Gastric epithelial cell death caused by Helicobacter suis and Helicobacter pylori γ-glutamyl transpeptidase is mainly glutathione degradation-dependent

Abstract

SummaryHelicobacter (H.) suis is the most prevalent non-H. pylori Helicobacter species colonizing the stomach of humans suffering from gastric disease. In the present study, we aimed to unravel the mechanism used by H. suis to induce gastric epithelial cell damage. H. suis lysate induced mainly apoptotic death of human gastric epithelial cells. Inhibition of g-glutamyl transpeptidase (GGT) activity present in H. suis lysate and incubation of AGS cells with purified native and recombinant H. suis GGT showed that this enzyme was partly responsible for the observed apoptosis. Supplementation of H. suis or H. pylori GGT-treated cells with glutathione strongly enhanced the harmful effect of both enzymes and resulted in the induction of oncosis/necrosis, demonstrating that H. suis and H. pylori GGT-mediated degradation of glutathione and the resulting formation of glutathione degradation products play a direct and active role in the induction of gastric epithelial cell death. This was preceded by an increase of extracellular H 2O2 concentrations, generated in a cell-independent manner and causing lipid peroxidation. In conclusion, H. suis and H. pylori GGTmediated generation of pro-oxidant glutathione degradation products brings on cell damage and causes apoptosis or necrosis, dependent on the amount of extracellular glutathione available as a GGT substrate.

Helicobacter heilmannii sensu lato: An overview of the infection in humans

“…Colonization with H. suis induced parietal cell necrosis in the 3 animal strains, epithelial cell hyperproliferation, and inflammation. In vitro data confirmed that H. suis causes apoptosis and necrosis of gastric epithelial cells, and indicated that the γ-glutamyl transpeptidase (GGT) virulence factor is involved in epithelial cell death [100] . H. suis GGT was also shown to inhibit T lymphocyte proliferation, and bacterial outer membrane vesicles were identified as a putative delivery route of GGT to the lymphocytes residing in the deeper mucosal layers [101] .…”

Structure ofBacillus subtilisγ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

“…1a; Stole et al, 1994;Flahou et al, 2011) as an electrophilic glutamate analogue. We previously reported the first X-ray crystal structure of GGT in complex with acivicin (Wada et al, 2008).…”

In the Aftermath of <b><i>Helicobacter pylori</i></b>: Other Helicobacters Rising Up to Become the Next Gastric Epidemic?

“…Although more studies of human subjects infected with gastric NHPH should be undertaken in order to gain more knowledge of the pathogenesis in humans, studies in animal models have been conducted. Upon gastric H. suis infection in mice parietal cell necrosis, epithelial hyperproliferation and inflammation in the stomach were observed [50,52] . The induction of cell death by H. suis on gastric epithelial cells was also confirmed in an in vitro study where it was also shown that GGT may be an important virulence factor for these observations [50] .…”

“…Upon gastric H. suis infection in mice parietal cell necrosis, epithelial hyperproliferation and inflammation in the stomach were observed [50,52] . The induction of cell death by H. suis on gastric epithelial cells was also confirmed in an in vitro study where it was also shown that GGT may be an important virulence factor for these observations [50] . The immune response upon H. suis infection in mice has also been studied.…”

“…It has also been reported that close proximity of bacterial cells to surface mucous cells led to damages in the cell membrane and the microvilli [6] . An in vitro study using human gastric cancer cells showed that H. suis -insult induced apoptosis in these cells, and that GGT activity was partially to account for [50] . Current treatment strategy for curing gastric NHPH in humans includes a triple therapy agent approach similar to that of H. pylori .…”