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

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.从进化视角来看，病原体可通过调控炎症反应获得生存优势：一方面可促进自身在宿主内的定植建立，另一方面可避免宿主出现危及生命的病症，例如脓毒性休克（septic shock）。与此假说相符，化脓性链球菌（Streptococcus pyogenes）可通过I型干扰素信号通路（type I IFN-signaling）抑制感染小鼠体内的有害炎症反应，但目前诱导该I型干扰素应答的宿主-病原体互作机制仍未明确。本研究采用巨噬细胞感染模型开展实验，结果发现化脓性链球菌以M蛋白依赖的方式诱导抗炎性细胞因子白细胞介素10（IL-10）的产生，该功能被定位至M5蛋白的B、C重复结构域。有趣的是，IL-10的产生依赖于I型干扰素信号通路的下游事件，而I型干扰素的产生则通过M蛋白依赖的STING信号通路（STING signaling pathway）激活得以实现。STING的激活不依赖于胞质双链DNA传感器cGAS（cGAS），且该感染并未诱导线粒体DNA、细胞核DNA或细菌DNA向胞质发生可检测到的释放——这表明在化脓性链球菌感染的巨噬细胞中，STING通路的激活不依赖于DNA。本研究结果为化脓性链球菌诱导I型干扰素应答的机制提供了新的见解，并首次揭示了化脓链球菌M蛋白具有调控巨噬细胞的此前未被认知的功能，该功能或有助于抑制机体针对感染的炎症应答。