Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production

Abstract

SUMMARY Induction of type I interferon in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis.

Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

“…In the present study, we confirmed that Ply treatment can damage mitochondrial membrane to induce mtDNA release, and then promote the expression of type I IFN, which agreed with a recent report indicating that exposure to Ply leads to mitochondrial damage in epithelial cells, as well as the release of mtDNA, and contributes to IL‐1β expression . In addition to mtDNA, the c‐di‐AMP of Group B Streptococcus and Chlamydia trachomatis can also activate STING signaling pathway and then mediated the expression of IFN‐β . S. pn has been reported to secrete c‐di‐AMP ; however, whether the c‐di‐AMP of S. pn is related to the IFN‐β expression has not been reported.…”

The Emerging Roles of STING in Bacterial Infections

“…The immune response is mostly dependent on the TLR pathway upon macrophage exposure to heat-killed Group B Streptococcus whereas live bacteria elicit a cGAS-STING dependent pathway [73–74]. Interestingly, Andrade et al showed that S. agalactiae can degrade c-di-AMP present outside the bacteria via a cell-wall anchored ectonucleotidase.…”

“…Strikingly, this ectonucleotidase has no action on mammalian cGAMP. This mechanism of self-degrading extracellular CDN avoids over activation of STING and promotes bacterial virulence [74]. Identification of related strategies by other pathogens would be of great interest.…”

DNA sensor cGAS-mediated immune recognition

“…Moreover, vIRF1 from Kaposi’s sarcoma-associated Herpesvirus (KSHV) also binds to STING, preventing the interaction between STING and TBK1 (Ma et al, 2015). CdnP, an ectonucleotidase encoded by group B streptococcus, degrades c-di-AMP secreted by bacteria, alleviating host immune responses (Andrade et al, 2016). Above findings suggest that microbes utilize a universal way to suppress cGAS activity through blocking STING activity either directly or indirectly.…”