Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway

Abstract

From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.

TMEM173 Drives Lethal Coagulation in Sepsis

“…Unlike Tmem173 À/À , the deletion of cGAS (cGAS À/À ) failed to protect against CLP-induced septic death (Figure S1A) and systemic coagulation activation (Figures S1B-S1H). These findings suggest that a cGAS-independent TMEM173 pathway (Costa Franco et al, 2018;Holm et al, 2016;Movert et al, 2018;Suschak et al, 2016) could promote systemic coagulation activation in polymicrobial sepsis.…”

Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells’ Type 1 Interferon Response

“…There are studies proposing that other pathways are important for the IFN-1 response, including the cGAS-STING pathway. cGAS-STING is a receptor expressed by skinresident macrophages that leads to IFN-b secretion upon activation through sensing of PAMPs in the cytosol (Bode et al, 2016;Gratz et al, 2011;Movert et al, 2018). Whether cGAS-STINGeinduced IFN-b attracts pDCs to the site of infection or whether pDC recruitment rather depends on other signals such as chemerin or CCL19/CCL21 requires further research (Albanesi et al, 2009;Seth et al, 2011).…”

Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors

“…Mycobacterium tuberculosis secretes the cyclic di‐nucleotide phosphodiesterase CdnP (also known as Rv2837c), which degrades cGAMP and bacterial cyclic dinucleotides, thus inhibiting both DNA‐ and cyclic‐dinucleotide‐induced STING activation . Group A streptococcus, Streptococcus pyogenes , subverts, rather than evades, STING signalling: it uses its M protein to activate STING, resulting in the production of the anti‐inflammatory cytokine interleukin‐10 downstream of type I interferon signalling . In this way, the bacterium exploits the reciprocal antagonism between the interferon response and inflammation, and shapes the immune response to favour the pathogen, rather than the host.…”