title: Helicobacter pylori cag-Pathogenicity island-dependent early immunological response triggers later precancerous gastric changes in Mongolian gerbils.
abstract: Infection with Helicobacter pylori, carrying a functional cag type IV secretion system (cag-T4SS) to inject the Cytotoxin associated antigen (CagA) into gastric cells, is associated with an increased risk for severe gastric diseases in humans. Here we studied the pathomechanism of H. pylori and the role of the cag-pathogenicity island (cag-PAI) for the induction of gastric ulcer and precancerous conditions over time (2-64 weeks) using the Mongolian gerbil model. Animals were challenged with H. pylori B128 (WT), or an isogenic B128DeltacagY mutant-strain that produces CagA, but is unable to translocate it into gastric cells. H. pylori colonization density was quantified in antrum and corpus mucosa separately. Paraffin sections were graded for inflammation and histological changes verified by immunohistochemistry. Physiological and inflammatory markers were quantitated by RIA and RT-PCR, respectively. An early cag-T4SS-dependent inflammation of the corpus mucosa (4-8 weeks) occurred only in WT-infected animals, resulting in a severe active and chronic gastritis with a significant increase of proinflammatory cytokines, mucous gland metaplasia, and atrophy of the parietal cells. At late time points only WT-infected animals developed hypochlorhydria and hypergastrinemia in parallel to gastric ulcers, gastritis cystica profunda, and focal dysplasia. The early cag-PAI-dependent immunological response triggers later physiological and histopathological alterations towards gastric malignancies.
authors.affiliation: Max-von-Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wiedemann
authors.forename: Eva
authors.initials: E
authors.lastname: Loell
authors.forename: Susanna
authors.initials: S
authors.lastname: Mueller
authors.forename: Mechthild
authors.initials: M
authors.lastname: Stoeckelhuber
authors.forename: Manfred
authors.initials: M
authors.lastname: Stolte
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rieder
mesh_terms: D000126:Achlorhydria / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005755:Gastrins; D005756:Gastritis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D044404:Genomic Islands; D005849:Gerbillinae / Q000235:genetics; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D006984:Hypertrophy; D007124:Immunoenzyme Techniques; D011230:Precancerous Conditions / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D013276:Stomach Ulcer / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D005755:Gastrins; D012333:RNA, Messenger; C080866:cagA protein, Helicobacter pylori; D013004:Somatostatin