This study examined whether pattern recognition receptors beyond Toll-like receptors (TLRs) are broadly activated during bacterial infection, focusing on the role of STING (stimulator of interferon genes) in sensing bacterial cyclic dinucleotides (CDNs) — including both purine- and pyrimidine-based forms — released after bacteriolysis in phagolysosomes of macrophages.
STING was required for TLR-independent interferon responses across evolutionarily diverse bacteria; bacterial CDNs escaped phagolysosomes via two CDN transporters to activate STING. Bacterial CDNs were elevated in colonic biopsies from IBD patients, and systemic delivery of CDN-laden dead bacteria promoted anti-tumor immunity in mice. Pyrimidine-based CDNs, a newly recognized ligand class, activated STING through a distinct binding mode from purine-based CDNs.
Mechanistic transport and structural binding data are largely from murine and in vitro models; clinical relevance in IBD is correlative (biopsy data only, no functional patient immune data). Anti-tumor immunity findings are mouse-only and require validation in human systems.
STING-activating bacterial CDNs appear to be a common output of phagocytosis across many bacterial species, suggesting STING pathway status may influence tissue immune tone in infections and IBD. Dead, CDN-rich bacteria as systemic immune adjuvants for cancer is a potential therapeutic avenue warranting further clinical investigation.
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