Helicobacter pylori is the strongest identified risk factor for gastric cancer and contact between this chronic pathogen and epithelial cells dysregulates signaling pathways that influence oncogenesis. Thus, our long- term objective is to define molecular pathways induced by pathogenic H. pylori that lead to epithelial responses with carcinogenic potential. One H. pylori oncogenic determinant is the cag type IV secretion system (TFSS) which translocates pro-inflammatory effectors, such as CagA and peptidoglycan, into epithelial cells. In addition to inducing inflammation, however, activation of certain host receptors can also suppress pro- inflammatory responses, conferring tolerance to chronic mucosal pathogens. In support of this, we have shown that pre-activation of Nod1 suppresses subsequent H. pylori-induced pro-inflammatory signaling via activation of a negative feedback loop. Similar to Nod1, activation of TLR9 by unmethylated CpG DNA can lead to either pro- or anti-inflammatory signaling. In exciting new studies, we have demonstrated for the first time that H. pylori activates TLR9 via cag-dependent DNA translocation. These results directly informed provocative new studies utilizing a genetic deficiency model which demonstrated that TLR9 suppresses the inflammatory response to H. pylori, indicating that the cag TFSS functions as a rheostat to precisely control levels of inflammation that develop in response to this organism. We have now enhanced the translational component of our work by examining H. pylori isolates harvested from a unique human population in Colombia in which individuals reside in either a high- or low-risk region of gastric cancer. These data indicate that high- risk H. pylori strains activate TLR9 more robustly than low-risk strains, which has focused our current studies on defining the role of TLR9 as a mediator of long-term persistence and disease. Our hypothesis is that selective activation of TLR9-dependent pathways contributes to the augmentation in carcinogenic risk conferred by H. pylori cag+ strains by promoting persistence and activating epithelial responses with carcinogenic potential. We will test this hypothesis via the following Aims: 1. Define microbial mechanisms that regulate DNA translocation and TLR9 activation in response to H. pylori. 2. Utilize novel replenishable models to define the role of TLR9 in regulating host inflammatory and injury responses to H. pylori. 3. Define the effects of TLR9 deficiency and activation on gastric carcinogenesis using rodent models of H. pylori-induced inflammation and injury.
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