title: Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells.
abstract: Helicobacter pylori colonizes the gastric epithelium of at least 50% of the world's human population, playing a causative role in the development of chronic gastritis, peptic ulcers, and gastric adenocarcinoma. Current evidence indicates that H. pylori can invade epithelial cells in the gastric mucosa. However, relatively little is known about the biology of H. pylori invasion and survival in host cells. Here, we analyze both the nature of and the mechanisms responsible for the formation of H. pylori's intracellular niche. We show that in AGS cells infected with H. pylori, bacterium-containing vacuoles originate through the fusion of late endocytic organelles. This process is mediated by the VacA-dependent retention of the small GTPase Rab7. In addition, functional interactions between Rab7 and its downstream effector, Rab-interacting lysosomal protein (RILP), are necessary for the formation of the bacterial compartment since expression of mutant forms of RILP or Rab7 that fail to bind each other impaired the formation of this unique bacterial niche. Moreover, the VacA-mediated sequestration of active Rab7 disrupts the full maturation of vacuoles as assessed by the lack of both colocalization with cathepsin D and degradation of internalized cargo in the H. pylori-containing vacuole. Based on these findings, we propose that the VacA-dependent isolation of the H. pylori-containing vacuole from bactericidal components of the lysosomal pathway promotes bacterial survival and contributes to the persistence of infection.
authors.affiliation: Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G 1X9.
authors.forename: M R
authors.initials: MR
authors.lastname: Terebiznik
authors.forename: C L
authors.initials: CL
authors.lastname: Vazquez
authors.forename: K
authors.initials: K
authors.lastname: Torbicki
authors.forename: D
authors.initials: D
authors.lastname: Banks
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Hong
authors.forename: S R
authors.initials: SR
authors.lastname: Blanke
authors.forename: M I
authors.initials: MI
authors.lastname: Colombo
authors.forename: N L
authors.initials: NL
authors.lastname: Jones
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D002402:Cathepsin D / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004705:Endocytosis; D011992:Endosomes / Q000382:microbiology / Q000502:physiology / Q000648:ultrastructure; D005753:Gastric Mucosa / Q000382:microbiology* / Q000648:ultrastructure; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000382:microbiology / Q000502:physiology / Q000648:ultrastructure; D008561:Membrane Fusion; D009154:Mutation; D014617:Vacuoles / Q000382:microbiology* / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; C423317:RILP protein, human; C074689:VacA protein, Helicobacter pylori; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D002402:Cathepsin D; D020691:rab GTP-Binding Proteins