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An Overview of Helicobacter pylori VacA Toxin Biology

Nora Foegeding, Rhonda Caston, Mark McClain and 2 more

Toxins · 2016 · Review · CC BY

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 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 text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Helicobacter pylori was first cultured from human gastric tissue in 1983. Several years later, it was reported that H. pylori broth culture supernatants contained a proteinaceous component known as “vacuolating cytotoxin”, which, when added to cultured eukaryotic cells, caused the cells to become vacuolated. Bacterial toxins with similar activity had not been described previously, and initially there was controversy about whether or not a H. pylori vacuolating toxin actually existed. Subsequent studies revealed the identity of the vacuolating toxin (termed VacA) and showed that it has properties and activities substantially different from those of other bacterial toxins.

2. Features of vacA and Related Genes in Helicobacter Species

2All H. pylori strains contain a single chromosomal vacA gene. The intact H. pylori vacA gene encodes a protein about 140 kDa in mass. The genus Helicobacter includes at least 20 different species, but intact vacA genes are present only in H. pylori and H. cetorum, a species isolated from stomachs or fecal contents of marine mammals. Similar to the association between H. pylori and gastritis in humans, H. cetorum is associated with gastritis in cetaceans and perhaps pinnipeds (seals). Genome sequence analysis of H. cetorum strains from a dolphin and a whale revealed the presence of an intact vacA gene next to cysS, consistent with the linkage of vacA and cysS in H. pylori. The proteins encoded by these H. cetorum vacA genes exhibit about 60%–70% protein-level identity to the most closely related H. pylori vacA gene product, and about 66% identity to one another (Figure 1A,B). The dolphin isolate of H. cetorum also contains an extra triplet of divergent vacA genes. It is not yet known whether H. cetorum VacA proteins elicit cytotoxic effects similar to those described for H. pylori VacA.

3Fragmented vacA pseudogenes are found in H. acinonychis, a Helicobacter species isolated from cheetahs and other large cats. Whole genome sequencing of one strain revealed the presence of two nearly identical vacA pseudogenes. The gene duplication presumably occurred after the vacA gene was disrupted. A protein encoded by a precursor of the H. acinonychis vacA pseudogene has been reconstructed in silico and exhibits about 64% amino acid identity to its closest match in H. pylori.

4H. pylori and several other Helicobacter species (including H. bilis, H. heilmannii, H. ailurogastricus, H. felis, H. bizzozeronii, H. suis, H. acinonychis, and H. cetorum) contain “vacA-like” genes. This designation is a bit of a misnomer as the similarity between VacA and these “VacA-like” gene products is limited mainly to the C-terminal ends of the proteins (Figure 1C–E). This C-terminal region is required for secretion of H. pylori VacA, but is not part of the soluble VacA toxin. To our knowledge, the three vacA-like genes from H. pylori are the only vacA-like genes that have been studied experimentally. In H. pylori, these genes are designated imaA (immunomodulatory autotransporter A, HP0289), faaA (flagella-associated autotransporter A, HP0609/0610), and vlpC (VacA-like protein C, HP0922). Each of the vacA-like genes enhances the capacity of H. pylori to colonize the stomach in rodent models, and transcription of each gene is upregulated in the gastric environment compared to the level of transcription during bacterial growth in vitro. The H. pylori VacA-like proteins localize to the bacterial surface, where ImaA and VlpC localize to a bacterial pole and FaaA localizes to the flagella. Little is known about the functions of these three proteins, but analysis of mutant strains has provided clues. Specifically, analyses of a faaA mutant revealed mislocalization of the flagella and decreased bacterial motility; gastric epithelial cells co-cultured with an imaA mutant produce higher levels of IL-8 and TNF-α than cells co-cultured with wild-type H. pylori; mutations in vlpC have been associated with high-level resistance to metronidazole.

3. VacA Transcription, Regulation, and Secretion

5The H. pylori vacA transcriptional start site is located about 120 nucleotides upstream from the ATG start codon. A stem-loop structure in the 5′ untranslated region (UTR) of the vacA transcript stabilizes the vacA mRNA, particularly during conditions of environmental stress. The transcription of vacA is regulated in response to growth phase, with the highest levels of transcription occurring in late log phase. There has been relatively little in-depth analysis of vacA regulation in response to environmental conditions, but some studies suggest that vacA transcription is regulated in response to low pH, iron concentration, salt concentration, and bacterial contact with host cells.

6VacA is translated into a 140 kDa protein, which undergoes Sec-dependent cleavage of an amino-terminal signal sequence and carboxy-terminal proteolytic cleavage (Figure 2A). Cleavage yields an active toxin about 88 kDa in mass, as well as a ~12 kDa peptide and a ~33 kDa protein with a predicted β-barrel structure (autotransporter β-barrel). The protease responsible for carboxy-terminal proteolytic cleavage has not been identified. The 88 kDa toxin molecules are translocated across the outer membrane and then can be either released into the extracellular space as soluble proteins (along with the 12 kDa peptide) or retained on the bacterial surface. The 33 kDa autotransporter β-barrel localizes to the outer membrane, and is required for secretion of the 88 kDa toxin. These features suggest that VacA is secreted by an autotransporter or type V mode of secretion.

4. Membrane Channel Formation by VacA

7Many bacterial toxins enter host cells and cause alterations by exerting an enzymatic activity in intracellular sites, and others act by forming pores in the plasma membrane of host cells. VacA enters host cells, but is not known to have any enzymatic activity. Based on its capacity to form anion-selective channels in planar lipid bilayers, VacA has been classified as a pore-forming toxin. VacA channels can conduct chloride, bicarbonate, and small organic molecules, and have properties similar to those of ClC channels in host cells. VacA mutant proteins lacking the ability to form a membrane channel in artificial bilayers lack vacuolating toxic activity in cell culture assays. Similarly, chemical inhibitors of chloride channels impair VacA channel activity in lipid bilayers and impair vacuolation in cell culture. Notably, the chemical inhibitors used for these experiments might not act exclusively on VacA channels, but might also act on other cellular targets. Most evidence indicates that the effects of VacA on host cells are directly attributable to channel formation by VacA, rather than activation of endogenous cellular channels.

5. VacA Structure

8The 88 kDa secreted VacA protein can undergo limited proteolysis in the presence of trypsin or during prolonged storage to yield 33 kDa and 55 kDa fragments (Figure 2B). These are considered to be two domains of VacA (p33 and p55). Mixtures of recombinant p33 and p55 proteins can reconstitute a functionally active form of VacA. The p55 domain has a predominantly β-helical structure, which is a feature shared by the passenger domains of several proteins secreted by an autotransporter mechanism in other Gram-negative bacterial species. No high resolution structural data are available for the p33 domain. The amino acid sequence of the 88 kDa secreted VacA protein is not closely related to sequences of any other known bacterial toxins.

9Both p33 and p55 are required for efficient binding of the toxin to the plasma membrane when VacA is added externally to cells. The p33 domain is required for insertion of VacA into membranes to form anion-selective channels. When expressed intracellularly, the minimal VacA region required for cell vacuolation encompasses residues 1–422, which includes the entire p33 domain plus 111 amino acids from the amino-terminal portion of the p55 domain.

10The N-terminus of the p33 domain contains a sequence of 32 uncharged amino acids, corresponding to the only predicted hydrophobic segment within VacA long enough to span a membrane. Deletion of this region results in a VacA mutant lacking cell-vacuolating activity and defective in membrane channel formation in planar lipid bilayers. The amino-terminal hydrophobic region of VacA includes three tandem GXXXG transmembrane association motifs (defined by glycine residues at positions 14, 18, 22, and 26). Mutagenesis of amino acids within this region, including glycine residues at positions 14 and 18 or a proline residue at position 9, abolishes VacA channel formation and vacuolating activity.

11VacA oligomerizes in solution to form an assortment of flower- or snowflake-shaped structures. These include double-layered structures (dodecamers and tetradecamers) as well as single layered structures (mainly hexamers and heptamers, but occasionally higher order forms) (Figure 3). Several lines of evidence indicate that oligomerization is required for VacA activity. The structure of water-soluble, single layered VacA oligomers is proposed to resemble the structure of VacA membrane channels.

12Exposure of VacA oligomers to acidic pH or alkaline pH results in the disassembly of VacA oligomers into monomers. When added to cultured cells, preparations of VacA exposed to low pH or high pH have greatly increased cytotoxic activity compared to preparations of oligomeric VacA. Therefore, it is thought that VacA first interacts with the plasma membrane of host cells as a monomer, where it oligomerizes and inserts to form a functional membrane channel.

6. VacA Diversity among H. pylori Strains

13Early studies noted that there is considerable variation in vacuolating toxin activity among H. pylori strains. One contributing factor is variation among strains in VacA transcription. There is also variation among strains in levels of VacA protein secretion. At present, it is not known whether differences among strains in levels of VacA secretion are primarily due to differences in VacA transcription, differences in transcript stability, or differences in the efficiency with which various forms of VacA are secreted.

14All H. pylori strains contain a vacA gene, and in most strains the vacA open reading frame is intact. Frameshift mutations in vacA are present in a small proportion of isolates, resulting in an absence of VacA protein production. Phylogenetic analysis of vacA sequences from a large number of H. pylori strains has revealed the existence of several distinct groups of vacA alleles, several of which have distinct geographical distributions. For example, vacA alleles found in many H. pylori strains isolated in East Asia are considerably different from the vacA alleles typically found in strains isolated in Europe or Africa. Divergence among groups of vacA alleles is principally due to positively selected sequence changes in the region of vacA encoding the p55 domain, and corresponds to surface-exposed sites in the p55 crystal structure.

15Three main regions of diversity in VacA sequences have been recognized: the signal sequence region (s-region), the intermediate region (i-region), and middle region (m-region) (Figure 2B). Within each of these regions, sequences can be classified into two main types (s1 or s2, i1 or i2, and m1 or m2). The s-region of VacA corresponds to the amino-terminal signal sequence and the amino-terminus of the secreted toxin (Figure 2C). The i-region is found within the p33 domain of VacA (Figure 2D). The m-region corresponds to part of the p55 domain. Homologous recombination occurs commonly in H. pylori, and consequently, vacA alleles can contain multiple possible combinations of s-, i- and m-region types (s1-i1-m1; s2-i2-m2; s1-i1-m2, etc.).

16In contrast to type s1 forms of VacA, type s2 forms of VacA do not cause vacuolation of mammalian cells. This dichotomy in activity is attributable to different sites of signal sequence cleavage in s1 and s2 VacA proteins. Specifically, a hydrophilic 12 amino acid N-terminal extension is present in type s2 proteins, but absent from type s1 proteins. Several studies have reported that type m1 and m2 forms of VacA exhibit distinct cell-type specificities. For example, the activity of type m1 VacA toward HeLa cells is greater than the activity of type m2 VacA toward these cells, whereas both m1 and m2 forms are highly active toward RK-13 cells. The difference in activity of m1 and m2 VacA proteins has been attributed to cell-type dependent variations in VacA binding to cells, and may also be attributable to differences in channel-forming properties. Cell type specificity has been mapped to a 148-residue segment within the m-region of VacA. One study reported that the i-region (within the p33 domain) is a determinant of vacuolating toxin activity in strains that produce type s1-m2 forms of VacA. Type i1 forms of VacA are more active than type i2 forms of VacA in experiments conducted with Jurkat T cells.

17Epidemiological studies have demonstrated a correlation between the type of vacA allele present in H. pylori strains and the risk of gastroduodenal disease. Specifically, the risk of gastric cancer or peptic ulcer disease is higher in persons infected with strains containing type s1, i1 or m1 forms of vacA, compared to persons infected with strains containing type s2, i2 or m2 forms of vacA. The increased risk of disease observed with strains containing s1, i1, or m1 forms of vacA is probably attributable not only to the effects of VacA, but also to the effects of additional virulence determinants. Specifically, strains containing a type s1 vacA allele typically harbor the cag pathogenicity island (which encodes several important virulence determinants, including CagA and a type IV secretion system) and the outer membrane protein adhesin BabA, whereas strains containing a type s2 vacA allele typically lack the cag pathogenicity island and often lack babA.

7.1.1. Endosomal Alterations

18The most extensively studied activity of VacA is its ability to cause vacuolation of cultured cells. Most studies of this phenomenon and other VacA activities have been conducted with the highly active s1-i1-m1 form of VacA. Vacuolation can be observed within a few hours after addition of VacA to cells and is enhanced by the presence of weak bases. The membranes of VacA-induced vacuoles contain markers typically found in membranes of late endosomes (LEs), which suggests that the vacuoles arise from late endosomal compartments. The current model for VacA-induced vacuolation proposes that the secreted monomeric form of VacA binds to the plasma membrane. Upon binding, VacA monomers form oligomers, which are trafficked to LEs, where they form anion-selective channels in the LE membrane. Transit of chloride ions through VacA channels in the LE membrane leads to an increase in intraluminal chloride concentration, which in turn triggers the enhancement of V-ATPase proton pumping activity and a decrease in intraluminal pH. Membrane-permeant weak bases diffuse into LEs, where they are protonated in the acidic environment and trapped. As a result, LEs undergo osmotic swelling, resulting in cell vacuolation. In addition to causing cell vacuolation, VacA causes a variety of functional alterations related to disruption of proper endocytic compartment trafficking. These include inhibition of intracellular degradation of epidermal growth factor, inhibition of procathepsin D maturation, perturbation of transferrin recycling, and in immune cells, inhibition of antigen presentation.

7.1.2. Autophagy

19When added to cultured gastric epithelial cells, VacA induces autophagy, the regulated degradation and recycling of cellular components in the cytoplasm. VacA is necessary and sufficient for H. pylori-induced autophagy. Similar to VacA-induced vacuole formation, VacA-induced autophagy is dependent on the capacity of VacA to form membrane channels, but the autophagosomes formed in response to VacA are distinct from the more abundant and larger intracellular vacuoles that form in response to VacA. Although the mechanisms by which VacA induces autophagy are not fully understood, VacA-induced autophagy has been shown to depend on binding of VacA to low-density lipoprotein receptor-related protein 1 (LRP1). Inhibition of autophagy leads to increased stability of intracellular VacA and increased cell vacuolation. One hypothesis is that the induction of autophagy upon exposure to VacA is a response initiated by the host cell to degrade VacA and prevent additional toxin-induced cell damage. Although acute exposure of host cells to VacA induces autophagy, prolonged exposure of host cells to VacA has been shown to disrupt autophagy.

7.1.3. Mitochondrial Alterations

20Treatment of cells with VacA results in an assortment of mitochondrial alterations, including reduction of mitochondrial transmembrane potential, release of cytochrome c, activation of Bax and Bak, and mitochondrial fragmentation. After entry into host cells, VacA can localize to mitochondria, leading to the hypothesis that the toxin acts directly on mitochondria. In support of this model, VacA can cause a reduction in the transmembrane potential of isolated mitochondria, and VacA is imported into the inner mitochondrial membrane (IMM). The ability of VacA to induce mitochondrial dysfunction is dependent on VacA channel activity. Thus, one model proposes that VacA is imported into mitochondria and induces mitochondrial transmembrane potential reduction, perhaps by pore formation. This depolarization stimulates an initial release of cytochrome c, the activation of Bax/Bak, and the subsequent Bax/Bak-dependent release of cytochrome c. Another hypothesis is that VacA-induced mitochondrial dysfunction is due to indirect actions of VacA. For example, VacA may act indirectly by activating pro-apoptotic factors to trigger mitochondrial-dependent apoptosis.

7.1.4. Epithelial Barrier Alterations

21When added to cultured epithelial cells, VacA causes increased plasma membrane permeability, resulting in efflux of various anions and other small molecules, including chloride, urea, and bicarbonate, into the extracellular space. VacA-induced permeabilization of cells is attributed to the formation of VacA channels in the plasma membrane. In addition to causing increased permeability of the plasma membrane, VacA causes increased paracellular permeability of polarized monolayers. The mechanism by which VacA causes increased paracellular permeability is not well understood.

7.1.5. Altered Cell Signaling

22Several cellular alterations can be detected very rapidly after exposure of cells to VacA, and are likely due to the binding of VacA to the surface of host cells. In both gastric epithelial cells and T cells, VacA activates p38, a mitogen-activated protein (MAP) kinase. VacA-induced activation of the p38 signaling pathway leads to induction of cyclooxygenase 2 (COX-2) expression, which results in enhanced prostaglandin E2 production. VacA-induced activation of the p38 signaling pathway also can lead to the activation of activating transcription factor 2 (ATF-2). VacA can also activate another MAP kinase, ERK1/2. In addition to activating MAP kinases, VacA can activate a signaling pathway that activates G protein-coupled receptor kinase interactor (Git1), a signaling pathway that leads to the upregulation of vascular endothelial growth factor (VEGF), and the β-catenin signaling pathway. The VacA cell surface receptors required for activating most of these pathways have not been characterized, but RPTP-β is reported to be the VacA receptor required for activation of Git1 and epidermal growth factor receptor is reported to be required for upregulation of VEGF.

7.1.6. Cell Death

23VacA-induced cell vacuolation is not a cytolethal alteration, but exposure of epithelial cells to VacA can potentially result in cell death. AZ-521 cells (which are of duodenal origin) are particularly susceptible to VacA-induced cell death. VacA-induced cell death is preceded by an assortment of mitochondrial alterations, which suggests that these alterations are mechanistically important in the process by which VacA causes cell death. VacA reduces the expression of pro-survival factors and causes endoplasmic reticulum (ER) stress, which could also contribute to VacA-induced cell death. VacA can cause cell death by both apoptosis and necrosis.

7.2.1. Effects on Immune Cells

24VacA can alter the function of many types of immune cells, including lymphocytes, macrophages, eosinophils, mast cells, and dendritic cells. VacA inhibits activation and proliferation of T cells and B cells, and can interfere with antigen presentation in B cells. In macrophages, VacA contributes to the formation of large vesicles termed megasomes, and impairs the maturation and function of vesicular compartments. VacA alters various signal transduction pathways in macrophages, and can cause macrophage apoptosis. These VacA-induced effects may impair the ability of macrophages to engulf H. pylori. In addition to immunosuppressive effects, VacA stimulates the expression of the proinflammatory enzyme COX-2 in macrophages and neutrophils.

7.2.2. Effects on Parietal Cells

25Two studies reported that VacA inhibits gastric acid secretion from parietal cells. In one study, exposure of parietal cells to VacA resulted in permeabilization of the plasma membrane and calcium influx that ultimately caused the disruption of actin arrangement in apical microvilli and an inhibition of acid secretion. At present, it is not known whether this effect of VacA on parietal cells contributes to a reduction in gastric acid secretion that is sometimes observed in the course of H. pylori infection.

8.1. Cell Surface Binding and Receptors

26Various studies have reached differing conclusions about whether VacA binding to cells is saturable or nonsaturable. Therefore, it is unclear whether VacA binds to a single abundant, low-affinity receptor or to multiple cell surface components. Multiple putative VacA receptors on the surface of epithelial cells have been reported, including both protein and lipid receptors. These include receptor protein tyrosine phosphatases (RPTP) α and β, low-density lipoprotein receptor-related protein-1 (LRP1), epidermal growth factor receptor (EGFR), heparan sulphate, sphingomyelin, glycosphingolipids, and phospholipids. Among these putative receptors, sphingomyelin is the only plasma membrane component whose presence or absence is a functionally important determinant of sensitivity of epithelial cells to VacA, and also an important determinant of the extent to which VacA binds to the cell surface. Binding of VacA to sphingomyelin probably accounts for localization of the toxin to lipid rafts. Although several putative receptors for VacA have been identified on epithelial cells, β2 integrin subunit (CD18) is the only VacA receptor that has been identified on T cells.

27VacA binding to RPTP-β triggers alterations in cell signaling that ultimately lead to gastric tissue damage. Correspondingly, oral administration of VacA to wild-type mice results in gastric damage, whereas RPTP-β knockout mice are resistant to VacA-induced gastric damage. RPTP-β is not the sole receptor for VacA, as VacA is still internalized into epithelial cells in RPTP-β knockout mice. VacA binding to LRP1 is important for VacA-induced autophagy and apoptosis.

8.2. Pore Formation at the Cell Surface

28After binding to the cell surface, VacA increases plasma membrane permeability and causes membrane depolarization. These alterations are attributed to insertion of VacA into the plasma membrane and formation of anion-selective membrane channels. It is proposed that the toxin can also form channels in intracellular sites (endosomes and mitochondria). Relatively little is known about the relationships between VacA channel formation and intracellular trafficking of the toxin.

8.3. VacA Internalization and Intracellular Trafficking

29Upon binding to the cell surface, VacA is internalized by a clathrin-independent, Cdc42 dependent, and Rac1 dependent route that requires actin polymerization. Within 10 min after internalization, VacA is found in glycosylphosphatidyl inositol anchored protein (GPI-AP)-enriched early endosomal compartments (GEECs), within 30 min in early endosomes (EEs), and within 2 h in LEs.

30Several studies have provided evidence that the intracellular localization of VacA is not limited to endosomal compartments. As one example, VacA has been detected in association with mitochondria in host cells. The mechanisms by which VacA traffics to mitochondria are not well understood. One model proposes that a subset of VacA-containing endosomes co-localize with mitochondria, and that VacA is transferred directly from endosomes to mitochondria. In support of this model, VacA causes cellular changes that result in the co-fractionation of endosomes with mitochondria. Another model proposes that VacA is released into the cytosol and is imported into mitochondria via mitochondrial import proteins. Although VacA gains access to the cytosol if expressed in host cells or microinjected into cells, it is not known whether VacA added externally to cells can ultimately gain access to the cytosol (either by directly crossing the plasma membrane or by release from endosomes). It has been suggested that VacA may travel retrograde through the Golgi and ER, but this has not been investigated in detail. Further studies are needed to better understand VacA trafficking within host cells.

9. Activity of VacA in Animal Models

31Animal models have been utilized to investigate a potential role of VacA in promoting H. pylori colonization of the mammalian stomach. VacA mutant strains of H. pylori can colonize mice, gerbils, and gnotobiotic piglets, which indicates that VacA is not essential for gastric colonization. However, when coinfections are performed with isogenic wild-type and VacA mutant strains, VacA mutant strains are at a competitive disadvantage. In addition, ΔvacA mutant strains colonize mice less efficiently or at reduced levels compared to wild-type strains.

32Experiments in animal models have also revealed a role for VacA in promoting gastric pathology. Oral or intragastric administration of purified VacA to mice results in damage to the gastric mucosa and recruitment of inflammatory cells. Based on the capacity of VacA to induce ulceration in mice when administered intragastrically, it has been suggested that VacA contributes to the pathogenesis of gastric ulceration in humans. The intragastric concentration of VacA in animals receiving intragastrically administered VacA substantially exceeds the 20–800 pg per mL concentration of VacA estimated to be present in gastric juice, based on a bead-based ELISA performed on samples from H. pylori-positive patients, but local concentrations of VacA at sites of H. pylori interaction with gastric epithelial cells might be considerably higher than concentrations in gastric juice. In studies of gerbils experimentally infected with H. pylori, vacA mutant strains are less likely than isogenic wild-type strains to produce gastric ulcers. In addition, colonization studies in mice indicate that H. pylori strains producing forms of VacA that are most active in vitro (s1-i1) induce more severe and extensive metaplasia and inflammation in the stomach than strains producing forms of VacA that are less active in vitro (s1-i2 or s2-i2). Another study showed that, in comparison to a wild-type strain, ΔvacA mutants induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses and trigger more severe gastric pathology in mice. This latter observation may be attributable to immunomodulatory activities of VacA.

33H. pylori-infected humans often develop serum and gastric mucosal antibody responses to VacA (as well as many other H. pylori antigens), but these humoral immune responses do not result in clearance of H. pylori infection. In contrast, immunization of animals with VacA provides protective immunity against subsequent challenge with H. pylori. VacA has also been used as a component of vaccines used for therapeutic immunization (i.e., immunization designed to promote clearance of H. pylori infection).

34The presence of H. pylori in humans is inversely correlated with the incidence of allergy and asthma. Studies in mice have shown that H. pylori infection protects against development of allergic asthma, and that the protective effect of H. pylori is attributed to tolerogenic reprogramming of dendritic cells. VacA (and also gamma-glutamyl transpeptidase, GGT) contribute to the ability of H. pylori to induce tolerizing effects on murine dendritic cells in vitro and in vivo and VacA is required for protection against allergic asthma in a mouse model.

10. Comparisons of VacA Activities in Vitro and in Vivo

35VacA causes a wide spectrum of alterations in multiple cell types in vitro. One might presume that some VacA activities observed in vitro are more relevant in vivo than others. Therefore, there is considerable interest in defining VacA activities that are most relevant in vivo for promoting H. pylori colonization of the stomach or the development of diseases such as peptic ulceration or gastric cancer.

36Cell vacuolation is one of the most extensively studied VacA-induced phenomena in vitro. Human gastric epithelial cells are susceptible to VacA and vacuolation is occasionally observed in epithelial cells from gastric biopsies, albeit less prominently than in cultured cells treated with VacA. One study reported that VacA can promote intracellular survival of H. pylori in gastric epithelial cells. Conversely, H. pylori is predominantly an extracellular organism and does not replicate within intracellular vacuoles. Therefore, it is difficult to envision a mechanism by which vacuole formation per se would be relevant for H. pylori colonization of the stomach or H. pylori-associated gastric diseases. On the other hand, alterations in host cells resulting from VacA-induced perturbation of endocytic trafficking could be advantageous for the bacteria (for example, by inhibiting antigen presentation).

37One plausible action for VacA in vivo is to enhance the availability of nutrients or essential growth factors (such as metals), thereby promoting growth of H. pylori. Nutrients could be released through VacA channels in the plasma membrane or by VacA-induced changes in paracellular permeability. One study provided evidence that VacA perturbs transferrin recycling in host cells, leading to enhanced availability of iron and enhanced growth of H. pylori on the surface of epithelial cells. VacA-induced cell death could also result in release of nutrients.

38VacA interferes with the functions of several types of immune cells in vitro, and this could also be an important action of the toxin in vivo. Specifically, by interfering with the normal functions of T cells, B cells, neutrophils, macrophages, and eosinophils, VacA may attenuate the host immune response and thereby facilitate persistent H. pylori colonization of the stomach.

39H. pylori strains producing s1 forms of VacA, which are most active in vivo, typically contain the cag pathogenicity island, whereas strains producing s2 forms of VacA often lack the cag PAI. The cag PAI encodes an effector protein, CagA, which causes numerous alterations in host cells, as well as a type IV secretion system required for entry of CagA into host cells. The co-selection of type s1 vacA and the cag PAI, as well as similarities in the phylogenetic structure of vacA and cagA genes, suggests the existence of a functional interaction between VacA and products of the cag PAI. In support of this hypothesis, several studies have shown that VacA partially inhibits the actions of CagA in vitro, and CagA partially inhibits the trafficking or actions of VacA. Thus, another important action of VacA in vivo may be to provide an optimal counterbalance for the actions of CagA.

11. Summary

40In summary, VacA is a secreted bacterial toxin that differs substantially from other known toxins in amino acid sequence, structure, intracellular trafficking, and actions. Many different cell types are susceptible to VacA in vitro, and the toxin can cause a wide spectrum of cellular alterations. In vivo, VacA enhances the capacity of H. pylori to colonize the stomach and contributes to the pathogenesis of H. pylori-induced diseases. In future studies, it will be important to define more clearly the mechanisms by which VacA causes alterations in host cells and to define the actions of this toxin that are most relevant in vivo.

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Not in our library10.1016/j.rvsc.2008.04.001
11.
Dailidiene D., Dailide G., Ogura K., Zhang M., Mukhopadhyay A.K., Eaton K.A., Cattoli G., Kusters J.G., Berg D.E. Helicobacter acinonychis: Genetic and rodent infection studies of a Helicobacter pylori-like gastric pathogen of cheetahs and other big cats. J. Bacteriol. 2004;186:356-365.
Not in our library10.1128/jb.186.2.356-365.2004
12.
Who Ate Whom? Adaptive Helicobacter Genomic Changes That Accompanied a Host Jump from Early Humans to Large Felines · 2006
No notice
13.
Gangwer K.A., Shaffer C.L., Suerbaum S., Lacy D.B., Cover T.L., Bordenstein S.R. Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J. Bacteriol. 2010;192:6126-6135.
Not in our library10.1128/jb.01081-10
14.
Fischer W., Buhrdorf R., Gerland E., Haas R. Outer membrane targeting of passenger proteins by the vacuolating cytotoxin autotransporter of Helicobacter pylori. Infect. Immun. 2001;69:6769-6775.
Not in our library10.1128/iai.69.11.6769-6775.2001
15.
Sause W.E., Castillo A.R., Ottemann K.M. The Helicobacter pylori autotransporter ImaA (HP0289) modulates the immune response and contributes to host colonization. Infect. Immun. 2012;80:2286-2296.
Not in our library10.1128/iai.00312-12
16.
Flagellar Localization of a <named-content content-type="genus-species">Helicobacter pylori</named-content> Autotransporter Protein · 2013
Not checked
17.
Kavermann H., Burns B.P., Angermuller K., Odenbreit S., Fischer W., Melchers K., Haas R. Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J. Exp. Med. 2003;197:813-822.
Not in our library10.1084/jem.20021531
18.
Baldwin D.N., Shepherd B., Kraemer P., Hall M.K., Sycuro L.K., Pinto-Santini D.M., Salama N.R. Identification of Helicobacter pylori genes that contribute to stomach colonization. Infect. Immun. 2007;75:1005-1016.
Not in our library10.1128/iai.01176-06
19.
Castillo A.R., Woodruff A.J., Connolly L.E., Sause W.E., Ottemann K.M. Recombination-based in vivo expression technology identifies Helicobacter pylori genes important for host colonization. Infect. Immun. 2008;76:5632-5644.
Not in our library10.1128/iai.00627-08
20.
Voss B.J., Gaddy J.A., McDonald W.H., Cover T.L. Analysis of surface-exposed outer membrane proteins in Helicobacter pylori. J. Bacteriol. 2014;196:2455-2471.
Not in our library10.1128/jb.01768-14
21.
Albert T.J., Dailidiene D., Dailide G., Norton J.E., Kalia A., Richmond T.A., Molla M., Singh J., Green R.D., Berg D.E. Mutation discovery in bacterial genomes: Metronidazole resistance in Helicobacter pylori. Nat. Methods. 2005;2:951-953.
Not in our library10.1038/nmeth805
22.
Forsyth M.H., Cover T.L. Mutational analysis of the vacA promoter provides insight into gene transcription in Helicobacter pylori. J. Bacteriol. 1999;181:2261-2266.
Not in our library10.1128/jb.181.7.2261-2266.1999
23.
Amilon K.R., Letley D.P., Winter J.A., Robinson K., Atherton J.C. Expression of the Helicobacter pylori virulence factor vacuolating cytotoxin A (vacA) is influenced by a potential stem-loop structure in the 5′ untranslated region of the transcript. Mol. Microbiol. 2015;98:831-846.
Not in our library10.1111/mmi.13160
24.
Forsyth M.H., Cover T.L. Intercellular communication in Helicobacter pylori: LuxS is essential for the production of an extracellular signaling molecule. Infect. Immun. 2000;68:3193-3199.
Not in our library10.1128/iai.68.6.3193-3199.2000
25.
Snider C.A., Voss B.J., McDonald W.H., Cover T.L. Growth phase-dependent composition of the Helicobacter pylori exoproteome. J. Proteom. 2016;130:94-107.
Not in our library10.1016/j.jprot.2015.08.025
26.
Merrell D.S., Thompson L.J., Kim C.C., Mitchell H., Tompkins L.S., Lee A., Falkow S. Growth phase-dependent response of Helicobacter pylori to iron starvation. Infect. Immun. 2003;71:6510-6525.
Not in our library10.1128/iai.71.11.6510-6525.2003
27.
Van Amsterdam K., van Vliet A.H., Kusters J.G., Feller M., Dankert J., van der Ende A. Induced Helicobacter pylori vacuolating cytotoxin VacA expression after initial colonisation of human gastric epithelial cells. FEMS Immunol. Med. Microbiol. 2003;39:251-256.
Not in our library10.1016/s0928-8244(03)00226-8
28.
Gancz H., Jones K.R., Merrell D.S. Sodium chloride affects Helicobacter pylori growth and gene expression. J. Bacteriol. 2008;190:4100-4105.
Not in our library10.1128/jb.01728-07
29.
Nguyen V.Q., Caprioli R.M., Cover T.L. Carboxy-terminal proteolytic processing of Helicobacter pylori vacuolating toxin. Infect. Immun. 2001;69:543-546.
Not in our library10.1128/iai.69.1.543-546.2001
30.
Bumann D., Aksu S., Wendland M., Janek K., Zimny-Arndt U., Sabarth N., Meyer T.F., Jungblut P.R. Proteome analysis of secreted proteins of the gastric pathogen Helicobacter pylori. Infect. Immun. 2002;70:3396-3403.
Not in our library10.1128/iai.70.7.3396-3403.2002
31.
Ilver D., Barone S., Mercati D., Lupetti P., Telford J.L. Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism. Cell. Microbiol. 2004;6:167-174.
Not in our library10.1046/j.1462-5822.2003.00349.x
32.
Czajkowsky D.M., Iwamoto H., Cover T.L., Shao Z. The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc. Natl. Acad. Sci. USA. 1999;96:2001-2006.
Not in our library10.1073/pnas.96.5.2001
33.
Tombola F., Carlesso C., Szabo I., de Bernard M., Reyrat J.M., Telford J.L., Rappuoli R., Montecucco C., Papini E., Zoratti M. Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: Possible implications for the mechanism of cellular vacuolation. Biophys. J. 1999;76:1401-1409.
Not in our library10.1016/s0006-3495(99)77301-7
34.
Iwamoto H., Czajkowsky D.M., Cover T.L., Szabo G., Shao Z. VacA from Helicobacter pylori: A hexameric chloride channel. FEBS Lett. 1999;450:101-104.
Not in our library10.1016/s0014-5793(99)00474-3
35.
Tombola F., Oregna F., Brutsche S., Szabo I., Del Giudice G., Rappuoli R., Montecucco C., Papini E., Zoratti M. Inhibition of the vacuolating and anion channel activities of the VacA toxin of Helicobacter pylori. FEBS Lett. 1999;460:221-225.
Not in our library10.1016/s0014-5793(99)01348-4
36.
Szabo I., Brutsche S., Tombola F., Moschioni M., Satin B., Telford J.L., Rappuoli R., Montecucco C., Papini E., Zoratti M. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. Embo J. 1999;18:5517-5527.
Not in our library10.1093/emboj/18.20.5517
37.
Czajkowsky D.M., Iwamoto H., Szabo G., Cover T.L., Shao Z. Mimicry of a host anion channel by a Helicobacter pylori pore-forming toxin. Biophys. J. 2005;89:3093-3101.
Not in our library10.1529/biophysj.105.066746
38.
Vinion-Dubiel A.D., McClain M.S., Czajkowsky D.M., Iwamoto H., Ye D., Cao P., Schraw W., Szabo G., Blanke S.R., Shao Z., et al. A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J. Biol. Chem. 1999;274:37736-37742.
Not in our library10.1074/jbc.274.53.37736
39.
McClain M.S., Iwamoto H., Cao P., Vinion-Dubiel A.D., Li Y., Szabo G., Shao Z., Cover T.L. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J. Biol. Chem. 2003;278:12101-12108.
Not in our library10.1074/jbc.m212595200
40.
Torres V.J., McClain M.S., Cover T.L. Interactions between p-33 and p-55 domains of the Helicobacter pylori vacuolating cytotoxin (VacA). J. Biol. Chem. 2004;279:2324-2331.
Not in our library10.1074/jbc.m310159200
41.
Torres V.J., Ivie S.E., McClain M.S., Cover T.L. Functional properties of the p33 and p55 domains of the Helicobacter pylori vacuolating cytotoxin. J. Biol. Chem. 2005;280:21107-21114.
Not in our library10.1074/jbc.m501042200
42.
Gonzalez-Rivera C., Gangwer K.A., McClain M.S., Eli I.M., Chambers M.G., Ohi M.D., Lacy D.B., Cover T.L. Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry. 2010;49:5743-5752.
Not in our library10.1021/bi100618g
43.
Gangwer K.A., Mushrush D.J., Stauff D.L., Spiller B., McClain M.S., Cover T.L., Lacy D.B. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc. Natl. Acad. Sci. USA. 2007;104:16293-16298.
Not in our library10.1073/pnas.0707447104
44.
Junker M., Schuster C.C., McDonnell A.V., Sorg K.A., Finn M.C., Berger B., Clark P.L. Pertactin beta-helix folding mechanism suggests common themes for the secretion and folding of autotransporter proteins. Proc. Natl. Acad. Sci. USA. 2006;103:4918-4923.
Not in our library10.1073/pnas.0507923103
45.
De Bernard M., Arico B., Papini E., Rizzuto R., Grandi G., Rappuoli R., Montecucco C. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol. Microbiol. 1997;26:665-674.
Not in our library10.1046/j.1365-2958.1997.5881952.x
46.
De Bernard M., Burroni D., Papini E., Rappuoli R., Telford J., Montecucco C. Identification of the Helicobacter pylori VacA toxin domain active in the cell cytosol. Infect. Immun. 1998;66:6014-6016.
Not in our library10.1128/iai.66.12.6014-6016.1998
47.
Ye D., Willhite D.C., Blanke S.R. Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J. Biol. Chem. 1999;274:9277-9282.
Not in our library10.1074/jbc.274.14.9277
48.
Kim S., Chamberlain A.K., Bowie J.U. Membrane channel structure of Helicobacter pylori vacuolating toxin: Role of multiple GXXXG motifs in cylindrical channels. Proc. Natl. Acad. Sci. USA. 2004;101:5988-5991.
Not in our library10.1073/pnas.0308694101
49.
McClain M.S., Cao P., Cover T.L. Amino-terminal hydrophobic region of Helicobacter pylori vacuolating cytotoxin (VacA) mediates transmembrane protein dimerization. Infect. Immun. 2001;69:1181-1184.
Not in our library10.1128/iai.69.2.1181-1184.2001
50.
Ye D., Blanke S.R. Mutational analysis of the Helicobacter pylori vacuolating toxin amino terminus: Identification of amino acids essential for cellular vacuolation. Infect. Immun. 2000;68:4354-4357.
Not in our library10.1128/iai.68.7.4354-4357.2000
51.
McClain M.S., Czajkowsky D.M., Torres V.J., Szabo G., Shao Z., Cover T.L. Random mutagenesis of Helicobacter pylori VacA to identify amino acids essential for vacuolating cytotoxic activity. Infect. Immun. 2006;74:6188-6195.
Not in our library10.1128/iai.00915-06
52.
Lupetti P., Heuser J.E., Manetti R., Massari P., Lanzavecchia S., Bellon P.L., Dallai R., Rappuoli R., Telford J.L. Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J. Cell Biol. 1996;133:801-807.
Not in our library10.1083/jcb.133.4.801
53.
El-Bez C., Adrian M., Dubochet J., Cover T.L. High resolution structural analysis of Helicobacter pylori VacA toxin oligomers by cryo-negative staining electron microscopy. J. Struct. Biol. 2005;151:215-228.
Not in our library10.1016/j.jsb.2005.07.001
54.
Chambers M.G., Pyburn T.M., Gonzalez-Rivera C., Collier S.E., Eli I., Yip C.K., Takizawa Y., Lacy D.B., Cover T.L., Ohi M.D. Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin. J. Mol. Biol. 2013;425:524-535.
Not in our library10.1016/j.jmb.2012.11.020
55.
Ye D., Blanke S.R. Functional complementation reveals the importance of intermolecular monomer interactions for Helicobacter pylori VacA vacuolating activity. Mol. Microbiol. 2002;43:1243-1253.
Not in our library10.1046/j.1365-2958.2002.02818.x
56.
Willhite D.C., Ye D., Blanke S.R. Fluorescence resonance energy transfer microscopy of the Helicobacter pylori vacuolating cytotoxin within mammalian cells. Infect. Immun. 2002;70:3824-3832.
Not in our library10.1128/iai.70.7.3824-3832.2002
57.
Genisset C., Galeotti C.L., Lupetti P., Mercati D., Skibinski D.A., Barone S., Battistutta R., de Bernard M., Telford J.L. A Helicobacter pylori vacuolating toxin mutant that fails to oligomerize has a dominant negative phenotype. Infect. Immun. 2006;74:1786-1794.
Not in our library10.1128/iai.74.3.1786-1794.2006
58.
Ivie S.E., McClain M.S., Torres V.J., Algood H.M., Lacy D.B., Yang R., Blanke S.R., Cover T.L. Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infect. Immun. 2008;76:2843-2851.
Not in our library10.1128/iai.01664-07
59.
Cover T.L., Hanson P.I., Heuser J.E. Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J. Cell Biol. 1997;138:759-769.
Not in our library10.1083/jcb.138.4.759
60.
Yahiro K., Niidome T., Kimura M., Hatakeyama T., Aoyagi H., Kurazono H., Imagawa K., Wada A., Moss J., Hirayama T. Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyrosine phosphatase beta. J. Biol. Chem. 1999;274:36693-36699.
Not in our library10.1074/jbc.274.51.36693
61.
De Bernard M., Papini E., de Filippis V., Gottardi E., Telford J., Manetti R., Fontana A., Rappuoli R., Montecucco C. Low pH activates the vacuolating toxin of Helicobacter pylori, which becomes acid and pepsin resistant. J. Biol. Chem. 1995;270:23937-23940.
Not in our library10.1074/jbc.270.41.23937
62.
McClain M.S., Schraw W., Ricci V., Boquet P., Cover T.L. Acid-activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells. Mol. Microbiol. 2000;37:433-442.
Not in our library10.1046/j.1365-2958.2000.02013.x
63.
Forsyth M.H., Atherton J.C., Blaser M.J., Cover T.L. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect. Immun. 1998;66:3088-3094.
Not in our library10.1128/iai.66.7.3088-3094.1998
64.
Ito Y., Azuma T., Ito S., Suto H., Miyaji H., Yamazaki Y., Kohli Y., Kuriyama M. Full-length sequence analysis of the vacA gene from cytotoxic and noncytotoxic Helicobacter pylori. J. Infect. Dis. 1998;178:1391-1398.
Not in our library10.1086/314435
65.
Duncan S.S., Valk P.L., McClain M.S., Shaffer C.L., Metcalf J.A., Bordenstein S.R., Cover T.L. Comparative genomic analysis of east asian and non-asian Helicobacter pylori strains identifies rapidly evolving genes. PLoS ONE. 2013;8:173.
Not in our library10.1371/journal.pone.0055120
66.
Atherton J.C., Cao P., Peek R.M., Tummuru M.K., Blaser M.J., Cover T.L. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J. Biol. Chem. 1995;270:17771-17777.
Not in our library10.1074/jbc.270.30.17771
67.
Rhead J.L., Letley D.P., Mohammadi M., Hussein N., Mohagheghi M.A., Eshagh Hosseini M., Atherton J.C. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133:926-936.
Not in our library10.1053/j.gastro.2007.06.056
68.
Letley D.P., Atherton J.C. Natural diversity in the n terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J. Bacteriol. 2000;182:3278-3280.
Not in our library10.1128/jb.182.11.3278-3280.2000
69.
McClain M.S., Cao P., Iwamoto H., Vinion-Dubiel A.D., Szabo G., Shao Z., Cover T.L. A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. J. Bacteriol. 2001;183:6499-6508.
Not in our library10.1128/jb.183.22.6499-6508.2001
70.
Letley D.P., Rhead J.L., Twells R.J., Dove B., Atherton J.C. Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J. Biol. Chem. 2003;278:26734-26741.
Not in our library10.1074/jbc.m304071200
71.
Pagliaccia C., de Bernard M., Lupetti P., Ji X., Burroni D., Cover T.L., Papini E., Rappuoli R., Telford J.L., Reyrat J.M. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc. Natl. Acad. Sci. USA. 1998;95:10212-10217.
Not in our library10.1073/pnas.95.17.10212
72.
Ji X., Fernandez T., Burroni D., Pagliaccia C., Atherton J.C., Reyrat J.M., Rappuoli R., Telford J.L. Cell specificity of Helicobacter pylori cytotoxin is determined by a short region in the polymorphic midregion. Infect. Immun. 2000;68:3754-3757.
Not in our library10.1128/iai.68.6.3754-3757.2000
73.
Tombola F., Pagliaccia C., Campello S., Telford J.L., Montecucco C., Papini E., Zoratti M. How the loop and middle regions influence the properties of Helicobacter pylori VacA channels. Biophys. J. 2001;81:3204-3215.
Not in our library10.1016/s0006-3495(01)75956-5
74.
Gonzalez-Rivera C., Algood H.M., Radin J.N., McClain M.S., Cover T.L. The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a jurkat t cell assay. Infect. Immun. 2012;80:2578-2588.
Not in our library10.1128/iai.00052-12
75.
Figueiredo C., Machado J.C., Pharoah P., Seruca R., Sousa S., Carvalho R., Capelinha A.F., Quint W., Caldas C., van Doorn L.J., et al. Helicobacter pylori and interleukin 1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma. J. Natl. Cancer Inst. 2002;94:1680-1687.
Not in our library10.1093/jnci/94.22.1680
76.
<named-content content-type="genus-species">Helicobacter pylori</named-content> Diversity and Gastric Cancer Risk · 2016
Not checked
77.
Cover T.L., Vaughn S.G., Cao P., Blaser M.J. Potentiation of Helicobacter pylori vacuolating toxin activity by nicotine and other weak bases. J. Infect. Dis. 1992;166:1073-1078.
Not in our library10.1093/infdis/166.5.1073
78.
Papini E., de Bernard M., Milia E., Bugnoli M., Zerial M., Rappuoli R., Montecucco C. Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments. Proc. Natl. Acad. Sci. USA. 1994;91:9720-9724.
Not in our library10.1073/pnas.91.21.9720
79.
Molinari M., Galli C., Norais N., Telford J.L., Rappuoli R., Luzio J.P., Montecucco C. Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. J. Biol. Chem. 1997;272:25339-25344.
Not in our library10.1074/jbc.272.40.25339
80.
Li Y., Wandinger-Ness A., Goldenring J.R., Cover T.L. Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin. Mol. Biol. Cell. 2004;15:1946-1959.
Not in our library10.1091/mbc.e03-08-0618
81.
Kern B., Jain U., Utsch C., Otto A., Busch B., Jimenez-Soto L., Becher D., Haas R. Characterization of Helicobacter pylori VacA-containing vacuoles (VCVs), VacA intracellular trafficking and interference with calcium signalling in T lymphocytes. Cell. Microbiol. 2015;17:1811-1832.
Not in our library10.1111/cmi.12474
82.
De Bernard M., Moschioni M., Habermann A., Griffiths G., Montecucco C. Cell vacuolization induced by Helicobacter pylori VacA cytotoxin does not depend on late endosomal snares. Cell. Microbiol. 2002;4:11-18.
Not in our library10.1046/j.1462-5822.2002.00163.x
83.
Montecucco C., Rappuoli R. Living dangerously: How Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol. 2001;2:457-466.
Not in our library10.1038/35073084
84.
Cover T.L., Blanke S.R. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat. Rev. Microbiol. 2005;3:320-332.
Not in our library10.1038/nrmicro1095
85.
Ricci V., Sommi P., Fiocca R., Romano M., Solcia E., Ventura U. Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J. Pathol. 1997;183:453-459.
Not in our library10.1002/(sici)1096-9896(199712)183:4<453::aid-path950>3.0.co;2-2
86.
Morbiato L., Tombola F., Campello S., Del Giudice G., Rappuoli R., Zoratti M., Papini E. Vacuolation induced by VacA toxin of Helicobacter pylori requires the intracellular accumulation of membrane permeant bases, Cl(-) and water. FEBS Lett. 2001;508:479-483.
Not in our library10.1016/s0014-5793(01)03133-7
87.
Genisset C., Puhar A., Calore F., de Bernard M., Dell’Antone P., Montecucco C. The concerted action of the Helicobacter pylori cytotoxin VacA and of the v-atpase proton pump induces swelling of isolated endosomes. Cell. Microbiol. 2007;9:1481-1490.
Not in our library10.1111/j.1462-5822.2006.00886.x
88.
Satin B., Norais N., Telford J., Rappuoli R., Murgia M., Montecucco C., Papini E. Effect of Helicobacter pylori vacuolating toxin on maturation and extracellular release of procathepsin d and on epidermal growth factor degradation. J. Biol. Chem. 1997;272:25022-25028.
Not in our library10.1074/jbc.272.40.25022
89.
Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface · 2011
No notice
90.
Molinari M., Salio M., Galli C., Norais N., Rappuoli R., Lanzavecchia A., Montecucco C. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J. Exp. Med. 1998;187:135-140.
Not in our library10.1084/jem.187.1.135
91.
Terebiznik M.R., Raju D., Vazquez C.L., Torbricki K., Kulkarni R., Blanke S.R., Yoshimori T., Colombo M.I., Jones N.L. Effect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy. 2009;5:370-379.
Not in our library10.4161/auto.5.3.7663
92.
Yahiro K., Satoh M., Nakano M., Hisatsune J., Isomoto H., Sap J., Suzuki H., Nomura F., Noda M., Moss J., et al. Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J. Biol. Chem. 2012;287:31104-31115.
Not in our library10.1074/jbc.m112.387498
93.
Raju D., Hussey S., Ang M., Terebiznik M.R., Sibony M., Galindo-Mata E., Gupta V., Blanke S.R., Delgado A., Romero-Gallo J., et al. Vacuolating cytotoxin and variants in Atg16l1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology. 2012;142:1160-1171.
Not in our library10.1053/j.gastro.2012.01.043
94.
Greenfield L.K., Jones N.L. Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol. 2013;21:602-612.
Not in our library10.1016/j.tim.2013.09.004
95.
Kimura M., Goto S., Wada A., Yahiro K., Niidome T., Hatakeyama T., Aoyagi H., Hirayama T., Kondo T. Vacuolating cytotoxin purified from Helicobacter pylori causes mitochondrial damage in human gastric cells. Microb. Pathog. 1999;26:45-52.
Not in our library10.1006/mpat.1998.0241
96.
Willhite D.C., Blanke S.R. Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell. Microbiol. 2004;6:143-154.
Not in our library10.1046/j.1462-5822.2003.00347.x
97.
Yamasaki E., Wada A., Kumatori A., Nakagawa I., Funao J., Nakayama M., Hisatsune J., Kimura M., Moss J., Hirayama T. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J. Biol. Chem. 2006;281:11250-11259.
Not in our library10.1074/jbc.m509404200
98.
Galmiche A., Rassow J., Doye A., Cagnol S., Chambard J.C., Contamin S., de Thillot V., Just I., Ricci V., Solcia E., et al. The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. Embo J. 2000;19:6361-6370.
Not in our library10.1093/emboj/19.23.6361
99.
Willhite D.C., Cover T.L., Blanke S.R. Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation. J. Biol. Chem. 2003;278:48204-48209.
Not in our library10.1074/jbc.m304131200
100.
Jain P., Luo Z.Q., Blanke S.R. Helicobacter pylori vacuolating cytotoxin a (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc. Natl. Acad. Sci. USA. 2011;108:16032-16037.
Not in our library10.1073/pnas.1105175108
101.
Oldani A., Cormont M., Hofman V., Chiozzi V., Oregioni O., Canonici A., Sciullo A., Sommi P., Fabbri A., Ricci V., et al. Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog. 2009;5:173.
Not in our library10.1371/journal.ppat.1000603
102.
Domanska G., Motz C., Meinecke M., Harsman A., Papatheodorou P., Reljic B., Dian-Lothrop E.A., Galmiche A., Kepp O., Becker L., et al. Helicobacter pylori VacA toxin/subunit p34: Targeting of an anion channel to the inner mitochondrial membrane. PLoS Pathog. 2010;6:173.
Not in our library10.1371/journal.ppat.1000878
103.
Foo J.H., Culvenor J.G., Ferrero R.L., Kwok T., Lithgow T., Gabriel K. Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria. J. Mol. Biol. 2010;401:792-798.
Not in our library10.1016/j.jmb.2010.06.065
104.
Tombola F., Morbiato L., Del Giudice G., Rappuoli R., Zoratti M., Papini E. The Helicobacter pylori VacA toxin is a urea permease that promotes urea diffusion across epithelia. J. Clin. Investig. 2001;108:929-937.
Not in our library10.1172/jci13045
105.
Debellis L., Papini E., Caroppo R., Montecucco C., Curci S. Helicobacter pylori cytotoxin VacA increases alkaline secretion in gastric epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2001;281:G1440-G1448.
Not in our library10.1152/ajpgi.2001.281.6.g1440
106.
Papini E., Satin B., Norais N., de Bernard M., Telford J.L., Rappuoli R., Montecucco C. Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J. Clin. Investig. 1998;102:813-820.
Not in our library10.1172/jci2764
107.
Amieva M.R., Vogelmann R., Covacci A., Tompkins L.S., Nelson W.J., Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300:1430-1434.
Not in our library10.1126/science.1081919
108.
Pelicic V., Reyrat J.M., Sartori L., Pagliaccia C., Rappuoli R., Telford J.L., Montecucco C., Papini E. Helicobacter pylori VacA cytotoxin associated with the bacteria increases epithelial permeability independently of its vacuolating activity. Microbiology. 1999;145:2043-2050.
Not in our library10.1099/13500872-145-8-2043
109.
Nakayama M., Kimura M., Wada A., Yahiro K., Ogushi K.I., Niidome T., Fujikawa A., Shirasaka D., Aoyama N., Kurazono H., et al. Helicobacter pylori VacA activates the p38/ATF-2-mediated signal pathway in AZ-521 cells. J. Biol. Chem. 2004;279:7024-7028.
Not in our library10.1074/jbc.m308898200
110.
Hisatsune J., Yamasaki E., Nakayama M., Shirasaka D., Kurazono H., Katagata Y., Inoue H., Han J., Sap J., Yahiro K., et al. Helicobacter pylori VacA enhances PGE2 production through induction of COX-2 expression via a p38 MAP kinase/ATF-2 cascade in AZ-521 cells. Infect. Immun. 2007;75:4472-4481.
Not in our library10.1128/iai.00500-07
111.
Boncristiano M., Paccani S.R., Barone S., Ulivieri C., Patrussi L., Ilver D., Amedei A., D’Elios M.M., Telford J.L., Baldari C.T. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J. Exp. Med. 2003;198:1887-1897.
Not in our library10.1084/jem.20030621
112.
Fujikawa A., Shirasaka D., Yamamoto S., Ota H., Yahiro K., Fukada M., Shintani T., Wada A., Aoyama N., Hirayama T., et al. Mice deficient in protein tyrosine phosphatase receptor type z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat. Genet. 2003;33:375-381.
Not in our library10.1038/ng1112
113.
Caputo R., Tuccillo C., Manzo B.A., Zarrilli R., Tortora G., Blanco Cdel V., Ricci V., Ciardiello F., Romano M. Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an epidermal growth factor receptor-, cyclooxygenase-2-dependent mechanism. Clin. Cancer Res. 2003;9:2015-2021.
Not in our library
114.
Nakayama M., Hisatsune J., Yamasaki E., Isomoto H., Kurazono H., Hatakeyama M., Azuma T., Yamaoka Y., Yahiro K., Moss J., et al. Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J. Biol. Chem. 2009;284:1612-1619.
Not in our library10.1074/jbc.m806981200
115.
Kuck D., Kolmerer B., Iking-Konert C., Krammer P.H., Stremmel W., Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line ags. Infect. Immun. 2001;69:5080-5087.
Not in our library10.1128/iai.69.8.5080-5087.2001
116.
Cover T.L., Krishna U.S., Israel D.A., Peek R.M. Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res. 2003;63:951-957.
Not in our library
117.
Radin J.N., Gonzalez-Rivera C., Ivie S.E., McClain M.S., Cover T.L. Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect. Immun. 2011;79:2535-2543.
Not in our library10.1128/iai.01370-10
118.
Radin J.N., Gonzalez-Rivera C., Frick-Cheng A.E., Sheng J., Gaddy J.A., Rubin D.H., Algood H.M., McClain M.S., Cover T.L. Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect. Immun. 2014;82:423-432.
Not in our library10.1128/iai.00827-13
119.
Calore F., Genisset C., Casellato A., Rossato M., Codolo G., Esposti M.D., Scorrano L., de Bernard M. Endosome-mitochondria juxtaposition during apoptosis induced by H. pylori VacA. Cell Death Differ. 2010;17:1707-1716.
Not in our library10.1038/cdd.2010.42
120.
Matsumoto A., Isomoto H., Nakayama M., Hisatsune J., Nishi Y., Nakashima Y., Matsushima K., Kurazono H., Nakao K., Hirayama T., et al. Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-XL, leading to apoptosis in gastric epithelial cells. Dig. Dis. Sci. 2011;56:999-1006.
Not in our library10.1007/s10620-010-1420-1
121.
Akazawa Y., Isomoto H., Matsushima K., Kanda T., Minami H., Yamaghchi N., Taura N., Shiozawa K., Ohnita K., Takeshima F., et al. Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. PLoS ONE. 2013;8:173.
Not in our library10.1371/journal.pone.0082322
122.
Remodeling the Host Environment: Modulation of the Gastric Epithelium by the Helicobacter pylori vacuolating toxin (VacA) · 2012
Not checked
123.
Kim J.M., Kim J.S., Lee J.Y., Kim Y.J., Youn H.J., Kim I.Y., Chee Y.J., Oh Y.K., Kim N., Jung H.C., et al. Vacuolating cytotoxin in Helicobacter pylori water-soluble proteins upregulates chemokine expression in human eosinophils via Ca2+ influx, mitochondrial reactive oxygen intermediates, and NF-kappaB activation. Infect. Immun. 2007;75:3373-3381.
Not in our library10.1128/iai.01940-06
124.
Kim J.M., Kim J.S., Lee J.Y., Sim Y.S., Kim Y.J., Oh Y.K., Yoon H.J., Kang J.S., Youn J., Kim N., et al. Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation. Eur. J. Immunol. 2010;40:1651-1662.
Not in our library10.1002/eji.200939882
125.
Supajatura V., Ushio H., Wada A., Yahiro K., Okumura K., Ogawa H., Hirayama T., Ra C. Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J. Immunol. 2002;168:2603-2607.
Not in our library10.4049/jimmunol.168.6.2603
126.
De Bernard M., Cappon A., Pancotto L., Ruggiero P., Rivera J., Del Giudice G., Montecucco C. The Helicobacter pylori VacA cytotoxin activates RBL-2H3 cells by inducing cytosolic calcium oscillations. Cell. Microbiol. 2005;7:191-198.
Not in our library10.1111/j.1462-5822.2004.00446.x
127.
Kim J.M., Kim J.S., Yoo D.Y., Ko S.H., Kim N., Kim H., Kim Y.J. Stimulation of dendritic cells with Helicobacter pylori vacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1. Clin. Exp. Immunol. 2011;166:34-45.
Not in our library10.1111/j.1365-2249.2011.04447.x
128.
Oertli M., Noben M., Engler D.B., Semper R.P., Reuter S., Maxeiner J., Gerhard M., Taube C., Muller A. Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc. Natl. Acad. Sci. USA. 2013;110:3047-3052.
Not in our library10.1073/pnas.1211248110
129.
Gebert B., Fischer W., Weiss E., Hoffman R., Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003;301:1099-1102.
Not in our library10.1126/science.1086871
130.
Sundrud M.S., Torres V.J., Unutmaz D., Cover T.L. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc. Natl. Acad. Sci. USA. 2004;101:7727-7732.
Not in our library10.1073/pnas.0401528101
131.
Torres V.J., VanCompernolle S.E., Sundrud M.S., Unutmaz D., Cover T.L. Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets. J. Immunol. 2007;179:5433-5440.
Not in our library10.4049/jimmunol.179.8.5433
132.
Allen L.A., Schlesinger L.S., Kang B. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J. Exp. Med. 2000;191:115-128.
Not in our library10.1084/jem.191.1.115
133.
Zheng P.Y., Jones N.L. Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell. Microbiol. 2003;5:25-40.
Not in our library10.1046/j.1462-5822.2003.00250.x
134.
Weiss G., Forster S., Irving A., Tate M., Ferrero R.L., Hertzog P., Frokiaer H., Kaparakis-Liaskos M. Helicobacter pylori VacA suppresses lactobacillus acidophilus-induced interferon beta signaling in macrophages via alterations in the endocytic pathway. MBio. 2013;4:e00609-12.
Not in our library10.1128/mbio.00609-12
135.
Hisatsune J., Nakayama M., Isomoto H., Kurazono H., Mukaida N., Mukhopadhyay A.K., Azuma T., Yamaoka Y., Sap J., Yamasaki E., et al. Molecular characterization of Helicobacter pylori VacA induction of IL-8 in U937 cells reveals a prominent role for p38 MAPK in activating transcription factor-2, cAMP response element binding protein, and NF-kappaB activation. J. Immunol. 2008;180:5017-5027.
Not in our library10.4049/jimmunol.180.7.5017
136.
Menaker R.J., Ceponis P.J., Jones N.L. Helicobacter pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Infect. Immun. 2004;72:2889-2898.
Not in our library10.1128/iai.72.5.2889-2898.2004
137.
Kobayashi H., Kamiya S., Suzuki T., Kohda K., Muramatsu S., Kurumada T., Ohta U., Miyazawa M., Kimura N., Mutoh N., et al. The effect of Helicobacter pylori on gastric acid secretion by isolated parietal cells from a guinea pig. Association with production of vacuolating toxin by H. pylori. Scand. J. Gastroenterol. 1996;31:428-433.
Not in our library10.3109/00365529609006760
138.
Wang F., Xia P., Wu F., Wang D., Wang W., Ward T., Liu Y., Aikhionbare F., Guo Z., Powell M., et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J. Biol. Chem. 2008;283:26714-26725.
Not in our library10.1074/jbc.m800527200
139.
Massari P., Manetti R., Burroni D., Nuti S., Norais N., Rappuoli R., Telford J.L. Binding of the Helicobacter pylori vacuolating cytotoxin to target cells. Infect. Immun. 1998;66:3981-3984.
Not in our library10.1128/iai.66.8.3981-3984.1998
140.
Wang H.J., Wang W.C. Expression and binding analysis of GST-VacA fusions reveals that the C-terminal approximately 100-residue segment of exotoxin is crucial for binding in hela cells [in process citation]. Biochem. Biophys. Res. Commun. 2000;278:449-454.
Not in our library10.1006/bbrc.2000.3820
141.
Wang W.-C., Wang H.-J., Kuo C.-H. Two distinctive cell binding patterns by vacuolating toxin fused with glutathione S-transferase: One high-affinity m1-specific binding and the other lower-affinity binding for variant m forms. Biochemistry. 2001;40:11887-11896.
Not in our library10.1021/bi010065u
142.
High Cell Sensitivity to Helicobacter pylori VacA Toxin Depends on a GPI-anchored Protein and is not Blocked by Inhibition of the Clathrin-mediated Pathway of Endocytosis · 2000
Not checked
143.
Patel H.K., Willhite D.C., Patel R.M., Ye D., Williams C.L., Torres E.M., Marty K.B., MacDonald R.A., Blanke S.R. Plasma membrane cholesterol modulates cellular vacuolation induced by the Helicobacter pylori vacuolating cytotoxin. Infect. Immun. 2002;70:4112-4123.
Not in our library10.1128/iai.70.8.4112-4123.2002
144.
Yahiro K., Wada A., Nakayama M., Kimura T., Ogushi K., Niidome T., Aoyagi H., Yoshino K., Yonezawa K., Moss J., et al. Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. J. Biol. Chem. 2003;278:19183-19189.
Not in our library10.1074/jbc.m300117200
145.
Yahiro K., Wada A., Yamasaki E., Nakayama M., Nishi Y., Hisatsune J., Morinaga N., Sap J., Noda M., Moss J., et al. Essential domain of receptor tyrosine phosphatase beta (RPTPbeta) for interaction with Helicobacter pylori vacuolating cytotoxin. J. Biol. Chem. 2004;279:51013-51021.
Not in our library10.1074/jbc.m406473200
146.
Seto K., Hayashi-Kuwabara Y., Yoneta T., Suda H., Tamaki H. Vacuolation induced by cytotoxin from Helicobacter pylori is mediated by the EGF receptor in hela cells. FEBS Lett. 1998;431:347-350.
Not in our library10.1016/s0014-5793(98)00788-1
147.
Utt M., Danielsson B., Wadstrom T. Helicobacter pylori vacuolating cytotoxin binding to a putative cell surface receptor, heparan sulfate, studied by surface plasmon resonance. FEMS Immunol. Med. Microbiol. 2001;30:109-113.
Not in our library10.1111/j.1574-695x.2001.tb01557.x
148.
Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. · 2008
Not checked
149.
Gupta V.R., Wilson B.A., Blanke S.R. Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA. Cell. Microbiol. 2010;12:1517-1533.
Not in our library10.1111/j.1462-5822.2010.01487.x
150.
Roche N., Ilver D., Angstrom J., Barone S., Telford J.L., Teneberg S. Human gastric glycosphingolipids recognized by Helicobacter pylori vacuolating cytotoxin VacA. Microbes Infect. 2007;9:605-614.
Not in our library10.1016/j.micinf.2007.01.023
151.
Molinari M., Galli C., de Bernard M., Norais N., Ruysschaert J.M., Rappuoli R., Montecucco C. The acid activation of Helicobacter pylori toxin VacA: Structural and membrane binding studies. Biochem. Biophys. Res. Commun. 1998;248:334-340.
Not in our library10.1006/bbrc.1998.8808
152.
Schraw W., Li Y., McClain M.S., van der Goot F.G., Cover T.L. Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J. Biol. Chem. 2002;277:34642-34650.
Not in our library10.1074/jbc.m203466200
153.
Geisse N.A., Cover T.L., Henderson R.M., Edwardson J.M. Targeting of Helicobacter pylori vacuolating toxin to lipid raft membrane domains analysed by atomic force microscopy. Biochem. J. 2004;381:911-917.
Not in our library10.1042/bj20031719
154.
Sewald X., Gebert-Vogal B., Prassl S., Barwig I., Weiss E., Fabbri M., Osicka R., Schiemann M., Busch D.H., Semmrich M., et al. CD18 is the T-lymphocyte receptor of the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe. 2008;3:20-29.
Not in our library10.1016/j.chom.2007.11.003
155.
Gauthier N.C., Ricci V., Gounon P., Doye A., Tauc M., Poujeol P., Boquet P. Glycosylphosphatidylinositol-anchored proteins and actin cytoskeleton modulate chloride transport by channels formed by the Helicobacter pylori vacuolating cytotoxin VacA in Hela cells. J. Biol. Chem. 2004;279:9481-9489.
Not in our library10.1074/jbc.m312040200
156.
Gauthier N.C., Monzo P., Kaddai V., Doye A., Ricci V., Boquet P. Helicobacter pylori VacA cytotoxin: A probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol. Biol. Cell. 2005;16:4852-4866.
Not in our library10.1091/mbc.e05-05-0398
157.
Gauthier N.C., Monzo P., Gonzalez T., Doye A., Oldani A., Gounon P., Ricci V., Cormont M., Boquet P. Early endosomes associated with dynamic f-actin structures are required for late trafficking of H. pylori VacA toxin. J. Cell Biol. 2007;177:343-354.
Not in our library10.1083/jcb.200609061
158.
Sewald X., Jimenez-Soto L., Haas R. Pkc-dependent endocytosis of the Helicobacter pylori vacuolating cytotoxin in primary t lymphocytes. Cell. Microbiol. 2011;13:482-496.
Not in our library10.1111/j.1462-5822.2010.01551.x
159.
Eaton K.A., Cover T.L., Tummuru M.K., Blaser M.J., Krakowka S. Role of vacuolating cytotoxin in gastritis due to Helicobacter pylori in gnotobiotic piglets. Infect. Immun. 1997;65:3462-3464.
Not in our library10.1128/iai.65.8.3462-3464.1997
160.
Wirth H.P., Beins M.H., Yang M., Tham K.T., Blaser M.J. Experimental infection of mongolian gerbils with wild-type and mutant Helicobacter pylori strains. Infect. Immun. 1998;66:4856-4866.
Not in our library10.1128/iai.66.10.4856-4866.1998
161.
Ogura K., Maeda S., Nakao M., Watanabe T., Tada M., Kyutoku T., Yoshida H., Shiratori Y., Omata M. Virulence factors of Helicobacter pylori responsible for gastric diseases in mongolian gerbil. J. Exp. Med. 2000;192:1601-1610.
Not in our library10.1084/jem.192.11.1601
162.
Salama N.R., Otto G., Tompkins L., Falkow S. Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect. Immun. 2001;69:730-736.
Not in our library10.1128/iai.69.2.730-736.2001
163.
Winter J.A., Letley D.P., Cook K.W., Rhead J.L., Zaitoun A.A., Ingram R.J., Amilon K.R., Croxall N.J., Kaye P.V., Robinson K., et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J. Infect. Dis. 2014;210:954-963.
Not in our library10.1093/infdis/jiu154
164.
Ghiara P., Marchetti M., Blaser M.J., Tummuru M.K., Cover T.L., Segal E.D., Tompkins L.S., Rappuoli R. Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease. Infect. Immun. 1995;63:4154-4160.
Not in our library10.1128/iai.63.10.4154-4160.1995
165.
Shirasaka D., Aoyama N., Sakashita M., Kuroda K., Maekawa S., Wambura C.M., Miyamoto M., Tamura T., Yahiro K., Wada A., et al. Relationship between gastric ulcer and Helicobacter pylori VacA detected in gastric juice using bead-ELISA method. Helicobacter. 2002;7:281-286.
Not in our library10.1046/j.1523-5378.2002.00097.x
166.
Cover T.L., Cao P., Murthy U.K., Sipple M.S., Blaser M.J. Serum neutralizing antibody response to the vacuolating cytotoxin of Helicobacter pylori. J. Clin. Investig. 1992;90:913-918.
Not in our library10.1172/jci115967
167.
Perez-Perez G.I., Peek R.M., Atherton J.C., Blaser M.J., Cover T.L. Detection of anti-VacA antibody responses in serum and gastric juice samples using type s1/m1 and s2/m2 Helicobacter pylori VacA antigens. Clin. Diagn. Lab. Immunol. 1999;6:489-493.
Not in our library10.1128/cdli.6.4.489-493.1999
168.
Marchetti M., Aricò B., Burroni D., Figura N., Rappuoli R., Ghiara P. Development of a mouse model of Helicobacter pylori infection that mimics human disease. Science. 1995;267:1655-1658.
Not in our library10.1126/science.7886456
169.
Ghiara P., Rossi M., Marchetti M., Di Tommaso A., Vindigni C., Ciampolini F., Covacci A., Telford J.L., De Magistris M.T., Pizza M., et al. Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection. Infect. Immun. 1997;65:4996-5002.
Not in our library10.1128/iai.65.12.4996-5002.1997
170.
Marchetti M., Rossi M., Giannelli V., Giuliani M.M., Pizza M., Censini S., Covacci A., Massari P., Pagliaccia C., Manetti R., et al. Protection against Helicobacter pylori infection in mice by intragastric vaccination with H. pylori antigens is achieved using a non-toxic mutant of E. coli heat-labile enterotoxin (LT) as adjuvant. Vaccine. 1998;16:33-37.
Not in our library10.1016/s0264-410x(97)00153-9
171.
Rossi G., Ruggiero P., Peppoloni S., Pancotto L., Fortuna D., Lauretti L., Volpini G., Mancianti S., Corazza M., Taccini E., et al. Therapeutic vaccination against Helicobacter pylori in the beagle dog experimental model: Safety, immunogenicity, and efficacy. Infect. Immun. 2004;72:3252-3259.
Not in our library10.1128/iai.72.6.3252-3259.2004
172.
Malfertheiner P., Schultze V., Rosenkranz B., Kaufmann S.H., Ulrichs T., Novicki D., Norelli F., Contorni M., Peppoloni S., Berti D., et al. Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: A phase I study. Gastroenterology. 2008;135:787-795.
Not in our library10.1053/j.gastro.2008.05.054
173.
Liu K.Y., Shi Y., Luo P., Yu S., Chen L., Zhao Z., Mao X.H., Guo G., Wu C., Zou Q.M. Therapeutic efficacy of oral immunization with attenuated salmonella typhimurium expressing Helicobacter pylori CagA, VacA and UreB fusion proteins in mice model. Vaccine. 2011;29:6679-6685.
Not in our library10.1016/j.vaccine.2011.06.099
174.
Cover T.L., Blaser M.J. Helicobacter pylori in health and disease. Gastroenterology. 2009;136:1863-1873.
Not in our library10.1053/j.gastro.2009.01.073
175.
Atherton J.C., Blaser M.J. Coadaptation of Helicobacter pylori and humans: Ancient history, modern implications. J. Clin. Investig. 2009;119:2475-2487.
Not in our library10.1172/jci38605
176.
Oertli M., Sundquist M., Hitzler I., Engler D.B., Arnold I.C., Reuter S., Maxeiner J., Hansson M., Taube C., Quiding-Jarbrink M., et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J. Clin. Investig. 2012;122:1082-1096.
Not in our library10.1172/jci61029
177.
Engler D.B., Reuter S., van Wijck Y., Urban S., Kyburz A., Maxeiner J., Martin H., Yogev N., Waisman A., Gerhard M., et al. Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc. Natl. Acad. Sci. USA. 2014;111:11810-11815.
Not in our library10.1073/pnas.1410579111
178.
Smoot D.T., Resau J.H., Earlington M.H., Simpson M., Cover T.L. Effects of Helicobacter pylori vacuolating cytotoxin on primary cultures of human gastric epithelial cells. Gut. 1996;39:795-799.
Not in our library10.1136/gut.39.6.795
179.
Harris P.R., Cover T.L., Crowe D.R., Orenstein J.M., Graham M.F., Blaser M.J., Smith P.D. Helicobacter pylori cytotoxin induces vacuolation of primary human mucosal epithelial cells. Infect. Immun. 1996;64:4867-4871.
Not in our library10.1128/iai.64.11.4867-4871.1996
180.
Fiocca R., Luinetti O., Villani L., Chiaravalli A.M., Capella C., Solcia E. Epithelial cytotoxicity, immune responses, and inflammatory components of Helicobacter pylori gastritis. Scand. J. Gastroenterol. Suppl. 1994;205:11-21.
Not in our library10.3109/00365529409091404
181.
Terebiznik M.R., Vazquez C.L., Torbicki K., Banks D., Wang T., Hong W., Blanke S.R., Colombo M.I., Jones N.L. Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. Infect. Immun. 2006;74:6599-6614.
Not in our library10.1128/iai.01085-06
182.
Amieva M.R., Salama N.R., Tompkins L.S., Falkow S. Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells. Cell. Microbiol. 2002;4:677-690.
Not in our library10.1046/j.1462-5822.2002.00222.x
183.
Argent R.H., Thomas R.J., Letley D.P., Rittig M.G., Hardie K.R., Atherton J.C. Functional association between the Helicobacter pylori virulence factors VacA and CagA. J. Med. Microbiol. 2008;57:145-150.
Not in our library10.1099/jmm.0.47465-0
184.
Yokoyama K., Higashi H., Ishikawa S., Fujii Y., Kondo S., Kato H., Azuma T., Wada A., Hirayama T., Aburatani H., et al. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc. Natl. Acad. Sci. USA. 2005;102:9661-9666.
Not in our library10.1073/pnas.0502529102
185.
Tegtmeyer N., Zabler D., Schmidt D., Hartig R., Brandt S., Backert S. Importance of EGF receptor, Her2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: Antagonistic effects of the vacuolating cytotoxin VacA. Cell. Microbiol. 2009;11:488-505.
Not in our library10.1111/j.1462-5822.2008.01269.x
186.
Akada J.K., Aoki H., Torigoe Y., Kitagawa T., Kurazono H., Hoshida H., Nishikawa J., Terai S., Matsuzaki M., Hirayama T., et al. Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells. Dis. Models Mech. 2010;3:605-617.
Not in our library10.1242/dmm.004879
187.
Tsugawa H., Suzuki H., Saya H., Hatakeyama M., Hirayama T., Hirata K., Nagano O., Matsuzaki J., Hibi T. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe. 2012;12:764-777.
Not in our library10.1016/j.chom.2012.10.014

Cited by papers we hold 4

Construction and preservation of a stable and highly expressed recombinant Helicobacter pylori vacuolating cytotoxin A with apoptotic activity · 2021
Not checked
Endomembrane Tension and Trafficking · 2021
Not checked
Genome-Scale Metabolic Modeling for Unraveling Molecular Mechanisms of High Threat Pathogens · 2020
Not checked
Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps · 2019
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