title: Genetic Manipulation ofHelicobacter pyloriVirulence Function by Host Carcinogenic Phenotypes.
abstract: Helicobacter pyloriis the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is thecagtype 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of thecagT4SS is CagY, which becomes rapidly altered duringin vivoadaptation in mice and rhesus monkeys, rendering thecagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that theH. pylori cag+strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in conjunction with samples from patients with premalignant lesions, to define the effects of a carcinogenic host environment on the virulence phenotype ofH. pylorito understand how only a subset of infected individuals develop cancer.H. pylori cagYsequence differences andcagT4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils withH. pyloristrain 7.13 identified an oscillating pattern ofcagT4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robustcagT4SS function could be restored upon infection of new hosts. Changes in the genetic composition ofcagYmirroredcagT4SS function, although the mechanisms ofcagYalterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modifycagT4SS function via alteringcagY,allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.Cancer Res; 77(9); 2401-12. ©2017 AACR.
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Suarez
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Sierra
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Uma S
authors.initials: US
authors.lastname: Krishna
authors.affiliation: Department of Medicine, National University of Colombia, Bogota, Colombia.|Hospital El Tunal Unit of Gastroenterology, Bogota, Colombia.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Gomez
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.affiliation: Departments of Cancer Biology, Pathology, Microbiology, and Immunology, and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. richard.peek@vanderbilt.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D005849:Gerbillinae / Q000382:microbiology; D016481:Helicobacter Infections / Q000235:genetics / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori