Helicobacter pylori infects approximately 50% of the human population, causing severe gastric diseases including gastritis, peptic ulcers, and gastric cancer. H. pylori exerts an enormous amount of cellular energy on nitrogen metabolism including the urease enzyme. Therefore, the critical role of urease in virulence has been a major research focus. However, H. pylori has a substantial number of other nitrogen metabolizing proteins, whose role in virulence and maintaining nitrogen balance are poorly understood. Here, the focus is arginase, an enzyme metabolically upstream of urease that converts arginine to urea and ornithine. Polyamines (produced from ornithine) and arginase are elevated in the gastric mucosa of gastric cancer patients. Preliminary data demonstrate arginase is critical for H. pylori survival from acid and nitric oxide (NO), two innate host defenses. Furthermore, gerbils infected with wild type H. pylori develop gastritis and ulcers, whereas no pathologies are observed in gerbils infected with the isogenic arginase mutant. The central hypothesis of this proposal is that H. pylori arginase inhibits host NO, elevates polyamines, and contributes to gastritis, ulcers and cancer. To test this hypothesis, there are two specific aims: 1) Determine roles of H. pylori arginase in virulence in tissue culture models and 2) Determine the roles of H. pylori arginase in virulence using gerbils.
In aim 1, levels of arginase needed to inhibit macrophage NO and elevate polyamines will be assessed. Arginase-dependent cytokine profiles will be identified.
In aim 2 the role of arginase in virulence in the gerbil model will be assessed by determining whether arginase contributes to gastric cancer or ulcer development, induces an immune response, affects host NO, arginase or polyamine levels, and protects gerbils from H. pylori challenge. The proposed experiments will significantly enhance our understanding of the roles of H. pylori arginase in protection from innate defenses as well as roles in ulcer and cancer development and optimization of nitrogen levels in vivo.
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