title: Helicobacter pylori cholesteryl α-glucosides contribute to its pathogenicity and immune response by natural killer T cells.
abstract: Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer), while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl α-glucosides in H. pylori cell wall by α1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl α-glucosyltransferase (αCgT), which forms cholesteryl α-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of αCgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl α-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of αCgT showing a range of enzymatic activity. However, cholesteryl α-glucosides were recognized by invariant natural killer T (iNKT) cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active αCgT into iNKT cell-deficient (Jα18(-/-)) or wild-type mice, bacterial recovery significantly increased in Jα18(-/-) compared to wild-type mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in Jα18(-/-) compared to wild-type mice. These findings demonstrate that cholesteryl α-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.
authors: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors: Yuki
authors: Y
authors: Ito
authors: Jose Luis
authors: JL
authors: Vela
authors: Fumiko
authors: F
authors: Matsumura
authors: Hitomi
authors: H
authors: Hoshino
authors: Aaron
authors: A
authors: Tyznik
authors: Heeseob
authors: H
authors: Lee
authors: Enrico
authors: E
authors: Girardi
authors: Dirk M
authors: DM
authors: Zajonc
authors: Robert
authors: R
authors: Liddington
authors: Motohiro
authors: M
authors: Kobayashi
authors: Xingfeng
authors: X
authors: Bao
authors: Jeanna
authors: J
authors: Bugaytsova
authors: Thomas
authors: T
authors: Borén
authors: Rongsheng
authors: R
authors: Jin
authors: Yinong
authors: Y
authors: Zong
authors: Peter H
authors: PH
authors: Seeberger
authors: Jun
authors: J
authors: Nakayama
authors: Mitchell
authors: M
authors: Kronenberg
authors: Minoru
authors: M
authors: Fukuda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D005260:Female; D005757:Gastritis, Atrophic / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005960:Glucosides / Q000276:immunology*; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D005960:Glucosides