The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis

The microbiota are vital for immune homeostasis and provide a competitive barrier to bacterial and fungal pathogens. Here, we investigated how gut commensals modulate systemic immunity and response to viral infection. Antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming. The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions. Instead, membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells. DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner. In summary, this study establishes an important role for the microbiota in peripheral cGAS-STING activation, which promotes host resistance to systemic viral infections. Moreover, it uncovers an underappreciated risk of antibiotic use during viral infections. [Display omitted] •Suppression of gut microbiota renders mice susceptible to systemic viral infections•The gut microbiota drive systemic antiviral immunity via IFN-I priming•Microbiota-driven IFN-I priming involves the cGAS-STING axis•Microbiota mediate systemic IFN-I priming via DNA-containing membrane vesicles The microbiota influence systemic immunity in ways that are not fully understood. Erttmann et al. show that the release of the membrane vesicles from the gut microbiota leads to the systemic delivery of bacterial DNA to host cells. This triggers the tonic activation of the cytosolic cGAS-STING-IFN-I axis, protecting distal organs against viral infection.