Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans

Deepa Raju, Seamus Hussey, Michelle Ang, Mauricio R. Terebiznik, Michael Sibony, Esther Galindo-Mata, Vijay Gupta, Steven R. Blanke, Alberto Delgado, Judith Romero-Gallo, Mahendra Singh Ramjeet, Heidi Mascarenhas, Richard M. Peek, Pelayo Correa, Cathy Streutker, Georgina Hold, Erdmutte Kunstmann, Tamotsu Yoshimori, Mark S. Silverberg, Stephen E. Girardin & 3 others Dana J. Philpott, Emad El Omar, Nicola L. Jones

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)1160-1171
Number of pages12
JournalGastroenterology
Volume142
Issue number5
Early online date13 Feb 2012
DOIs
Publication statusPublished - May 2012

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Cytotoxins
Autophagy
Helicobacter Infections
Helicobacter pylori
Stomach
Pylorus
Infection
Monocytes
Cathepsin D
Crohn Disease
Reactive Oxygen Species
Carcinogenesis
Epithelial Cells
Genotype
Inflammation
Biopsy

Keywords

  • stomach cancer
  • genetic
  • bacteria toxin
  • tumor

Cite this

Raju, D., Hussey, S., Ang, M., Terebiznik, M. R., Sibony, M., Galindo-Mata, E., ... Jones, N. L. (2012). Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology, 142(5), 1160-1171. https://doi.org/10.1053/j.gastro.2012.01.043

Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. / Raju, Deepa; Hussey, Seamus; Ang, Michelle; Terebiznik, Mauricio R.; Sibony, Michael; Galindo-Mata, Esther; Gupta, Vijay; Blanke, Steven R.; Delgado, Alberto; Romero-Gallo, Judith; Ramjeet, Mahendra Singh; Mascarenhas, Heidi; Peek, Richard M.; Correa, Pelayo; Streutker, Cathy; Hold, Georgina; Kunstmann, Erdmutte; Yoshimori, Tamotsu; Silverberg, Mark S.; Girardin, Stephen E.; Philpott, Dana J.; El Omar, Emad; Jones, Nicola L.

In: Gastroenterology, Vol. 142, No. 5, 05.2012, p. 1160-1171.

Research output: Contribution to journalArticle

Raju, D, Hussey, S, Ang, M, Terebiznik, MR, Sibony, M, Galindo-Mata, E, Gupta, V, Blanke, SR, Delgado, A, Romero-Gallo, J, Ramjeet, MS, Mascarenhas, H, Peek, RM, Correa, P, Streutker, C, Hold, G, Kunstmann, E, Yoshimori, T, Silverberg, MS, Girardin, SE, Philpott, DJ, El Omar, E & Jones, NL 2012, 'Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans' Gastroenterology, vol. 142, no. 5, pp. 1160-1171. https://doi.org/10.1053/j.gastro.2012.01.043
Raju, Deepa ; Hussey, Seamus ; Ang, Michelle ; Terebiznik, Mauricio R. ; Sibony, Michael ; Galindo-Mata, Esther ; Gupta, Vijay ; Blanke, Steven R. ; Delgado, Alberto ; Romero-Gallo, Judith ; Ramjeet, Mahendra Singh ; Mascarenhas, Heidi ; Peek, Richard M. ; Correa, Pelayo ; Streutker, Cathy ; Hold, Georgina ; Kunstmann, Erdmutte ; Yoshimori, Tamotsu ; Silverberg, Mark S. ; Girardin, Stephen E. ; Philpott, Dana J. ; El Omar, Emad ; Jones, Nicola L. / Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. In: Gastroenterology. 2012 ; Vol. 142, No. 5. pp. 1160-1171.
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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.",
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author = "Deepa Raju and Seamus Hussey and Michelle Ang and Terebiznik, {Mauricio R.} and Michael Sibony and Esther Galindo-Mata and Vijay Gupta and Blanke, {Steven R.} and Alberto Delgado and Judith Romero-Gallo and Ramjeet, {Mahendra Singh} and Heidi Mascarenhas and Peek, {Richard M.} and Pelayo Correa and Cathy Streutker and Georgina Hold and Erdmutte Kunstmann and Tamotsu Yoshimori and Silverberg, {Mark S.} and Girardin, {Stephen E.} and Philpott, {Dana J.} and {El Omar}, Emad and Jones, {Nicola L.}",
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TY - JOUR

T1 - Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans

AU - Raju, Deepa

AU - Hussey, Seamus

AU - Ang, Michelle

AU - Terebiznik, Mauricio R.

AU - Sibony, Michael

AU - Galindo-Mata, Esther

AU - Gupta, Vijay

AU - Blanke, Steven R.

AU - Delgado, Alberto

AU - Romero-Gallo, Judith

AU - Ramjeet, Mahendra Singh

AU - Mascarenhas, Heidi

AU - Peek, Richard M.

AU - Correa, Pelayo

AU - Streutker, Cathy

AU - Hold, Georgina

AU - Kunstmann, Erdmutte

AU - Yoshimori, Tamotsu

AU - Silverberg, Mark S.

AU - Girardin, Stephen E.

AU - Philpott, Dana J.

AU - El Omar, Emad

AU - Jones, Nicola L.

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - stomach cancer

KW - genetic

KW - bacteria toxin

KW - tumor

U2 - 10.1053/j.gastro.2012.01.043

DO - 10.1053/j.gastro.2012.01.043

M3 - Article

VL - 142

SP - 1160

EP - 1171

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -