Oxidative Stress and Survival of Helicobacter pylori

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DESCRIPTION (provided by the applicant): Helicobacter pylori is a spiral bacterium that colonizes the gastric mucosa of humans, leading to a variety of inflammatory gastric diseases that include peptic ulcers, chronic gastritis, adenocarcinoma of the lower stomach, and MALToma (mucosal-associated lymphoma). The severity of the inflammatory-based disease is related to the persistent nature of the pathogen, and chronic infection is the predominant pre-disposing factor for carcinoma. The persistence is attributed to the pathogens' stringent adaptation to the harsh environment of the human stomach, which must include avoiding acidity and combating host defense mechanisms. The battery of host-produced partially reduced oxygen species and other reactive molecules that damage the bacterial cellular components needed for survival of the pathogen are in turn counteracted by enzymes produced by the successful pathogen. The goal is to identify and characterize the antioxidant enzymes produced by H pylori to combat oxidative stress and maintain virulence (stomach colonization). This will be approached by targeted mutagenesis of five specific antioxidant genes. Then each mutant will be characterized for its ability to withstand oxidative stresses, to acquire spontaneous mutations, to survive air-exposure, and to colonize mouse stomachs. The environmental host-related signals (such as iron, oxygen, mucin, pH, and oxidizing agent) that may regulate each of the five genes will be determined, and some of the antioxidant activities will be characterized. In addition to the five targeted antioxidant activities, global approaches involving proteomics and DNA microarray will be used to determine the number and nature of proteins that are expressed upon adaptation of H pylori to oxidative stress conditions.