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The Helicobacter pylori protein ImaA modulates the immune response and promotes chronic infection


The primary agent responsible for both gastric ulcers and cancers is the human pathogen Helicobacter pylori. The aim of this dissertation is to enhance our understanding of how this bacterium can cause disease in humans and persist in the host over many years. We have identified a novel H. pylori virulence factor, called ImaA, which dampens H. pylori caused inflammation and promotes long-term colonization in the host. ImaA is an outer membrane protein that H. pylori expresses at exceptionally high levels in the stomach and is critical for the bacterium's ability to survive.

The first part of this dissertation expands on the discovery that imaA is expressed at higher levels in the mouse stomach, when compared to laboratory conditions. We went on to demonstrate that an imaA isogenic mutant exhibits a colonization defect in the mouse and is greatly outcompeted for colonization in a co-infection with wild-type H. pylori. We furthermore performed localization assays using an ImaA-targeted antibody to verify that the ImaA protein resides in the outer membrane. We identified low pH to be the signal for imaA's upregulation in the stomach and demonstrated that this upregulation is dependent on the ArsRS two-component regulatory system. Concluding the first part of this dissertation, we revealed that the imaA mutant evokes a stronger immune response in gastric epithelial cells, compared to that of wild-type H. pylori.

The second part of this dissertation focuses on ImaA's interactions with the host. The primary mechanism for H. pylori caused inflammation is through the secretion of the effector molecule, CagA, into host cells. We show here that in an imaA mutant infection, there are more CagA molecules delivered into gastric epithelial cells, than in a wild-type infection. We went on to show that the imaA mutant induces elevated levels of inflammation, independently of CagA, as an imaA cagA double mutant causes more inflammation than a cagA single mutant. This result directed us to the cagPAI T4SS, the surface-exposed unit that delivers CagA into the host cell. Through flow cytometry experiments, we showed that imaA mutants bind higher levels of the host receptor for the cagPAI T4SS, @alpha;5β1 integrin. Finally, using the gerbil mode for infection, we discovered that ImaA is dispensable for the very initial stages of host colonization, but that the protein becomes essential very rapidly, as imaA mutants are cleared from the stomach within a week, post-infection.

Taken together, this dissertation characterizes the novel H. pylori virulence factor, ImaA, and demonstrates that this protein is critical for the bacterium's ability to control inflammation and persist in the host stomach.

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