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Gene Review

vacA  -  vacuolating cytotoxin

Helicobacter pylori J99

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Disease relevance of vacA


High impact information on vacA


Chemical compound and disease context of vacA


Biological context of vacA

  • Results: Turkish strains examined predominantly possessed the vacA s1,m2 (48.4%) and s1,m1 (40.7%) genotypes [11].
  • However, with the exception of the cag and vacA status, there is no universal consensus regarding the importance of the other virulence factors [12].
  • IMPLICATIONS: Increased cell proliferation in the absence of a corresponding increase in apoptosis may explain the heightened risk for gastric carcinoma that is associated with infection by cagA+ vacA s1a strains of H. pylori [13].
  • METHODS: Three of 5 strains of H. pylori induced platelet aggregation with a lag time of 5 +/- 2 minutes that was independent of the toxigenic genes cagA and vacA [14].
  • The presence of cagA (cytotoxin-associated gene A) was closely associated with the presence of vacA signal sequence type s1 (p < 0.001) [15].

Anatomical context of vacA

  • RESULTS: Gastric epithelial cell turnover was no different after infection with the wild-type, cagA(-), or vacA(-) strains [16].
  • RESULTS: vacA signal sequence type s1a strains were associated with greater antral mucosal neutrophil and lymphocyte infiltration than s1b or s2 strains (P < 0.05). vacA midregion type m1 strains were associated with greater gastric epithelial damage than m2 strains (P < 0.05) [17].
  • Two alleles, m1 and m2, of the mid-region of the vacA gene have been described, and the m2 cytotoxin always has been described as inactive in the in vitro HeLa cell assay [18].
  • The mid region of s2/m2 vacA does not cause the non-vacuolating phenotype, but if VacA is unblocked, it confers cell line specificity of vacuolation as in natural s1/m2 strains [19].
  • Approximately 50% of Helicobacter pylori strains produce a cytotoxin, encoded by vacA, that induces vacuolation of eukaryotic cells [15].

Associations of vacA with chemical compounds

  • METHODS: Mongolian gerbils were challenged with H. pylori wild-type or isogenic cagA(-) and vacA(-) mutants, and apoptotic and proliferating cells were identified by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and proliferating cell nuclear antigen immunohistochemistry, respectively [16].
  • We then introduced the six alanine substitution mutations into the vacA chromosomal gene of H. pylori and analyzed the properties of purified mutant VacA proteins [20].
  • Although there was no significant association between 23S rDNA mutations and the vacA and cagA status, clarithromycin-susceptible strains more often contained mixed vacA genotypes, indicating the presence of multiple H. pylori strains [21].
  • We have used this cassette to perform a site-directed modification of two histidine residues encoded by the vacA gene in a two-step procedure [7].
  • Consequently, the insertion of a kanamycin resistance marker in the vacA gene produced an isogenic mutant lacking the cytotoxic activity [22].

Other interactions of vacA

  • The vacA s1a genotype was detected in 66.7, 96.4, and 87.9% of isolates from patients with NUD, DU, and GC, respectively, and its presence was significantly associated with that of DU (p = .004), GC (p = .043), and cagA gene (p = .021) [11].
  • The presence of vacA alleles, cagA, cagE, iceA, and babA2 genotypes were determined by polymerase chain reaction (PCR) [11].
  • Sequences of three gene fragments (flaA, flaB, and vacA) from Helicobacter pylori strains isolated from patients in Germany, Canada, and South Africa were analyzed for diversity and for linkage equilibrium by using the Homoplasy Test and compatibility matrices [23].
  • The presence of a 63- to 64-bp insertion in the cysS-vacA intergenic region was unrelated to the vacA genotype of the strains [24].
  • Gastric tissues obtained from infected and uninfected cats were evaluated for H. pylori ureB, cagPAI, vacA allele, and oipA and colonization density (urease, histology, and real-time PCR) [25].

Analytical, diagnostic and therapeutic context of vacA

  • We examined the role of two genes, vacA and cagE, in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model [3].
  • Sequence analysis of a 1541-bp region of polymerase chain reaction-amplified vacA from tox- strain 87-203 indicated 64.8% amino acid identity with the corresponding region from tox+ strain 60190 [26].
  • AIM: To investigate the relationship between peptic ulcer and expression of Lewis (Le) antigens as well as cagA, iceA, and vacA in H pylori isolates in Singapore. METHODS: Expression of Le antigens in H pylori isolates obtained from patients with dyspepsia was measured by enzyme linked immunosorbent assay [27].
  • Isogenic H. pylori mutants in vacA generated by transposon shuttle mutagenesis produce neither the VacA antigen nor a vacuolating activity in a cell culture model [28].
  • AIMS: To determine the relation between the vacA and the cagA status of H pylori, clinical disease, and treatment outcome [29].


  1. Distribution of vacA alleles and cagA status of Helicobacter pylori in peptic ulcer disease and non-ulcer dyspepsia. Aydin, F., Kaklikkaya, N., Ozgur, O., Cubukcu, K., Kilic, A.O., Tosun, I., Erturk, M. Clin. Microbiol. Infect. (2004) [Pubmed]
  2. Helicobacter pylori BabA expression, gastric mucosal injury, and clinical outcome. Fujimoto, S., Olaniyi Ojo, O., Arnqvist, A., Wu, J.Y., Odenbreit, S., Haas, R., Graham, D.Y., Yamaoka, Y. Clin. Gastroenterol. Hepatol. (2007) [Pubmed]
  3. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. Ogura, K., Maeda, S., Nakao, M., Watanabe, T., Tada, M., Kyutoku, T., Yoshida, H., Shiratori, Y., Omata, M. J. Exp. Med. (2000) [Pubmed]
  4. Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Fujikawa, A., Shirasaka, D., Yamamoto, S., Ota, H., Yahiro, K., Fukada, M., Shintani, T., Wada, A., Aoyama, N., Hirayama, T., Fukamachi, H., Noda, M. Nat. Genet. (2003) [Pubmed]
  5. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. Figueiredo, C., Machado, J.C., Pharoah, P., Seruca, R., Sousa, S., Carvalho, R., Capelinha, A.F., Quint, W., Caldas, C., van Doorn, L.J., Carneiro, F., Sobrinho-Simões, M. J. Natl. Cancer Inst. (2002) [Pubmed]
  6. Geographic distribution of vacA allelic types of Helicobacter pylori. Van Doorn, L.J., Figueiredo, C., Mégraud, F., Pena, S., Midolo, P., Queiroz, D.M., Carneiro, F., Vanderborght, B., Pegado, M.D., Sanna, R., De Boer, W., Schneeberger, P.M., Correa, P., Ng, E.K., Atherton, J., Blaser, M.J., Quint, W.G. Gastroenterology (1999) [Pubmed]
  7. Introduction of unmarked mutations in the Helicobacter pylori vacA gene with a sucrose sensitivity marker. Copass, M., Grandi, G., Rappuoli, R. Infect. Immun. (1997) [Pubmed]
  8. Evaluation of clarithromycin resistance and cagA and vacA genotyping of Helicobacter pylori strains from the west of Ireland using line probe assays. Ryan, K.A., van Doorn, L.J., Moran, A.P., Glennon, M., Smith, T., Maher, M. J. Clin. Microbiol. (2001) [Pubmed]
  9. Helicobacter pylori Vacuolating Cytotoxin Induces Activation of the Proapoptotic Proteins Bax and Bak, Leading to Cytochrome c Release and Cell Death, Independent of Vacuolation. Yamasaki, E., Wada, A., Kumatori, A., Nakagawa, I., Funao, J., Nakayama, M., Hisatsune, J., Kimura, M., Moss, J., Hirayama, T. J. Biol. Chem. (2006) [Pubmed]
  10. Glycosylphosphatidylinositol-anchored proteins and actin cytoskeleton modulate chloride transport by channels formed by the Helicobacter pylori vacuolating cytotoxin VacA in HeLa cells. Gauthier, N.C., Ricci, V., Gounon, P., Doye, A., Tauc, M., Poujeol, P., Boquet, P. J. Biol. Chem. (2004) [Pubmed]
  11. Prevalence of Helicobacter pylori vacA, cagA, cagE, iceA, babA2 Genotypes and Correlation with Clinical Outcome in Turkish Patients with Dyspepsia. Erzin, Y., Koksal, V., Altun, S., Dobrucali, A., Aslan, M., Erdamar, S., Dirican, A., Kocazeybek, B. Helicobacter (2006) [Pubmed]
  12. Prevalence of Helicobacter pylori cagA, iceA and babA2 alleles in Brazilian patients with upper gastrointestinal diseases. Gatti, L.L., Módena, J.L., Payão, S.L., Smith, M.d.e. .A., Fukuhara, Y., Módena, J.L., de Oliveira, R.B., Brocchi, M. Acta Trop. (2006) [Pubmed]
  13. Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. Peek, R.M., Moss, S.F., Tham, K.T., Pérez-Pérez, G.I., Wang, S., Miller, G.G., Atherton, J.C., Holt, P.R., Blaser, M.J. J. Natl. Cancer Inst. (1997) [Pubmed]
  14. Helicobacter pylori binds von Willebrand factor and interacts with GPIb to induce platelet aggregation. Byrne, M.F., Kerrigan, S.W., Corcoran, P.A., Atherton, J.C., Murray, F.E., Fitzgerald, D.J., Cox, D.M. Gastroenterology (2003) [Pubmed]
  15. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. Atherton, J.C., Cao, P., Peek, R.M., Tummuru, M.K., Blaser, M.J., Cover, T.L. J. Biol. Chem. (1995) [Pubmed]
  16. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Peek, R.M., Wirth, H.P., Moss, S.F., Yang, M., Abdalla, A.M., Tham, K.T., Zhang, T., Tang, L.H., Modlin, I.M., Blaser, M.J. Gastroenterology (2000) [Pubmed]
  17. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Atherton, J.C., Peek, R.M., Tham, K.T., Cover, T.L., Blaser, M.J. Gastroenterology (1997) [Pubmed]
  18. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Pagliaccia, C., de Bernard, M., Lupetti, P., Ji, X., Burroni, D., Cover, T.L., Papini, E., Rappuoli, R., Telford, J.L., Reyrat, J.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  19. Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. Letley, D.P., Rhead, J.L., Twells, R.J., Dove, B., Atherton, J.C. J. Biol. Chem. (2003) [Pubmed]
  20. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. McClain, M.S., Iwamoto, H., Cao, P., Vinion-Dubiel, A.D., Li, Y., Szabo, G., Shao, Z., Cover, T.L. J. Biol. Chem. (2003) [Pubmed]
  21. Accurate prediction of macrolide resistance in Helicobacter pylori by a PCR line probe assay for detection of mutations in the 23S rRNA gene: multicenter validation study. van Doorn, L.J., Glupczynski, Y., Kusters, J.G., Mégraud, F., Midolo, P., Maggi-Solcà, N., Queiroz, D.M., Nouhan, N., Stet, E., Quint, W.G. Antimicrob. Agents Chemother. (2001) [Pubmed]
  22. Pathological significance and molecular characterization of the vacuolating toxin gene of Helicobacter pylori. Phadnis, S.H., Ilver, D., Janzon, L., Normark, S., Westblom, T.U. Infect. Immun. (1994) [Pubmed]
  23. Free recombination within Helicobacter pylori. Suerbaum, S., Smith, J.M., Bapumia, K., Morelli, G., Smith, N.H., Kunstmann, E., Dyrek, I., Achtman, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  24. Analysis of genetic diversity in cytotoxin-producing and non-cytotoxin-producing Helicobacter pylori strains. Garner, J.A., Cover, T.L. J. Infect. Dis. (1995) [Pubmed]
  25. Quantitative evaluation of inflammatory and immune responses in the early stages of chronic Helicobacter pylori infection. Straubinger, R.K., Greiter, A., McDonough, S.P., Gerold, A., Scanziani, E., Soldati, S., Dailidiene, D., Dailide, G., Berg, D.E., Simpson, K.W. Infect. Immun. (2003) [Pubmed]
  26. Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. Cover, T.L., Tummuru, M.K., Cao, P., Thompson, S.A., Blaser, M.J. J. Biol. Chem. (1994) [Pubmed]
  27. Association of peptic ulcer with increased expression of Lewis antigens but not cagA, iceA, and vacA in Helicobacter pylori isolates in an Asian population. Zheng, P.Y., Hua, J., Yeoh, K.G., Ho, B. Gut (2000) [Pubmed]
  28. Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: structural similarities with the IgA protease type of exported protein. Schmitt, W., Haas, R. Mol. Microbiol. (1994) [Pubmed]
  29. Importance of Helicobacter pylori cagA and vacA status for the efficacy of antibiotic treatment. van Doorn, L.J., Schneeberger, P.M., Nouhan, N., Plaisier, A.P., Quint, W.G., de Boer, W.A. Gut (2000) [Pubmed]
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