The gastric carcinogen Helicobacter pylori induces superficial gastritis and transient hypochlorhydria which may progress to atrophic gastritis and eventually gastric adenocarcinoma. Acute hypochlorhydria is critical for initial establishment of infection, but its mechanistic basis and its role in facilitating H. pylori-induced pre-malignancy is poorly understood. The H. pylori cytotoxin-associated gene (cag) pathogenicity island (PAI) is a genetic locus encoding the type IV secretory system (TFSS), and its presence favors H. pylori colonization of the acid-secreting gastric corpus, leading to development of the pre-cancer phenotype. The Hypothesis is that H. pylori acutely suppresses gastric proton pump (H,K-ATPase) 1 subunit (HK1) gene expression by interactions of cag PAI virulence factors CagL, CagA and peptidoglycan with parietal cells via the TFSS, perturbing signaling pathways essential to acid secretion. Studies in the last award suggested that certain H. pylori cag PAI genes repress HK1 promoter constructs transfected into gastric cells by promoting NF-:B p50 homodimer binding to an HK1 cis-response element. These and other studies lay the foundation for testing the hypothesis and related sub-hypotheses in three Specific Aims: (1) Investigate the role of CagL, a structural protein of the H. pylori pilus, in perturbing gastric epithelial cell signal transduction, culminating in suppression of HK1 gene transcription. We hypothesize that CagL dissociates host cell proteinase ADAM17 from 15ss1 integrin, activating the proteinase, and causing release of EGF and/or TNF1 receptor ligands that induce aberrant protein tyrosine kinase-mediated signaling to NF-:B. (2) Define the mechanisms by which the secreted H. pylori factors CagA and peptidoglycan perturb gastric epithelial cell regulation of HK1 transcription. We hypothesize that the H. pylori oncoprotein CagA and the peptidoglycan GM-tripeptide target signal transduction pathways that converge to repress HK1 transcription. (3) Investigate the effects of acute H. pylori infection on human gastric mucosal acid secretion. We hypothesize that H. pylori-induced signaling perturbations in gastric parietal cells are reflected in marked acid secretory inhibition in human gastric mucosa. Significance. Involvement of the pro-carcinogenic cag PAI in acid secretory inhibition confers high clinical relevance to mechanisms of H. pylori-induced hypochlorhydria. This study will define these mechanisms and provide insights into early stages of H. pylori pathophysiology.
H. pylori is a gastric carcinogen that facilitates gastric colonization by inhibiting gastric acid secretion. This proposal addresses the molecular basis of acid inhibition by H. pylori. Clarification of the inhibitory mechanism is a high priority because the virulence factors involved in acid secretory inhibition also cause development of the pre-cancer phenotype.
The specific aims will identify causative H. pylori gene products and define how they inhibit gastric proton pump gene transcription resulting in hypochlorhydria. Improved mechanistic understanding of H. pylori pathophysiology will inform later studies in translational models and in humans.
|Hammond, Charles E; Beeson, Craig; Suarez, Giovanni et al. (2015) Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion. Am J Physiol Gastrointest Liver Physiol 309:G193-201|
|Zhang, Yong-Mei; Noto, Jennifer M; Hammond, Charles E et al. (2014) Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase ?-subunit gene expression by miRNA. Am J Physiol Gastrointest Liver Physiol 306:G606-13|
|Mueller, Doreen; Tegtmeyer, Nicole; Brandt, Sabine et al. (2012) c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122:1553-66|
|Kumar Pachathundikandi, Suneesh; Brandt, Sabine; Madassery, Joseph et al. (2011) Induction of TLR-2 and TLR-5 expression by Helicobacter pylori switches cagPAI-dependent signalling leading to the secretion of IL-8 and TNF-?. PLoS One 6:e19614|
|Tegtmeyer, Nicole; Wessler, Silja; Backert, Steffen (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278:1190-202|
|Tegtmeyer, Nicole; Backert, Steffen (2011) Role of Abl and Src family kinases in actin-cytoskeletal rearrangements induced by the Helicobacter pylori CagA protein. Eur J Cell Biol 90:880-90|
|Saha, Arindam; Backert, Steffen; Hammond, Charles E et al. (2010) Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology 139:239-48|
|Saha, Arindam; Hammond, Charles E; Beeson, Craig et al. (2010) Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa. Gut 59:874-81|