INVESTIGATION OF THE HELICOBACTER PYLORI CAG TYPE IV SECRETION SYSTEM IN VITRO AND IN VIVO

Abstract

Helicobacter pylori colonizes the stomach in about half of the world’s population. Gastric colonization with H. pylori strains containing the cag pathogenicity island (cag PAI) is a risk factor for gastric adenocarcinoma and peptic ulcer disease. The cag PAI encodes a type IV secretion system (T4SS) that mediates delivery of effector molecules into gastric epithelial cells. The Cag T4SS spans the bacterial cell envelope and is composed of at least 15 components, including three ATPases - Cagα, Cagβ, and CagE. In this dissertation, I show that these ATPases have non-redundant functional properties, based on co-culture experiments with H. pylori mutant strains and gastric epithelial cells. Experiments using a Mongolian gerbil model of H. pylori-induced gastric carcinogenesis show that Cag T4SS activity contributes to the development of gastric cancer and help to define the stages of H. pylori infection when Cag T4SS activity contributes to cancer pathogenesis. Finally, by using imaging mass spectrometry methods, I show that H. pylori infection of the Mongolian gerbil stomach can lead to alterations in gastric lipid composition, a finding that lays the foundation for identifying biomarkers of gastric atrophy and premalignant changes.