Role of γ-glutamyltranspeptidase in the pathogenesis of Helicobacter suis and Helicobacter pylori infections

Abstract

Helicobacter (H.) suis can colonize the stomach of pigs as well as humans, causing chronic gastritis and other gastric pathological changes including gastric ulceration and mucosa-associated lymphoid tissue (MALT) lymphoma. Recently, a virulence factor of H. suis, γ-glutamyl transpeptidase (GGT), has been demonstrated to play an important role in the induction of human gastric epithelial cell death and modulation of lymphocyte proliferation depending on glutamine and glutathione catabolism. In the present study, the relevance of GGT in the pathogenesis of H. suis infection was studied in mouse and Mongolian gerbil models. In addition, the relative importance of H. suis GGT was compared with that of the H. pylori GGT. A significant and different contribution of the GGT of H. suis and H. pylori was seen in terms of bacterial colonization, inflammation and the evoked immune response. In contrast to H. pyloriΔggt strains, H. suisΔggt strains were capable of colonizing the stomach at levels comparable to WT strains, although they induced significantly less overall gastric inflammation in mice. This was characterized by lower numbers of T and B cells, and a lower level of epithelial cell proliferation. In general, compared to WT strain infection, ggt mutant strains of H. suis triggered lower levels of Th1 and Th17 signature cytokine expression. A pronounced upregulation of B-lymphocyte chemoattractant CXCL13 was observed, both in animals infected with WT and ggt mutant strains of H. suis. Interestingly, H. suis GGT was shown to affect the glutamine metabolism of gastric epithelium through downregulation of the glutamine transporter ASCT2.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-015-0163-6) contains supplementary material, which is available to authorized users.

Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10 −/− Mice

“…(43)(44)(45)(46). Also, in vitro data show that GGT inhibits gastrointestinal and lymphocyte cell proliferation as well as having a role in producing reactive free oxygen species (43)(44)(45)(46). NF-B activation and IL-8 secretion in gastrointestinal cell lines may have also been stimulated by GGT expression.…”

“…Importantly, H. saguini is sufficient by itself to cause IBD in monoassociated IL-10 Ϫ/Ϫ mice, unlike H. hepaticus (41,42), suggesting that the expression of virulence properties of H. saguini does not require cocolonization of the lower bowel with other flora to initiate an inflammatory response. (43)(44)(45)(46). Also, in vitro data show that GGT inhibits gastrointestinal and lymphocyte cell proliferation as well as having a role in producing reactive free oxygen species (43)(44)(45)(46).…”

Species‐specific immunity to Helicobacter suis

“…3,4 The immune response induced by H. pylori infection, on the other hand, is characterized by a Th17/Th1 response and the absence of a Th2 response in C57BL/6 and BALB/c mice. 3,4 The immune response induced by H. pylori infection, on the other hand, is characterized by a Th17/Th1 response and the absence of a Th2 response in C57BL/6 and BALB/c mice.…”

“…Several immune evasion mechanisms have been proposed for H. pylori, which focus to a great extent on the CagA protein, encoded in the cag (cytotoxin-associated gene) pathogenicity island (cagPAI), and vacuolating toxin A (VacA). 4,16,17 In addition, high levels of CD4 + CD25 high regulatory T-cells that efficiently block effector T-cell responses have been detected in the gastric mucosa of H. pylori-infected patients, which probably also contribute to bacterial persistence. 12,13 In addition, VacA may inhibit T-cell proliferation and signaling.…”

The Other Helicobacters

“…The γ‐glutamyl transpeptidase of H. suis was shown to be involved in the induction of inflammation in mice and gerbils, and the enzyme appeared to affect the glutamine metabolism of the gastric epithelium . In contrast to H. pylori Δggt strains, H. suis Δggt strains were capable of colonizing the stomach at levels comparable to WT strains.…”