title: Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans.
abstract: OBJECTIVE
  The Helicobacter pylori toxin vacuolating cytotoxin (VacA) promotes gastric colonization, and its presence (VacA(+)) is associated with more-severe disease. The exact mechanisms by which VacA contributes to infection are unclear. We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection.
  
  
  METHODS
  We investigated the effect of VacA on autophagy in human gastric epithelial cells and primary gastric cells from mice. Expression of p62, a marker of autophagy, was also assessed in gastric tissues from patients infected with toxigenic (VacA(+)) or nontoxigenic strains. We analyzed the effect of VacA on autophagy in peripheral blood monocytes obtained from subjects with different genotypes of ATG16L1, which regulates autophagy. We performed genotyping for ATG16L1 in 2 cohorts of infected and uninfected subjects.
  
  
  RESULTS
  Prolonged exposure of human gastric epithelial cells and mouse gastric cells to VacA disrupted induction of autophagy in response to the toxin, because the cells lacked cathepsin D in autophagosomes. Loss of autophagy resulted in the accumulation of p62 and reactive oxygen species. Gastric biopsy samples from patients infected with VacA(+), but not nontoxigenic strains of H pylori, had increased levels of p62. Peripheral blood monocytes isolated from individuals with polymorphisms in ATG16L1 that increase susceptibility to Crohn's disease had reduced induction of autophagy in response to VacA(+) compared to cells from individuals that did not have these polymorphisms. The presence of the ATG16L1 Crohn's disease risk variant increased susceptibility to H pylori infection in 2 separate cohorts.
  
  
  CONCLUSIONS
  Autophagy protects against infection with H pylori; the toxin VacA disrupts autophagy to promote infection, which could contribute to inflammation and eventual carcinogenesis.
authors.affiliation: Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Deepa
authors.initials: D
authors.lastname: Raju
authors.forename: Seamus
authors.initials: S
authors.lastname: Hussey
authors.forename: Michelle
authors.initials: M
authors.lastname: Ang
authors.forename: Mauricio R
authors.initials: MR
authors.lastname: Terebiznik
authors.forename: Michal
authors.initials: M
authors.lastname: Sibony
authors.forename: Esther
authors.initials: E
authors.lastname: Galindo-Mata
authors.forename: Vijay
authors.initials: V
authors.lastname: Gupta
authors.forename: Steven R
authors.initials: SR
authors.lastname: Blanke
authors.forename: Alberto
authors.initials: A
authors.lastname: Delgado
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.forename: Mahendra Singh
authors.initials: MS
authors.lastname: Ramjeet
authors.forename: Heidi
authors.initials: H
authors.lastname: Mascarenhas
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.forename: Cathy
authors.initials: C
authors.lastname: Streutker
authors.forename: Georgina
authors.initials: G
authors.lastname: Hold
authors.forename: Erdmutte
authors.initials: E
authors.lastname: Kunstmann
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Emad
authors.initials: E
authors.lastname: El Omar
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Jones
mesh_terms: D000483:Alleles; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D002402:Cathepsin D / Q000502:physiology; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics; D005838:Genotype; D016481:Helicobacter Infections / Q000209:etiology*; D016480:Helicobacter pylori; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D010588:Phagosomes / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; C074689:VacA protein, Helicobacter pylori; D002402:Cathepsin D