| dc.description.abstract | Chronic mucosal pathogens have evolved multiple strategies to manipulate the host immune response; consequently, microbes contribute to the development of >2 million cases of cancer/year. Gastric adenocarcinoma is the fourth leading cause of cancer-related death and Helicobacter pylori confers the highest risk for this disease. Gastric innate immune effectors can either eliminate bacteria or mobilize adaptive immune responses including Toll-like receptors (TLRs), and cytosolic DNA sensor/adaptor proteins (e.g., stimulator of interferon genes, STING). The H. pylori strain-specific cag pathogenicity island (PAI) encodes a type IV secretion system (T4SS) which augments gastric cancer risk and translocates DNA into epithelial cells which activates the microbial DNA sensor TLR9 and suppresses injury in vivo. However, most cag-PAI+ infected persons do not develop cancer and cag T4SS-independent bacterial constituents, as well as additional nucleic acid pattern recognition receptors (PRR) remain understudied. First, the capacity of bacterial constituents to promote gastric injury was explored, specifically the virulence associated adhesin HopQ. Interrogation of a large cohort of H. pylori strains derived from human clinical specimens demonstrated that genetically distinct families of hopQ alleles were significantly associated with magnitude of gastric injury, cag T4SS function, and TLR9 activation. Additionally, the role of HopQ in TLR9 activation was further defined by genetic deletion of hopQ, which significantly decreased H. pylori-induced TLR9 activation in vitro, implicating this adhesin in H. pylori-mediated disease. Second, utilizing in vitro and ex vivo experiments, a novel mechanism was identified through which H. pylori actively suppress additional nucleic acid PRR-signaling, STING and RIG-I, via downregulation of IRF3. Further, a Sting-deficient mouse infection model revealed that pro-carcinogenic Th17 inflammatory responses to H. pylori are augmented within the context of Sting-deficiency in conjunction with induction of a known host immune regulator, TRIM30a. Additionally, of direct clinical relevance, significant upregulation of TRIM30a orthologs was uncovered in human gastric cancer samples harboring inflammation or cancer. These novel mechanisms of innate immune activation and suppression by H. pylori are likely a component of a finely tuned rheostat that H. pylori regulates to control the inflammatory response and maintain persistence in the host, and ultimately drive long-term carcinogenic pathways. | |
