Secretion of c-di-AMP by Listeria monocytogenes Leads to a STING-Dependent Antibacterial Response during Enterocolitis

Abstract

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.

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity

“…During L. monocytogenes infection, STING is activated by bacterial DNA-activated cGAS (73). However, the STINGdependent immune response was suggested to defend against L. monocytogenes by reducing the influx of inflammatory monocytes and systemic bacterial loads during enterocolitis (95). This result indicated that in addition to the IFN-I response, STING activation in enterocolitis could also exert immunomodulatory effects through other mechanisms that need further investigation.…”

“…Recently, the endogenous anaphylatoxins C5a and C3a have been found to suppress the expression of STING and phosphorylated TBK1 and IFN-β during L. monocytogenes infection, consequently attenuating the detrimental effect of IFN-β production, for example, inhibiting L. monocytogenes- mediated-apoptosis of immune cells ( 73 ). However, the STING-dependent immune response was suggested to defend against L. monocytogenes by reducing the influx of inflammatory monocytes and systemic bacterial loads during enterocolitis ( 95 ). This result indicated that in addition to the IFN-I response, STING activation in enterocolitis could also exert immunomodulatory effects through other mechanisms that need further investigation.…”

Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

“…The investigators found that STING activation led to reduced bacterial burden and correlated with the recruitment of monocytes to the intestines during L. monocytogenes -induced enterocolitis. This STING-mediated protective response was triggered by the secretion of L. monocytogenes c-di-AMP, while the disruption of type I IFN signaling during L. monocytogenes -induced enterocolitis did not recapitulate STING deficiency [ 71 ]. Strikingly, IFNAR and IRF3/7 signaling were detrimental for the host protection against Listeria -induced enterocolitis [ 71 ].…”

“…This STING-mediated protective response was triggered by the secretion of L. monocytogenes c-di-AMP, while the disruption of type I IFN signaling during L. monocytogenes -induced enterocolitis did not recapitulate STING deficiency [ 71 ]. Strikingly, IFNAR and IRF3/7 signaling were detrimental for the host protection against Listeria -induced enterocolitis [ 71 ]. These results suggest that STING activation can be crucial for infection resistance in specific tissues, and that in some situations its antibacterial properties are unrelated to type I IFN production.…”

“…The detrimental effect of type I IFN signaling in L. monocytogenes , was initially evidenced by enhanced resistance in IFNAR KO mice inoculated intravenously or intraperitoneally with L. monocytogenes [ 94 , 95 , 96 , 97 ]. Accordingly, disrupted IFN signaling during L. monocytogenes -induced enterocolitis, led to reduced bacterial loads at systemic sites [ 71 ]. The mechanisms described for these effects in L. monocytogenes infection are particularly diverse: resistance in IFNAR KO mice in L. monocytogenes infection was associated with decreased lymphocytes and macrophage apoptosis [ 97 ]; attenuated innate immunity, as a result of enhanced IL-10 secretion upon T cell apoptosis [ 95 , 98 ]; downregulation of IFN-γR (resulting in reduced protective IFN-γ signaling) [ 99 ]; and restriction of neutrophil recruitment [ 100 , 101 ].…”