The function of the essential Helicobacter pylori virulence factor gamma-glutamyltranspeptidase for gastric colonization and immune response in vivo

幽门螺杆菌（Helicobacter pylori，H.幽门螺杆菌）是一种非常常见的疾病，因为它影响了世界人口的一半。这种持续性感染会导致胃炎症和更严重的胃病理，在某些情况下甚至最终导致胃癌。几个毒力因素决定了临床结果。其中，H。幽门螺杆菌γ-谷氨酰转移酶（HpgGT）已成为一种重要的毒力因子，其活性与感染个体的胃病严重程度相关。这种周质酶催化γ-谷氨酰化合物（如谷氨酰胺和谷胱甘肽）的水解。HpgGT对细菌、分离的宿主细胞和细胞系的作用已经揭示了几种可能的作用模式，例如支持细菌代谢和耐酸性、诱导氧化应激、谷氨酰胺剥夺和产生有毒氨。然而，这种酶在体内感染的不同阶段的具体功能以及它如何影响定植和胃炎症仍不清楚。因此，我们建议使用H. pylori PMSS 1野生型及其同基因gGT缺陷型菌株在小鼠感染模型中的表达。我们的初步数据表明HpgGT在支持细菌代谢和影响持续定植期间的胃免疫反应中的双重作用;然而，需要进一步分析以澄清潜在的分子和细胞机制。总之，本研究不仅有助于理解H。幽门螺杆菌感染和胃病理学，但也可能为开发新的治疗方法奠定基础。

Infection with Helicobacter pylori (H. pylori) is an extremely common condition, as it affects half of the world population. This persistent infection causes gastric inflammation and more severe gastric pathology that in some cases even culminates in gastric cancer. Several virulence factors determine the clinical outcome. Of those, H. pylori gamma-glutamyltransferase (HpgGT) has emerged as an essential virulence factor whose activity is associated with severity of gastric disease in infected individuals. This periplasmic enzyme catalyzes hydrolysis of gamma-glutamyl compounds, such as glutamine and glutathione. Effects of HpgGT on bacteria, isolated host cells and cell lines have revealed several possible modes of action, such as support of bacterial metabolism and acid resistance, induction of oxidative stress, glutamine deprivation and production of toxic ammonia. However, the specific function of this enzyme at different stages of infection in vivo as well as how it influences colonization and gastric inflammation remain unclear. Therefore, we propose to elucidate gGT-dependent effects using H. pylori PMSS1 wild type and its isogenic gGT-deficient strain in a mouse model of infection. Our preliminary data indicate a dual role of HpgGT in supporting bacterial metabolism and in affecting the gastric immune response during persistent colonization; however, further analyses are necessary to clarify the underlying molecular and cellular mechanisms. Taken together, this study will not only contribute to the understanding of H. pylori infection and of the gastric pathology, but might also prepare the ground for the development of novel therapeutic approaches.