Abstract
BACKGROUND & AIMS: 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 (AGS) 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 ATG16L1in two cohorts of infected and uninfected subjects.
RESULTS: Prolonged exposure of AGS 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 biopsies 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 ATG16L1that 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 ATG16L1Crohn'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.
METHODS: We investigated the effect of VacA on autophagy in human gastric epithelial cells (AGS) 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 ATG16L1in two cohorts of infected and uninfected subjects.
RESULTS: Prolonged exposure of AGS 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 biopsies 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 ATG16L1that 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 ATG16L1Crohn'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.
| Original language | English |
|---|---|
| Pages (from-to) | 1160-1171 |
| Number of pages | 12 |
| Journal | Gastroenterology |
| Volume | 142 |
| Issue number | 5 |
| Early online date | 13 Feb 2012 |
| DOIs | |
| Publication status | Published - May 2012 |
Keywords
- stomach cancer
- genetic
- bacteria toxin
- tumor
Access to Document
- Raju et al Gastroenterology 2012
NOTICE: this is the author’s version of a work that was accepted for publication in Gastroenterology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. DOI: 10.1053/j.gastro.2012.01.043