Helicobacter pylori is the strongest risk factor for gastric cancer and interactions between this chronic pathogen and innate immune cells dysregulate signaling pathways that influence oncogenesis. One H. pylori oncogenic determinant is the cag type IV secretion system (TFSS) which translocates pro-inflammatory effectors, such as CagA, into epithelial cells. In studies supported by R01 DK 58587, we demonstrated for the first time that the cag TFSS can also translocate microbial DNA, which activates TLR9. In addition to inducing inflammation, however, activation of certain host pattern-recognition receptors can suppress inflammatory responses, conferring tolerance to chronic pathogens. In the last funding period, we used a genetic deficiency model to demonstrate that TLR9 suppresses the inflammatory response to H. pylori. These data coalesce with our recent efforts to more broadly define consequences of microbial DNA translocation, and exciting data from our laboratory now demonstrate that H. pylori can suppress activation of the DNA sensor/adaptor STING. Chronic pathogens such as oncogenic DNA viruses utilize multiple mechanisms to abrogate STING signaling and in other models of inflammation-induced disease with pre-malignant potential (e.g., chronic pancreatitis), inhibition of STING worsens disease via promoting Th17 polarization. Pertinent to this model, our provocative new data using mouse, gerbil, and human samples indicate that 1) STING signaling is absent in H. pylori-infected gastric tissue within the context of increased expression of the Th17 cytokine IL- 17A, a key driver in cancer initiation and progression, 2) genetic deficiency of IL-17A significantly reduces the severity of H. pylori-induced inflammation, and 3) H. pylori up-regulates Th17 differentiation and stabilization factors, but not STING targets in gastroid:macrophage co-culture systems. We have also identified a focused subset of H. pylori proteins that harbor homology to viral effectors that inhibit STING signaling. Finally, we have gastric tissue from a unique longitudinal cohort in Colombia from persons who either progressed to irreversible premalignant gastric lesions or remained stable, which will provide critical clinical validation of our mechanistic studies. Our hypothesis is that active suppression of STING signaling contributes to the augmentation in carcinogenic risk conferred by H. pylori by promoting persistence and deploying immune responses (Th17) with carcinogenic potential. We will test this hypothesis via the following Aims: 1. Identify, define, and validate microbial effectors that regulate STING suppression by H. pylori 2. Define mechanisms through which STING suppression promotes H. pylori-induced injury 3. Perform targeted interventions to activate STING within the context of H. pylori infection
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