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Toxins
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Vacuolating Toxin
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Vacuolating Toxin

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (28 February 2016) | Viewed by 63026

Special Issue Editor

Prof. Dr. Timothy L. Cover

E-Mail Website
Guest Editor
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Interests: bacteria-host interactions; bacterial toxins; Helicobacter pylori; gastric cancer

Special Issue Information

Dear Colleagues,

The VacA toxin of Helicobacter pylori was originally identified based on its ability to cause vacuolation in cultured cells, but is now known to have a considerably broader range of activities. Gastric epithelial cells as well as multiple types of immune cells are susceptible to VacA. VacA enhances the ability of H. pylori to colonize the stomach and contributes to the pathogenesis of peptic ulcer disease and gastric cancer. Therefore, understanding the molecular mechanisms of VacA action and the role of VacA in the biology of H. pylori-human interactions is an important priority. This Special Issue focuses on multiple topics pertaining to the H. pylori VacA toxin, including the following:

  • Evolution of the vacA gene
  • vacA orthologs and vacA paralogs
  • vacA transcription and transcriptional regulation
  • Secretion of VacA
  • Heterogeneity among H. pylori strains in VacA transcription, secretion, and activity
  • Membrane channel formation by VacA
  • Binding of VacA to host cells, internalization, and intracellular trafficking
  • Effects of VacA on epithelial cells
  • Effects of VacA on immune cells
  • Effects of VacA on parietal cells and gastric acidity
  • Intracellular vacuole formation and endosomal alterations in response to VacA
  • VacA-induced mitochondrial alterations
  • VacA-induced autophagy
  • Alterations in cell signaling in response to VacA
  • Effects of VacA on epithelial barrier functions
  • VacA-induced cell death
  • Host cell constituents required for VacA activity
  • Relationship between vacA types and development of disease in humans
  • Studies of VacA in animal models
  • Relationship between VacA activities and activities of other H. pylori products (including CagA and GGT)
  • Use of VacA as a vaccine antigen
  • Immunomodulatory activities of VacA relevant for extra-gastric disease states (such as asthma)
  • Vacuolating toxins in non-H. pylori species

Prof. Dr. Timothy L. Cover
Guest Editor

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Keywords

  • Helicobacter pylori
  • VacA, vacuolating toxin
  • gastric cancer
  • peptic ulcer disease
  • autotransporter
  • type V secretion
  • vaccine antigens
  • vacuolation
  • mitochondria
  • apoptosis
  • autophagy

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Published Papers (8 papers)

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Research

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248 KiB  
Article
Helicobacter pylori vacA Genotypes in Chronic Gastritis and Gastric Carcinoma Patients from Macau, China
by Ines Pinto-Ribeiro, Rui M. Ferreira, Sellma Batalha, Thazin Hlaing, Sio In Wong, Fatima Carneiro and Ceu Figueiredo
Toxins 2016, 8(5), 142; https://doi.org/10.3390/toxins8050142 - 5 May 2016
Cited by 18 | Viewed by 6146
Abstract
Helicobacter pylori is the major triggering factor for gastric carcinoma, but only a small proportion of infected patients develop this disease. Differences in virulence observed among H. pylori strains, namely in the vacuolating cytotoxin vacA gene, may contribute to this discrepancy. Infection with [...] Read more.
Helicobacter pylori is the major triggering factor for gastric carcinoma, but only a small proportion of infected patients develop this disease. Differences in virulence observed among H. pylori strains, namely in the vacuolating cytotoxin vacA gene, may contribute to this discrepancy. Infection with vacA s1, i1 and m1 strains increases the risk for progression of gastric premalignant lesions and for gastric carcinoma. However, in East Asian countries most of the H. pylori strains are vacA s1, regardless of the patients’ clinical status, and the significance of the vacA i1 and m1 genotypes for gastric carcinoma in this geographic area remains to be fully elucidated. The aim of the present study was to investigate this relationship in 290 patients from Macau, China. Using very sensitive and accurate genotyping methods, we detected infection with vacA i1 and with vacA m1 strains in, respectively, 85.2% and 52.6% of the patients that were infected with single genotypes. The prevalence of cagA-positive strains was 87.5%. No significant associations were observed between vacA genotypes or cagA and gastric carcinoma. It is worth noting that 37.5% of the infected patients had coexistence of H. pylori strains with different vacA genotypes. Additional studies directed to other H. pylori virulence factors should be performed to identify high risk patients in East Asia. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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Review

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942 KiB  
Review
Relationship between VacA Toxin and Host Cell Autophagy in Helicobacter pylori Infection of the Human Stomach: A Few Answers, Many Questions
by Vittorio Ricci
Toxins 2016, 8(7), 203; https://doi.org/10.3390/toxins8070203 - 1 Jul 2016
Cited by 50 | Viewed by 7039
Abstract
Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about half the global population and represents the greatest risk factor for gastric malignancy. The relevance of H. pylori for gastric cancer development is equivalent to that of tobacco smoking for lung [...] Read more.
Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about half the global population and represents the greatest risk factor for gastric malignancy. The relevance of H. pylori for gastric cancer development is equivalent to that of tobacco smoking for lung cancer. VacA toxin seems to play a pivotal role in the overall strategy of H. pylori towards achieving persistent gastric colonization. This strategy appears to involve the modulation of host cell autophagy. After an overview of autophagy and its role in infection and carcinogenesis, I critically review current knowledge about the action of VacA on host cell autophagy during H. pylori infection of the human stomach. Although VacA is a key player in modulation of H. pylori-induced autophagy, a few discrepancies in the data are also evident and many questions remain to be answered. We are thus still far from a definitive understanding of the molecular mechanisms through which VacA affects autophagy and the consequences of this toxin action on the overall pathogenic activity of H. pylori. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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1285 KiB  
Review
VacA’s Induction of VacA-Containing Vacuoles (VCVs) and Their Immunomodulatory Activities on Human T Cells
by Ciara Utsch and Rainer Haas
Toxins 2016, 8(6), 190; https://doi.org/10.3390/toxins8060190 - 18 Jun 2016
Cited by 20 | Viewed by 7904
Abstract
Vacuolating cytotoxin A (VacA) is a secreted pore-forming toxin and one of the major virulence factors of Helicobacter pylori (H. pylori), which actively supports the persistence and survival of the bacteria in the special ecological niche of the human stomach. H. [...] Read more.
Vacuolating cytotoxin A (VacA) is a secreted pore-forming toxin and one of the major virulence factors of Helicobacter pylori (H. pylori), which actively supports the persistence and survival of the bacteria in the special ecological niche of the human stomach. H. pylori genomes harbor different allelic forms of the vacA gene, which translate into functionally distinct VacA toxin types. VacA internalizes into various cell types via membrane or specific receptor interactions finally forming acidic endocytic VacA-containing vacuoles (VCVs). In this review, we focus on different characteristics of VacA, its interaction with host cells, the formation and protein content of VCVs and their intracellular transport into human T cells, which finally leads to the immunosuppressive phenotype of VacA. Immunomodulatory activities of VacA on human T cells are discussed with a focus on T-cell proliferation and calcium signaling. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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1101 KiB  
Review
The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells
by Aleksandra Djekic and Anne Müller
Toxins 2016, 8(6), 187; https://doi.org/10.3390/toxins8060187 - 16 Jun 2016
Cited by 44 | Viewed by 6976
Abstract
VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less [...] Read more.
VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirectly prevent H. pylori-specific T-cell responses and immune control of the infection. In particular, the ability of VacA-proficient H. pylori to skew T-cell responses towards regulatory T-cells and the effects of Tregs on H. pylori chronicity are highlighted. The by-stander effects of VacA-driven immunomodulation on extragastric diseases are discussed as well. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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556 KiB  
Review
Relationship between vacA Types and Development of Gastroduodenal Diseases
by Tran Thi Huyen Trang, Tran Thanh Binh and Yoshio Yamaoka
Toxins 2016, 8(6), 182; https://doi.org/10.3390/toxins8060182 - 9 Jun 2016
Cited by 39 | Viewed by 7321
Abstract
The Helicobacter pylori vacuolating cytotoxin (VacA) is a secreted pore-forming toxin and a major virulence factor in the pathogenesis of H. pylori infection. While VacA is present in almost all strains, only some forms are toxigenic and pathogenic. While vacA and its genotypes [...] Read more.
The Helicobacter pylori vacuolating cytotoxin (VacA) is a secreted pore-forming toxin and a major virulence factor in the pathogenesis of H. pylori infection. While VacA is present in almost all strains, only some forms are toxigenic and pathogenic. While vacA and its genotypes are considered as markers of H. pylori-related diseases or disorders, the pathophysiological mechanisms of VacA and its genotypes remain controversial. This review outlines key findings of publications regarding vacA with emphasis on the relationship between vacA genotypes and the development of human disease. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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226 KiB  
Review
Use of VacA as a Vaccine Antigen
by Mati Moyat and Dominique Velin
Toxins 2016, 8(6), 181; https://doi.org/10.3390/toxins8060181 - 8 Jun 2016
Cited by 10 | Viewed by 4627
Abstract
One of the major toxins secreted by H. pylori is the Vacuolating cytotoxin A (VacA) named after its ability to induce the formation of “vacuole”-like membrane vesicles in the cytoplasm of gastric cells. VacA has been associated with the disruption of mitochondrial functions, [...] Read more.
One of the major toxins secreted by H. pylori is the Vacuolating cytotoxin A (VacA) named after its ability to induce the formation of “vacuole”-like membrane vesicles in the cytoplasm of gastric cells. VacA has been associated with the disruption of mitochondrial functions, stimulation of apoptosis, blockade of T cell proliferation and promotion of regulatory T cells, thereby making it a promising vaccine target. Immunity to bacterial virulence factors is well known to protect humans against bacterial infections; hence, detoxified VacA has been evaluated as a vaccine antigen. Our short review summarizes the pre-clinical and clinical data that have been published on the use of VacA in the development of the H. pylori vaccine. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
2673 KiB  
Review
An Overview of Helicobacter pylori VacA Toxin Biology
by Nora J. Foegeding, Rhonda R. Caston, Mark S. McClain, Melanie D. Ohi and Timothy L. Cover
Toxins 2016, 8(6), 173; https://doi.org/10.3390/toxins8060173 - 3 Jun 2016
Cited by 156 | Viewed by 13733
Abstract
The VacA toxin secreted by Helicobacter pylori enhances the ability of the bacteria to colonize the stomach and contributes to the pathogenesis of gastric adenocarcinoma and peptic ulcer disease. The amino acid sequence and structure of VacA are unrelated to corresponding features of [...] Read more.
The VacA toxin secreted by Helicobacter pylori enhances the ability of the bacteria to colonize the stomach and contributes to the pathogenesis of gastric adenocarcinoma and peptic ulcer disease. The amino acid sequence and structure of VacA are unrelated to corresponding features of other known bacterial toxins. VacA is classified as a pore-forming toxin, and many of its effects on host cells are attributed to formation of channels in intracellular sites. The most extensively studied VacA activity is its capacity to stimulate vacuole formation, but the toxin has many additional effects on host cells. Multiple cell types are susceptible to VacA, including gastric epithelial cells, parietal cells, T cells, and other types of immune cells. This review focuses on the wide range of VacA actions that are detectable in vitro, as well as actions of VacA in vivo that are relevant for H. pylori colonization of the stomach and development of gastric disease. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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667 KiB  
Review
New Insights into VacA Intoxication Mediated through Its Cell Surface Receptors
by Kinnosuke Yahiro, Toshiya Hirayama, Joel Moss and Masatoshi Noda
Toxins 2016, 8(5), 152; https://doi.org/10.3390/toxins8050152 - 13 May 2016
Cited by 14 | Viewed by 8273
Abstract
Helicobacter pylori (H. pylori), a major cause of gastroduodenal diseases, produces VacA, a vacuolating cytotoxin associated with gastric inflammation and ulceration. The C-terminal domain of VacA plays a crucial role in receptor recognition on target cells. We have previously identified [...] Read more.
Helicobacter pylori (H. pylori), a major cause of gastroduodenal diseases, produces VacA, a vacuolating cytotoxin associated with gastric inflammation and ulceration. The C-terminal domain of VacA plays a crucial role in receptor recognition on target cells. We have previously identified three proteins (i.e., RPTPα, RPTPβ, and LRP1) that serve as VacA receptors. These receptors contribute to the internalization of VacA into epithelial cells, activate signal transduction pathways, and contribute to cell death and gastric ulceration. In addition, other factors (e.g., CD18, sphingomyelin) have also been identified as cell-surface, VacA-binding proteins. Since we believe that, following interactions with its host cell receptors, VacA participates in events leading to disease, a better understanding of the cellular function of VacA receptors may provide valuable information regarding the mechanisms underlying the pleiotropic actions of VacA and the pathogenesis of H. pylori-mediated disease. In this review, we focus on VacA receptors and their role in events leading to cell damage. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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