by TLR3/7 might be required for gut protection and homeostasis.