METX Ph.D. Will Sause identifies new mechanism for Helicobacter pylori to down regulate the host inflammatory response

March 13, 2017

Will Sause

The human pathogen Helicobacter pylori persists in the inhospitable environment of the human stomach for decades without being eradicated. One question is how the bacterium is able to survive for so long without inducing an immune response that is so severe that the pathogen is removed from the host. One interesting H. pylori protein involved in host immune down regulation is the outermembrane protein ImaA. METX Ph.D. student William Sause worked with other members of the Ottemann Lab to determine the mechanism by which ImaA regulates the severity of the immune response evoked by the bacterium during an infection.

Will’s earlier work had established that ImaA down regulates the strength of inflammation induced by the bacterium during infection. However, the mechanism of how this protein reduced the severity of the immune response was unknown. In this work, the aim was to elucidate the process by which ImaA controls inflammation in the context of an infection. 

A main challenge of the study was how to understand the function of ImaA without being able to purify the protein to perform in vitro biochemical analyses. This problem was due to the very large size of ImaA, and its substantial hydrophobic transmembrane domain. 

Will and undergraduate student Soufiane Aboulhouda overcame this challenge by developing a number of H. pylori null mutants and combining them with a novel flow cytometry based method we developed for observing binding to the host receptor, α5β1 integrin. Postdoc Daniela Keiberg worked with Will to use the imaA mutants and the binding assay to single out the activity of ImaA.

This study demonstrated that ImaA works to temper the activity of H. pylori’s main inflammation causing machinery, the cagPAI secretion system. The data suggests ImaA acts by reducing the bacterium’s opportunities to interact with the cognate receptor for the cagPAI secretion machinery, thus preventing H. pylori from over engaging the host and causing too severe of an immune response.

After completing this work, we now know that H. pylori has inherent checks and balances to control the action of its own inflammation causing proteins. Sause and colleagues believe this action is done to promote prolonged persistence in the host and to avoid being in an overly inflamed environment.