Secretion of c-di-AMP by Listeria monocytogenes leads to a STING-dependent antibacterial response during enterocolitis

Stimulator of interferon genes (STING) acts as a cytoplasmic signaling hub of innate immunity that is activated by host or bacterially-derived cyclic dinucleotides. Listeria monocytogenes is a food-borne, facultative intracellular pathogen that secretes c-di-AMP and activates STING, yet the in vivo role of the STING pathway during bacterial pathogenesis remains unclear. Here, we find that STING-deficient mice had increased weight loss and roughly 10-fold increased systemic bacterial burden during L. monocytogenes-induced enterocolitis. Infection with a L. monocytogenes mutant impaired in c-di-AMP secretion failed to elicit a protective response whereas a mutant with increased c-di-AMP secretion triggered enhanced protection. Type I interferon is a major output of STING signaling; however, disrupting IFN signaling during L. monocytogenes-induced enterocolitis did not recapitulate STING-deficiency. In the absence of STING, the intestinal immune response was associated with a reduced influx of inflammatory monocytes. These studies suggest that in barrier sites such as the intestinal tract, where pathogen associated molecular patterns are abundant, cytosolic surveillance systems such as STING are well-positioned to detect pathogenic bacteria.