Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA).

Ik Jung Kim, Steven R. Blanke

Research output: Contribution to journalReview article

Abstract

Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.

Original languageEnglish (US)
Number of pages1
JournalFrontiers in Cellular and Infection Microbiology
Volume2
StatePublished - 2012
Externally publishedYes

Fingerprint

Helicobacter pylori
Stomach
Epithelium
Homeostasis
Mitochondrial Dynamics
Bacterial Toxins
Exotoxins
Intracellular Membranes
Mosaicism
Membranes
Mitochondrial Membranes
Ion Channels
Genes
Virulence
Epidemiologic Studies
Mitochondria
Proteins
Animal Models
Alleles
Ions

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

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abstract = "Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.",
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N2 - Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.

AB - Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.

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