Helicobacter pylori provokes STING immunosurveillance via trans-kingdom conjugation
Recognition of foreign nucleic acids is an evolutionarily conserved mechanism by which the host detects microbial threats. Whereas some intracellular bacterial pathogens trigger DNA surveillance pathways following phagosomal membrane perturbation, mechanisms by which extracellular bacteria activate cytosolic nucleic acid reconnaissance systems remain unresolved. Here, we demonstrate that Helicobacter pylori exploits cag type IV secretion system (cag T4SS) activity to provoke STING signaling in gastric epithelial cells. We provide direct evidence that chromosomal fragments delivered to the host cell cytoplasm via trans-kingdom conjugation bind and activate the key DNA sensor cGMP-AMP synthase. To enable paracrine-like signal amplification, translocated H. pylori DNA is sorted into exosomes that stimulate DNA-sensing pathways in uninfected bystander cells. We show that DNA cargo is loaded into the cag T4SS apparatus in the absence of host cell contact to establish a ready-to-fire nanomachine and provide evidence that cag T4SS-dependent DNA translocation is mechanistically coupled to chromosomal replication and replichore decatenation. Collectively, these studies suggest that H. pylori evolved mechanisms to stimulate nucleic acid surveillance pathways that regulate both pro- and anti-inflammatory programs to facilitate chronic persistence in the gastric niche.