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  • Review Article
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Helicobacter pylori VacA, a paradigm for toxin multifunctionality

Nature Reviews Microbiology volume 3, pages 320–332 (2005)Cite this article

Key Points

  • Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach. H. pylori can persist in the stomach for decades despite the development of a gastric mucosal inflammatory response and a humoral immune response. H. pylori infection is associated with an increased risk for the development of peptic ulcer disease and gastric adenocarcinoma.

  • H. pylori secretes a toxin, VacA, that can cause a broad range of effects on human cells. Cellular effects produced by VacA include alteration of late endocytic compartments, reduction in mitochondrial membrane permeability and stimulation of cellular signalling pathways. VacA can modulate the functions of a variety of different cell types, including epithelial cells, antigen-presenting cells, phagocytic cells, mast cells and T lymphocytes.

  • VacA binds to the plasma membrane, is internalized by cells and can localize in either endocytic compartments or mitochondria. Many VacA-induced cellular effects can be attributed to the insertion of VacA into membranes to form anion-selective channels.

  • Experiments in an animal model indicate that VacA contributes to H. pylori colonization of the stomach. VacA inhibits the activation and proliferation of T lymphocytes in vitro, a phenomenon that may contribute to the persistence of H. pylori infection in vivo. Several studies indicate that VacA contributes to the pathogenesis of H. pylori-associated peptic ulceration and gastric adenocarcinoma.

  • Secreted protein toxins have an important role in allowing bacteria to colonize eukaryotic hosts, and toxins contribute to the pathogenesis of numerous infectious diseases. Similar to VacA, bacterial toxins that are produced by many other bacterial species can produce multiple cellular effects. We review the general topic of toxin multifunctionality, discuss common mechanistic themes that allow toxins to produce multiple cellular effects and discuss the role of toxin multifunctionality in bacterial pathogenesis.

Abstract

Bacterial protein toxins alter eukaryotic cellular processes and enable bacteria to successfully colonize their hosts. In recent years, there has been increased recognition that many bacterial toxins are multifunctional proteins that can have pleiotropic effects on mammalian cells and tissues. In this review, we examine a multifunctional toxin (VacA) that is produced by the bacterium Helicobacter pylori. The actions of H. pylori VacA represent a paradigm for how bacterial secreted toxins contribute to colonization and virulence in multiple ways.

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Figure 1: Mechanisms of cellular intoxication by bacterial protein toxins.
Figure 2: Cellular vacuolation induced by VacA.
Figure 3: vacA gene structure and allelic diversity.
Figure 4: Water-soluble oligomeric structures formed by VacA, imaged by deep-etch electron microscopy.
Figure 5: Multiple actions of VacA contribute to H. pylori colonization of the stomach.

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Acknowledgements

This work was supported in part by the National Institutes of Health and by the Medical Research Service of the Department of Veterans Affairs.

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Authors and Affiliations

  1. Departments of Medicine, Division of Infectious Diseases, and Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Administration Medical Center, Nashville, 37232, Tennessee, USA

    Timothy L. Cover

  2. Department of Microbiology and Molecular Genetics, University of Illinois, Urbana-Champaign, 61801, Illinois, USA

    Steven R. Blanke

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Correspondence to Timothy L. Cover.

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Timothy L. Cover may benefit from commercial exploitation of VacA-related intellectual property held by Vanderbilt University.

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DATABASES

Entrez

Helicobacter pylori

vacA

SwissProt

VacA

Glossary

TOXIN MULTIFUNCTIONALITY

In this review, toxin multifunctionality is defined as the ability of a bacterial protein toxin to cause multiple different cellular effects.

GASTRIC MUCUS LAYER

A thin layer of mucus covering gastric epithelial cells and consisting mainly of mucins (high-molecular-mass glycosylated proteins).

PEPTIC ULCER DISEASE

A disease that is characterized by ulcerative damage to the mucosal lining of the stomach or duodenum.

GASTRIC ADENOCARCINOMA

The most common form of stomach cancer. Two types can be differentiated based on histological features — intestinal and diffuse types.

VACUOLES

Large intracellular membrane-bound compartments.

ACID OR ALKALINE ACTIVATION

Exposure of oligomeric VacA complexes to acidic or alkaline pH results in disassembly of oligomers and is associated with an increase in vacuolating cytotoxic activity.

APOPTOSIS

An active process of programmed cell death, characterized by cleavage of chromosomal DNA, chromatin condensation and fragmentation of the nucleus.

MAP KINASES

A family of mitogen-activated protein kinases that regulate cell growth and differentiation.

PARACELLULAR EPITHELIAL PERMEABILITY

Diffusion across a polarized epithelial monolayer via the junctions betwen adjacent cells.

PRO-INFLAMMATORY CYTOKINES

Secreted proteins that regulate the inflammatory response.

LIPID RAFTS

Membrane microdomains enriched in cholesterol, sphingolipids and GPI-anchored proteins.

GPI-ANCHORED PROTEINS

Proteins that are anchored to a lipid bilayer by a glycosylphosphatidylinositol (GPI) moiety.

TOXIN RECEPTOR

A component of the eukaryotic cell surface to which a bacterial toxin can bind.

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Cover, T., Blanke, S. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 3, 320–332 (2005). https://doi.org/10.1038/nrmicro1095

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