<i>Helicobacter pylori</i> Vacuolating Cytotoxin Inhibits Activation-Induced Proliferation of Human T and B Lymphocyte Subsets

Torres, Victor J.; VanCompernolle, Scott E.; Sundrud, Mark S.; Unutmaz, Derya; Cover, Timothy L.

doi:10.4049/jimmunol.179.8.5433

Cited by 101 publications

(79 citation statements)

References 41 publications

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“…In addition, VacA suppressed IL-2-induced cell cycle progression without affecting IL-2-dependent survival (Sundrud et al 2004). Furthermore, Torres et al (2007) reported that VacA inhibited the proliferation of CD8+ T cells and B cells. VacA inhibited both T-cell-induced and PMA/anti-IgM-induced proliferation of purified B cells.…”

Section: Other Disruptions Of Cellular Signal Transductionmentioning

confidence: 97%

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Isomoto

Moss

Hirayama

2010

Tohoku J. Exp. Med.

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Section: Other Disruptions Of Cellular Signal Transductionmentioning

confidence: 97%

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Isomoto

Moss

Hirayama

2010

Tohoku J. Exp. Med.

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“…This suggests that the role of the vacA allele could differentially affect disease progression based on other virulence factors. This could be due to the finding that VacA acts as an immune modulator (16,52) and perhaps changes the immune response to the immunogenic CagA. Like CagA, VacA was found to disorganize the cytoskeleton of gastric epithelial cells, leading to increased cell spreading and growth (39).…”

Section: Vol 48 2010mentioning

confidence: 99%

“…VacA is another important toxin that is produced and secreted by all H. pylori strains (4,11) and was previously shown to have various modes of action (12,16,27,39,49,50,52,56). Like CagA, VacA has been shown to contain a number of polymorphisms.…”

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confidence: 99%

Epidemiological Link between Gastric Disease and Polymorphisms in VacA and CagA

et al. 2010

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Gastritis, peptic ulcer disease, and gastric cancer are a few of the diverse disease manifestations that have been shown to be associated with infection by Helicobacter pylori. Why some individuals develop more severe forms of disease remains largely unknown. In this study, 225 South Korean strains were genotyped for vacA and then analyzed to determine if particular genotypes varied across disease state, sex, or cagA allele. Of these strains, 206 strains carried an s1/i1/m1 allele, 11 strains carried an s1/i1/m2 allele, and 8 strains carried an s1/i2/m2 allele. By using Fisher's exact test, a statistical association between variations in the cagA and vacA alleles was identified (P ‫؍‬ 0.0007), and by using log linear modeling, this variation was shown to affect the severity of disease outcome (P ‫؍‬ 0.027). Additionally, we present evidence that variation within the middle region of VacA contributes significantly to the distribution of vacA alleles across gender (P ‫؍‬ 0.008) as well as the association with disease outcome (P ‫؍‬ 0.011). In this South Korean population, the majority of H. pylori strains carry the vacA s1/i1/m1 allele and the CagA EPIYA-ABD allele. These facts may contribute to the high incidence of gastric maladies, including gastric cancer.

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“…VacA causes multiple alterations in gastric epithelial cells, including swelling of endosomes (vacuolation) (11,12), permeabilization of mitochondrial membranes, and activation of mitogen-activated protein kinases (4,(7)(8)(9). In addition to its effects on gastric epithelial cells, VacA can disrupt the functions of many types of immune cells (T cells, B cells, neutrophils, eosinophils, and monocytes) (4,(7)(8)(9)(13)(14)(15)(16). The cellular activities of VacA are attributed mainly to its ability to form anion-selective channels in host cells (17)(18)(19)(20)(21).…”

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confidence: 99%

A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

et al. 2016

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Helicobacter pylori secretes a pore-forming VacA toxin that has structural features and activities substantially different from those of other known bacterial toxins. VacA can assemble into multiple types of water-soluble flower-shaped oligomeric structures, and most VacA activities are dependent on its capacity to oligomerize. The 88-kDa secreted VacA protein can undergo limited proteolysis to yield two domains, designated p33 and p55. The p33 domain is required for membrane channel formation and intracellular toxic activities, and the p55 domain has an important role in mediating VacA binding to cells. Previous studies showed that the p55 domain has a predominantly ␤-helical structure, but no structural data are available for the p33 domain. We report here the purification and analysis of a nonoligomerizing mutant form of VacA secreted by H. pylori. The nonoligomerizing 88-kDa mutant protein retains the capacity to enter host cells but lacks detectable toxic activity. Analysis of crystals formed by the monomeric protein reveals that the ␤-helical structure of the p55 domain extends into the C-terminal portion of p33. Fitting the p88 structural model into an electron microscopy map of hexamers formed by wild-type VacA (predicted to be structurally similar to VacA membrane channels) reveals that p55 and the ␤-helical segment of p33 localize to peripheral arms but do not occupy the central region of the hexamers. We propose that the amino-terminal portion of p33 is unstructured when VacA is in a monomeric form and that it undergoes a conformational change during oligomer assembly. Helicobacter pylori is a Gram-negative bacterium that persistently colonizes the stomach in about half of the human population worldwide (1-3). Most people tolerate the presence of this organism for long periods without any adverse consequences, but a small subset of H. pylori-infected individuals develop gastric adenocarcinoma or peptic ulcer disease.H. pylori is a relatively noninvasive organism that lives in the gastric mucus layer overlying gastric epithelial cells, sometimes adhering to the gastric epithelium. Many H. pylori-induced alterations in the gastric mucosa are attributable to the actions of secreted bacterial proteins on host cells (4-6). One such protein is the secreted vacuolating toxin, VacA (4, 7-10). VacA causes multiple alterations in gastric epithelial cells, including swelling of endosomes (vacuolation) (11, 12), permeabilization of mitochondrial membranes, and activation of mitogen-activated protein kinases (4, 7-9). In addition to its effects on gastric epithelial cells, VacA can disrupt the functions of many types of immune cells (T cells, B cells, neutrophils, eosinophils, and monocytes) (4, 7-9, 13-16). The cellular activities of VacA are attributed mainly to its ability to form anion-selective channels in host cells (17-21). VacA lacks sequence similarity to any other known bacterial toxins.H. pylori strains isolated from unrelated individuals are genetically heterogeneous, and the risk of developing gastric...

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Helicobacter pylori Vacuolating Cytotoxin Inhibits Activation-Induced Proliferation of Human T and B Lymphocyte Subsets

Cited by 101 publications

References 41 publications

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Epidemiological Link between Gastric Disease and Polymorphisms in VacA and CagA

A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

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