Phagosome-mediated activation of STING by purine and pyrimidine-based bacterial cyclic dinucleotides

The cytoplasm harbors a spectrum of microbial sensory proteins. Beyond pathogens and their membrane disruptive activities, the contexts and mechanisms whereby bacterial molecules access cytoplasmic sensors are unknown. In this study, we describe the intracellular cyclic dinucleotide (CDN) sensor STING from humans, mice, and other animals as a driver of immune responses to a spectrum of CDNs produced by evolutionarily diverse bacteria, including those containing pyrimidine bases. Diverse bacterial CDNs were present in murine tissues and increased in human inflammatory bowel diseases patients. After bacteriolysis in phagolysosomes, bacterial CDNs could activate STING via two CDN transporters. Systemic delivery of dead, CDN-laden bacteria promoted resistance to subcutaneous and liver-localized tumors in mice. X-ray crystallography of STING-CDN complexes revealed distinct binding modes for purine- and pyrimidine-based CDNs. We propose a connection between phagocytosis, bacterial CDNs, and STING that ensures cytoplasmic innate immune responses are a common outcome of host-bacteria interactions.