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

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.