Helicobacter pylori VacA toxin: regulation & strain-specific differences in activity

Abstract

Helicobacter pylori is a Gram-negative bacterium that colonizes the gastric mucosa and has the potential to cause peptic ulcer disease and gastric cancer. The risk of developing gastric cancer is determined by multiple factors, including H. pylori strain characteristics and host genetic characteristics. Several types of environmental exposure, including consumption of a high salt diet, also increase gastric cancer risk. H. pylori secretes a pore-forming toxin known as vacuolating cytotoxin A (VacA), which can cause a wide range of alterations in gastric epithelial cells, T-cells and several other cell types. There is a high level of sequence diversity among vacA alleles, which influences both toxin activity and the risk of gastric disease. In this thesis, I report the results of experiments analyzing the effects of a high salt environment on composition of the H. pylori exoproteome and show that high salt conditions promote increased secretion of VacA. In addition, I report the results of experiments examining how sequence diversity in a segment of VacA known as the m-region impacts VacA binding to gastric epithelial cells, localization within cells, and VacA-induced cellular alterations. Collectively, these studies provide further insight into the regulation of VacA and strain-specific variations in VacA activity.