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Science 301 (5636): 1099-1102

Copyright © 2003 by the American Association for the Advancement of Science

Helicobacter pylori Vacuolating Cytotoxin Inhibits T Lymphocyte Activation

Bettina Gebert, Wolfgang Fischer, Evelyn Weiss, Reinhard Hoffmann, Rainer Haas*

Abstract: Helicobacter pylori (Hp) vacuolating cytotoxin VacA induces cellular vacuolation in epithelial cells. We found that VacA could efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest. It interfered with the T cell receptor/interleukin-2 (IL-2) signaling pathway at the level of the Ca2+-calmodulin–dependent phosphatase calcineurin. Nuclear translocation of nuclear factor of activated T cells (NFAT), a transcription factor acting as a global regulator of immune response genes, was abrogated, resulting in down-regulation of IL-2 transcription. VacA partially mimicked the activity of the immunosuppressive drug FK506 by possibly inducing a local immune suppression, explaining the extraordinary chronicity of Hp infections.

Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, LMU München, Germany.

* To whom correspondence should be addressed. E-mail: haas{at}

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H. M. S. Algood, V. J. Torres, D. Unutmaz, and T. L. Cover (2007)
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Helicobacter pylori VacA Toxin Inhibits Human Immunodeficiency Virus Infection of Primary Human T Cells.
K. Oswald-Richter, V. J. Torres, M. S. Sundrud, S. E. VanCompernolle, T. L. Cover, and D. Unutmaz (2006)
J. Virol. 80, 11767-11775
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Clin. Microbiol. Rev. 19, 597-613
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J. S. Pratt, K. L. Sachen, H. D. Wood, K. A. Eaton, and V. B. Young (2006)
Infect. Immun. 74, 4496-4504
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M. L. Drakes, S. J. Czinn, and T. G. Blanchard (2006)
Infect. Immun. 74, 4624-4633
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Clin. Microbiol. Rev. 19, 449-490
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K. M. Anderson, S. J. Czinn, R. W. Redline, and T. G. Blanchard (2006)
J. Immunol. 176, 5306-5313
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Mapping of a Domain Required for Protein-Protein Interactions and Inhibitory Activity of a Helicobacter pylori Dominant-Negative VacA Mutant Protein.
V. J. Torres, M. S. McClain, and T. L. Cover (2006)
Infect. Immun. 74, 2093-2101
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C. Genisset, C. L. Galeotti, P. Lupetti, D. Mercati, D. A. G. Skibinski, S. Barone, R. Battistutta, M. de Bernard, and J. L. Telford (2006)
Infect. Immun. 74, 1786-1794
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S. Das, G. Suarez, E. J. Beswick, J. C. Sierra, D. Y. Graham, and V. E. Reyes (2006)
J. Immunol. 176, 3000-3009
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Iron and pH Homeostasis Intersect at the Level of Fur Regulation in the Gastric Pathogen Helicobacter pylori.
H. Gancz, S. Censini, and D. S. Merrell (2006)
Infect. Immun. 74, 602-614
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Production of ammonium by Helicobacter pylori mediates occludin processing and disruption of tight junctions in Caco-2 cells.
S. D. Lytton, W. Fischer, W. Nagel, R. Haas, and F. X. Beck (2005)
Microbiology 151, 3267-3276
   Abstract »    Full Text »    PDF »
Characterization of the Helicobacter pylori Cysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent.
L. Deml, M. Aigner, J. Decker, A. Eckhardt, C. Schutz, P. R. E. Mittl, S. Barabas, S. Denk, G. Knoll, N. Lehn, et al. (2005)
Infect. Immun. 73, 4732-4742
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Comparison of Helicobacter pylori Virulence Gene Expression In Vitro and in the Rhesus Macaque.
J. K. Boonjakuakul, D. R. Canfield, and J. V. Solnick (2005)
Infect. Immun. 73, 4895-4904
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The Biology of Helicobacter pylori Infection, a Major Risk Factor for Gastric Adenocarcinoma.
D. Pinto-Santini and N. R. Salama (2005)
Cancer Epidemiol. Biomarkers Prev. 14, 1853-1858
   Abstract »    Full Text »    PDF »
Etiology of Gastric Cancer: What Is New?.
P. Correa and B. G. Schneider (2005)
Cancer Epidemiol. Biomarkers Prev. 14, 1865-1868
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The Development of Therapeutic and Preventive Vaccines for Gastric Cancer and Helicobacter pylori.
S. Y. Chui, T. M. Clay, H. K. Lyerly, and M. A. Morse (2005)
Cancer Epidemiol. Biomarkers Prev. 14, 1883-1889
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Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.
K. Yokoyama, H. Higashi, S. Ishikawa, Y. Fujii, S. Kondo, H. Kato, T. Azuma, A. Wada, T. Hirayama, H. Aburatani, et al. (2005)
PNAS 102, 9661-9666
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Impact of Helicobacter pylori Virulence Factors and Compounds on Activation and Maturation of Human Dendritic Cells.
K. Kranzer, L. Sollner, M. Aigner, N. Lehn, L. Deml, M. Rehli, and W. Schneider-Brachert (2005)
Infect. Immun. 73, 4180-4189
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Events at the Host-Microbial Interface of the Gastrointestinal Tract IV. The pathogenesis of Helicobacter pylori persistence.
R. M. Peek Jr. (2005)
Am J Physiol Gastrointest Liver Physiol 289, G8-G12
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Functional Properties of the p33 and p55 Domains of the Helicobacter pylori Vacuolating Cytotoxin.
V. J. Torres, S. E. Ivie, M. S. McClain, and T. L. Cover (2005)
J. Biol. Chem. 280, 21107-21114
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Orchestration of Aberrant Epithelial Signaling by Helicobacter pylori CagA.
R. M. Peek Jr. (2005)
Sci. STKE 2005, pe14
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Host Adaptation and Immune Modulation Are Mediated by Homologous Recombination in Helicobacter pylori.
K. Robinson, M. F. Loughlin, R. Potter, and P. J. Jenks (2005)
The Journal of Infectious Disease 191, 579-587
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Essential Domain of Receptor Tyrosine Phosphatase {beta} (RPTP{beta}) for Interaction with Helicobacter pylori Vacuolating Cytotoxin.
K. Yahiro, A. Wada, E. Yamasaki, M. Nakayama, Y. Nishi, J. Hisatsune, N. Morinaga, J. Sap, M. Noda, J. Moss, et al. (2004)
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Helicobacter pylori Vacuolating Cytotoxin, VacA, Is Responsible for Gastric Ulceration.
A. Wada, E. Yamasaki, and T. Hirayama (2004)
J. Biochem. 136, 741-746
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Gastric Transcription Profile of Helicobacter pylori Infection in the Rhesus Macaque.
J. L. Huff, L. M. Hansen, and J. V. Solnick (2004)
Infect. Immun. 72, 5216-5226
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Transcription Profile of Helicobacter pylori in the Human Stomach Reflects Its Physiology In Vivo.
J. K. Boonjakuakul, M. Syvanen, A. Suryaprasad, C. L. Bowlus, and J. V. Solnick (2004)
The Journal of Infectious Disease 190, 946-956
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Induction of Maturation and Cytokine Release of Human Dendritic Cells by Helicobacter pylori.
K. Kranzer, A. Eckhardt, M. Aigner, G. Knoll, L. Deml, C. Speth, N. Lehn, M. Rehli, and W. Schneider-Brachert (2004)
Infect. Immun. 72, 4416-4423
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Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion.
M. S. Sundrud, V. J. Torres, D. Unutmaz, and T. L. Cover (2004)
PNAS 101, 7727-7732
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Membrane channel structure of Helicobacter pylori vacuolating toxin: Role of multiple GXXXG motifs in cylindrical channels.
S. Kim, A. K. Chamberlain, and J. U. Bowie (2004)
PNAS 101, 5988-5991
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Clustering and Redistribution of Late Endocytic Compartments in Response to Helicobacter pylori Vacuolating Toxin.
Y. Li, A. Wandinger-Ness, J. R. Goldenring, and T. L. Cover (2004)
Mol. Biol. Cell 15, 1946-1959
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Glycosylphosphatidylinositol-anchored Proteins and Actin Cytoskeleton Modulate Chloride Transport by Channels Formed by the Helicobacter pylori Vacuolating Cytotoxin VacA in HeLa Cells.
N. C. Gauthier, V. Ricci, P. Gounon, A. Doye, M. Tauc, P. Poujeol, and P. Boquet (2004)
J. Biol. Chem. 279, 9481-9489
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Molecular cloning and characterization of two Helicobacter pylori genes coding for plasminogen-binding proteins.
K. Jonsson, B. P. Guo, H.-J. Monstein, J. J. Mekalanos, and G. Kronvall (2004)
PNAS 101, 1852-1857
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Interactions between p-33 and p-55 Domains of the Helicobacter pylori Vacuolating Cytotoxin (VacA).
V. J. Torres, M. S. McClain, and T. L. Cover (2004)
J. Biol. Chem. 279, 2324-2331
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Immunosuppressive and Proinflammatory Activities of the VacA Toxin of Helicobacter pylori.
C. Montecucco and M. de Bernard (2003)
J. Exp. Med. 198, 1767-1771
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One Way that H. pylori Establishes Chronic Infection.
Journal Watch (General) 2003, 8
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