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The Helicobacter pylori vacuoloating cytotoxin: from cellular vacuolation to immunosuppressive activities

  • B. Gebert
  • W. Fisher
  • R. HaasEmail author
Chapter
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 152)

Abstract

Helicobacter pylori is a highly successful bacterial pathogen of humans, infecting the stomach of more than half of the world’s population. The H. pylori infection results in chronic gastritis, eventually followed by peptic ulceration and, more rarely, gastric cancer. H. pylori has developed a unique set of virulence factors, actively supporting its survival in the special ecological niche of the human stomach. Vacuolating cytotoxin (VacA) and cytotoxin-associated antigen A (CagA) are two major bacterial virulence factors involved in host cell modulation. VacA, so far mainly regarded as a cytotoxin of the gastric epithelial cell layer, now turns out to be a potent immunomodulatory toxin, targeting the adapted immune system. Thus, in addition to the well-known vacuolating activity, VacA has been reported to induce apoptosis in epithelial cells, to affect B lymphocyte antigen presentation, to inhibit the activation and proliferation of T lymphocytes, and to modulate the T cell-mediated cytokine response.

Keywords

Major Histocompatibility Complex Class Lipid Raft Gastric Epithelial Cell Cellular Vacuolation VacA Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Adrian M, Cover TL, Dubochet J, Heuser JE (2002) Multiple oligomeric states of the Helicobacter pylori vacuolating toxin demonstrated by cryo-electron microscopy. J Mol Biol 318:121–133PubMedGoogle Scholar
  2. Aebischer T, Lucas B, Koesling J, Bumann D, Meyer TF (2000) How CD4(+) T cells may eliminate extracellular gastric Helicobacter? J Biotechnol 83:77–84PubMedGoogle Scholar
  3. Allen LA, Schlesinger LS, Kang B (2000) Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med 191:115–128PubMedGoogle Scholar
  4. Amieva MR, Salama NR, Tompkins LS, Falkow S (2002) Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells. Cell Microbiol 4:677–690PubMedGoogle Scholar
  5. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S (2003) Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300:1430–1434PubMedGoogle Scholar
  6. Atherton JC, Cao P, Peek RM Jr, Tummuru MKR, Blaser MJ, Cover TL (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. J Biol Chem 270:17771–17777PubMedGoogle Scholar
  7. Azuma T, Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Dojo M, Yamazaki Y, Higashi H, Hatakeyama M (2003) The effects of cure of Helicobacter pylori infection on the signal transduction of gastric epithelial cells. Aliment Pharmacol Ther 18 [Suppl 1]:39–44Google Scholar
  8. Blanchard TG, Nedrud JG, Czinn SJ (1999) Local and systemic antibody responses in humans with Helicobacter pylori infection. Can J Gastroenterol 13:591–594PubMedGoogle Scholar
  9. Blaser MJ, Parsonnet J (1994) Parasitism by the “slow” bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest 94:4–8PubMedGoogle Scholar
  10. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D’Elios MM, Telford JL, et al (2003) The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 198:1887–1897PubMedGoogle Scholar
  11. Busiello I, Acquaviva R, Di Popolo A, Blanchard TG, Ricci V, Romano M, Zarrilli R (2004) Helicobacter pylori gamma-glutamyltranspeptidase upregulates COX-2 and EGF-related peptide expression in human gastric cells. Cell Microbiol 6:255–267PubMedGoogle Scholar
  12. Cover TL, Blaser MJ (1992) Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 267:10570–10575PubMedGoogle Scholar
  13. Cover TL, Tummuru MKR, Cao P, Thompson S, Blaser MJ (1994) Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem 269:10566–10573PubMedGoogle Scholar
  14. Cover TL, Hanson PI, Heuser JE (1997) Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J Cell Biol 138:759–769PubMedGoogle Scholar
  15. Cover TL, Krishna US, Israel DA, Peek RM Jr (2003) Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res 63:951–957PubMedGoogle Scholar
  16. Czajkowsky DM, Iwamoto H, Cover TL, Shao Z (1999) The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc Natl Acad Sci USA 96:2001–2006PubMedGoogle Scholar
  17. de Bernard M, Arico B, Papini E, Rizzuto R, Grandi G, Rappuoli R, Montecucco C (1997) Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Microbiol 26:665–674PubMedGoogle Scholar
  18. de Bernard M, Burroni D, Papini E, Rappuoli R, Telford J, Montecucco C (1998) Identification of the Helicobacter pylori VacA toxin domain active in the cell cytosol. Infect Immun 66:6014–6016PubMedGoogle Scholar
  19. de Bernard M, Moschioni M, Napolitani G, Rappuoli R, Montecucco C (2000) The VacA toxin of Helicobacter pylori identifies a new intermediate filament-interacting protein. EMBO J 19:48–56PubMedGoogle Scholar
  20. de Bernard M, Moschioni M, Habermann A, Griffiths G, Montecucco C (2002) Cell vacuolization induced by Helicobacter pylori VacA cytotoxin does not depend on late endosomal SNAREs. Cell Microbiol 4:11–18PubMedGoogle Scholar
  21. Ermak TH, Giannasca PJ, Nichols R, Myers GA, Nedrud J, Weltzin R, Lee CK, Kleanthous H, Monath TP (1998) Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses. J Exp Med 188:2277–2288PubMedGoogle Scholar
  22. Fan X, Gunasena H, Cheng Z, Espejo R, Crowe SE, Ernst PB, Reyes VE (2000) Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J Immunol 165:1918–1924PubMedGoogle Scholar
  23. Fan XJ, Chua A, Shahi CN, McDevitt J, Keeling PW, Kelleher D (1994) Gastric T lymphocyte responses to Helicobacter pylori in patients with H pylori colonisation. Gut 35:1379–1384PubMedGoogle Scholar
  24. Ferrari G, Langen H, Naito M, Pieters J (1999) A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 97:435–447PubMedGoogle Scholar
  25. Fischer W, Buhrdorf R, Gerland E, Haas R (2001) Outer membrane targeting of passenger proteins by the vacuolating cytotoxin autotransporter of Helicobacter pylori. Infect Immun 69:6769–6775PubMedGoogle Scholar
  26. Forsyth MH, Atherton JC, Blaser MJ, Cover TL (1998) Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun 66:3088–3094PubMedGoogle Scholar
  27. Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, Shintani T, Wada A, Aoyama N, et al (2003) Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 33:375–381PubMedGoogle Scholar
  28. Galmiche A, Rassow J, Doye A, Cagnol S, Chambard JC, Contamin S, de T, V, Just I, Ricci V, et al (2000) The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J 19:6361–6370PubMedGoogle Scholar
  29. Gauthier NC, Ricci V, Gounon P, Doye A, Tauc M, Poujeol P, Boquet P (2004) 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 279:9481–9489PubMedGoogle Scholar
  30. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301:1099–1102PubMedGoogle Scholar
  31. Hennig EE, Butruk E, Ostrowski J (2001) RACK1 protein interacts with Helicobacter pylori VacA cytotoxin: the yeast two-hybrid approach. Biochem Biophys Res Commun 289:103–110PubMedGoogle Scholar
  32. Hotchin NA, Cover TL, Akhtar N (2000) Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase. J Biol Chem 275:14009–14012PubMedGoogle Scholar
  33. Ikonomov OC, Sbrissa D, Yoshimori T, Cover TL, Shisheva A (2002) PIKfyve Kinase and SKD1 AAA ATPase define distinct endocytic compartments. Only PIKfyve expression inhibits the cell-vacuolating activity of Helicobacter pylori VacA toxin. J Biol Chem 277:46785–46790PubMedGoogle Scholar
  34. Ilver D, Barone S, Mercati D, Lupetti P, Telford JL (2004) Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism. Cell Microbiol 6:167–174PubMedGoogle Scholar
  35. Iwamoto H, Czajkowsky DM, Cover TL, Szabo G, Shao Z (1999) VacA from Helicobacter pylori: a hexameric chloride channel. FEBS LETT 450:101–104PubMedGoogle Scholar
  36. Jüttner S, Cramer T, Wessler S, Walduck A, Gao F, Schmitz F, Wunder C, Weber M, Fischer SM, et al (2003) Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors. Cell Microbiol 5:821–834PubMedGoogle Scholar
  37. Knipp U, Birkholz S, Kaup W, Mahnke K, Opferkuch W (1994) Suppression of human mononuclear cell response by Helicobacter pylori: effects on isolated monocytes and lymphocytes. FEMS Immunol Med Microbiol 8:157–166PubMedGoogle Scholar
  38. Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J (2001) Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun 69: 5080–5087PubMedGoogle Scholar
  39. Kuo CH, Wang WC (2003) Binding and internalization of Helicobacter pylori VacA via cellular lipid rafts in epithelial cells. Biochem Biophys Res Commun 303:640–644PubMedGoogle Scholar
  40. Kwok T, Backert S, Schwarz H, Berger J, Meyer TF (2002) Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism. Infect Immun 70:2108–2120PubMedGoogle Scholar
  41. Letley DP, Atherton JC (2000) Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J Bacteriol 182:3278–3280PubMedGoogle Scholar
  42. Letley DP, Rhead JL, Twells RJ, Dove B, Atherton JC (2003) Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J Biol Chem 278:26734–26741PubMedGoogle Scholar
  43. Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR (1988) Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol 26:93–99PubMedCrossRefGoogle Scholar
  44. Li Y, Wandinger-Ness A, Goldenring JR, Cover TL (2004) Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin. Mol Biol Cell 15:1946–1959PubMedGoogle Scholar
  45. Lucas B, Bumann D, Walduck A, Koesling J, Develioglu L, Meyer TF, Aebischer T (2001) Adoptive transfer of CD4(+) T cells specific for subunit A of Helicobacter pylori urease reduces H. pylori stomach colonization in mice in the absence of interleukin-4 (IL-4)/IL-13 receptor signaling. Infect Immun 69:1714–1721PubMedGoogle Scholar
  46. Lupetti P, Heuser JE, Manetti R, Massari P, Lanzavecchia S, Bellon, PL, Dallai R, Rappuoli R, et al (1996) Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J Cell Biol 133: 801–807PubMedGoogle Scholar
  47. Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ, et al (1996) Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56:3238–3243PubMedGoogle Scholar
  48. Marchetti M, Arico B, Burroni D, Figura N, Rappuoli R, Ghiara P (1995) Development of a mouse model of Helicobacter pylori infection that mimics human disease. Science 267:1655–1658PubMedGoogle Scholar
  49. McClain MS, Cao P, Cover TL (2001a) Amino-terminal hydrophobic region of Helicobacter pylori vacuolating cytotoxin (VacA) mediates transmembrane protein dimerization. Infect Immun 69:1181–1184PubMedGoogle Scholar
  50. McClain MS, Cao P, Iwamoto H, Vinion-Dubiel AD, Szabo G, Shao Z, Cover TL (2001b) 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 183:6499–6508PubMedGoogle Scholar
  51. McClain MS, Iwamoto H, Cao P, Vinion-Dubiel AD, Li Y, Szabo G, Shao Z, Cover TL (2003) Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J Biol ChemGoogle Scholar
  52. Molinari M, Galli C, Norais N, Telford JL, Rappuoli R, Luzio JP, Montecucco C (1997) Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. J Biol Chem 272:25339–25344PubMedGoogle Scholar
  53. Molinari M, Galli C, de Bernard M, Norais N, Ruysschaert JM, Rappuoli R, Montecucco C (1998a) The acid activation of Helicobacter pylori toxin VacA: structural and membrane binding studies. Biochem Biophys Res Commun 248:334–340PubMedGoogle Scholar
  54. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C (1998b) Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med 187:135–140PubMedGoogle Scholar
  55. Moll G, Papini E, Colonna R, Burroni D, Telford J, Rappuoli R, Montecucco C (1995) Lipid interaction of the 37-kDa and 58-kDa fragments of the Helicobacter pylori cytotoxin. Eur J Biochem 234:947–952PubMedGoogle Scholar
  56. Montecucco C, de Bernard M (2003) Immunosuppressive and proinflammatory activities of the VacA toxin of Helicobacter pylori. J Exp Med 198:1767–1771PubMedGoogle Scholar
  57. Moss SF, Calam J, Agarwal B, Wang S, Holt PR (1996) Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 38:498–501PubMedGoogle Scholar
  58. Nakayama M, Kimura M, Wada A, Yahiro K, Ogushi K, Niidome T, Fujikawa A, Shirasaka D, Aoyama N, et al (2004) Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells. J Biol Chem 279:7024–7028PubMedGoogle Scholar
  59. Neu B, Randlkofer P, Neuhofer M, Voland P, Mayerhofer A, Gerhard M, Schepp W, Prinz C (2002) Helicobacter pylori induces apoptosis of rat gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 283: G309–G318PubMedGoogle Scholar
  60. Nguyen VQ, Caprioli RM, Cover TL (2001) Carboxy-terminal proteolytic processing of Helicobacter pylori vacuolating toxin. Infect Immun 69:543–546PubMedGoogle Scholar
  61. Odenbreit S, Püls J, Sedlmaier B, Gerland E, Fischer W, Haas R (2000) Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287:1497–1500PubMedGoogle Scholar
  62. Odenbreit S, Gebert B, Püls J, Fischer W, Haas R (2001) Interaction of Helicobacter pylori with professional phagocytes: role of the cag pathogenicity island and translocation, phosphorylation and specific processing of CagA. Cell Microbiol 3:21–31PubMedGoogle Scholar
  63. Ogura K, Maeda S, Nakao M, Watanabe T, Tada M, Kyutoku T, Yoshida H, Shiratori Y, Omata M (2000) Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med 192: 1601–1610PubMedGoogle Scholar
  64. Pagliaccia C, Wang XM, Tardy F, Telford JL, Ruysschaert JM, Cabiaux V (2000) Structure and interaction of VacA of Helicobacter pylori with a lipid membrane. Eur J Biochem 267:104–109PubMedGoogle Scholar
  65. Papini E, Bugnoli M, de Bernard M, Figura N, Rappuoli R, Montecucco C (1993) Bafilomycin A1 inhibits Helicobacter pylori induced vacuolization of HeLa cells. Mol Microbiol 7:323–327PubMedGoogle Scholar
  66. Papini E, Satin B, Bucci C, Debernard M, Telford JL, Manetti R, Rappuoli R, Zerial M, Montecucco C (1997) The small GTP-binding protein Rab7 is essential for cellular vacuolation induced by Helicobacter pylori cytotoxin. EMBO J 16:15–24PubMedGoogle Scholar
  67. Papini E, Satin B, Norais N, de Bernard M, Telford JL, Rappuoli R, Montecucco C (1998) Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest 102:813–820PubMedGoogle Scholar
  68. Patel HK, Willhite DC, Patel RM, Ye D, Williams CL, Torres EM, Marty KB, MacDonald RA, Blanke SR (2002) Plasma membrane cholesterol modulates cellular vacuolation induced by the Helicobacter pylori vacuolating cytotoxin. Infect Immun 70:4112–4123PubMedGoogle Scholar
  69. Peek RM Jr, Blaser MJ, Mays DJ, Forsyth MH, Cover TL, Song SY, Krishna U, Pietenpol JA (1999) Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res 59:6124–6131PubMedGoogle Scholar
  70. Pelicic V, Reyrat JM, Sartori L, Pagliaccia C, Rappuoli R, Telford JL, Montecucco C, Papini E (1999) Helicobacter pylori VacA cytotoxin associated with the bacteria increases epithelial permeability independently of its vacuolating activity. Microbiology 145 (Pt 8):2043–2050PubMedCrossRefGoogle Scholar
  71. Petersen AM, Sorensen K, Blom J, Krogfelt KA (2001) Reduced intracellular survival of Helicobacter pylori vacA mutants in comparison with their wild-types indicates the role of VacA in pathogenesis. FEMS Immunol Med Microbiol 30:103–108PubMedGoogle Scholar
  72. Ramarao N, Gray-Owen SD, Backert S, Meyer TF (2000) Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol 37:1389–1404PubMedGoogle Scholar
  73. Ricci V, Galmiche A, Doye A, Necchi V, Solcia E, Boquet P (2000) 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. Mol Biol Cell 11:3897–3909PubMedGoogle Scholar
  74. Rittig MG, Shaw B, Letley DP, Thomas RJ, Argent RH, Atherton JC (2003) Helicobacter pylori-induced homotypic phagosome fusion in human monocytes is independent of the bacterial vacA and cag status. Cell Microbiol 5:887–899PubMedGoogle Scholar
  75. Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, Krammer PH, Galle PR, Stremmel W (1998) Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest 102:1506–1514PubMedGoogle Scholar
  76. Salama NR, Otto G, Tompkins L, Falkow S (2001) Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69:730–736PubMedGoogle Scholar
  77. Satin B, Norais N, Telford J, Rappuoli R, Murgia M, Montecucco C, Papini E (1997) Effect of Helicobacter pylori vacuolating toxin on maturation and extracellular release of procathepsin D and on epidermal growth factor degradation. J Biol Chem 272:25022–25028PubMedGoogle Scholar
  78. Schmitt W, Haas R (1994) Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: structural similarities with the IgA protease type of exported protein. Mol Microbiol 12:307–319PubMedGoogle Scholar
  79. Schraw W, Li Y, McClain MS, van der Goot FG, Cover TL (2002) Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J Biol Chem 277:34642–34650PubMedGoogle Scholar
  80. Seto K, Hayashi-Kuwabara Y, Yoneta T, Suda H, Tamaki H (1998) Vacuolation induced by cytotoxin from Helicobacter pylori is mediated by the EGF receptor in HeLa cells. FEBS Lett 431:347–350PubMedGoogle Scholar
  81. Shirai M, Arichi T, Nakazawa T, Berzofsky JA (1998) Persistent infection by Helicobacter pylori down-modulates virus-specific CD8+ cytotoxic T cell response and prolongs viral infection. J Infect Dis 177:72–80PubMedGoogle Scholar
  82. Supajatura V, Ushio H, Wada A, Yahiro K, Okumura K, Ogawa H, Hirayama T, Ra C (2002) Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J Immunol 168:2603–2607PubMedGoogle Scholar
  83. Suzuki J, Ohnsihi H, Shibata H, Wada A, Hirayama T, Iiri T, Ueda N, Kanamaru C, Tsuchida T, et al (2001) Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA. J Clin Invest 107:363–370PubMedCrossRefGoogle Scholar
  84. Suzuki J, Ohnishi H, Wada A, Hirayama T, Ohno H, Ueda N, Yasuda H, Iiri T, Wada Y, et al (2003) Involvement of syntaxin 7 in human gastric epithelial cell vacuolation induced by the Helicobacter pylori-produced cytotoxin VacA. J Biol Chem 278:25585–25590PubMedGoogle Scholar
  85. Suzuki K, Kokai Y, Sawada N, Takakuwa R, Kuwahara K, Isogai E, Isogai H, Mori M (2002) SS1 Helicobacter pylori disrupts the paracellular barrier of the gastric mucosa and leads to neutrophilic gastritis in mice. Virchows Arch 440:318–324PubMedGoogle Scholar
  86. Szabo I, Brutsche S, Tombola F, Moschioni M, Satin B, Telford JL, Rappuoli R, Montecucco C, Papini E, et al (1999) 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 18:5517–5527PubMedGoogle Scholar
  87. Telford JL, Ghiara P, Dell’Orco M, Commanducci M, Burroni D, Bugnoli M, Tecce MF, Censini S, Covacci A, et al (1994) Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med 179:1653–1658PubMedGoogle Scholar
  88. Telford JL, Covacci A, Rappuoli R, Chiara P (1997) Immunobiology of Helicobacter pylori infection. Curr Opin Immunol 9:498–503PubMedGoogle Scholar
  89. Terres AM, Pajares JM, Hopkins AM, Murphy A, Moran A, Baird AW, Kelleher D (1998) Helicobacter pylori disrupts epithelial barrier function in a process inhibited by protein kinase C activators. Infect Immun 66: 2943–2950PubMedGoogle Scholar
  90. Tombola F, Oregna F, Brutsche S, Szabo I, Del GG, Rappuoli R, Montecucco C, Papini E, Zoratti M (1999) Inhibition of the vacuolating and anion channel activities of the VacA toxin of Helicobacter pylori. FEBS Lett 460:221–225PubMedGoogle Scholar
  91. Tombola F, Morbiato L, Del Giudice G, Rappuoli R, Zoratti M, Papini E (2001) The Helicobacter pylori VacA toxin is a urea permease that promotes urea diffusion across epithelia. J Clin Invest 108:929–937PubMedGoogle Scholar
  92. Torres VJ, McClain MS, Cover TL (2004) Interactions between p-33 and p-55 domains of the Helicobacter pylori vacuolating cytotoxin (VacA). J Biol Chem 279:2324–2331PubMedGoogle Scholar
  93. Tsujimoto Y, Shimizu S (2002) The voltage-dependent anion channel: an essential player in apoptosis. Biochimie 84:187–193PubMedGoogle Scholar
  94. Vinion-Dubiel AD, McClain MS, Czajkowsky DM, Iwamoto H, Ye D, Cao P, Schraw W, Szabo G, Blanke SR, et al (1999) A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J Biol Chem 274:37736–37742PubMedGoogle Scholar
  95. Wagner S, Beil W, Westermann J, Logan RP, Bock CT, Trautwein C, Bleck JS, Manns MP (1997) Regulation of gastric epithelial cell growth by Helicobacter pylori: offdence for a major role of apoptosis. Gastroenterology 113: 1836–1847PubMedGoogle Scholar
  96. Wang J, Brooks EG, Bamford KB, Denning TL, Pappo J, Ernst PB (2001) Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J Immunol 167:926–934PubMedGoogle Scholar
  97. Willhite DC, Blanke SR (2004) Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell Microbiol 6:143–154PubMedGoogle Scholar
  98. Willhite DC, Ye D, Blanke SR (2002) Fluorescence resonance energy transfer microscopy of the Helicobacter pylori vacuolating cytotoxin within mammalian cells. Infect Immun 70:3824–3832PubMedGoogle Scholar
  99. Willhite DC, Cover TL, Blanke SR (2003) 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 278:48204–48209PubMedGoogle Scholar
  100. Yahiro K, Niidome T, Kimura M, Hatakeyama T, Aoyagi H, Kurazono H, Imagawa K, Wada A, Moss J, et al (1999) 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 274:36693–36699PubMedGoogle Scholar
  101. Yahiro K, Wada A, Nakayama M, Kimura T, Ogushi KI, Niidome T, Aoyagi H, Yoshino KI, Yonezawa K, et al (2003) Protein-tyrosine phosphatase a, RPTPa, is a Helicobacter pylori VacA receptor. J Biol Chem 278: 19183–19189PubMedGoogle Scholar
  102. Ye D, Blanke SR (2000) Mutational analysis of the Helicobacter pylori vacuolating toxin amino terminus: identification of amino acids essential for cellular vacuolation. Infect Immun 68:4354–4357PubMedGoogle Scholar
  103. Ye D, Blanke SR (2002) Functional complementation reveals the importance of intermolecular monomer interactions for Helicobacter pylori VacA vacuolating activity. Mol Microbiol 43:1243–1253PubMedGoogle Scholar
  104. Ye D, Willhite DC, Blanke SR (1999) Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J Biol Chem 274:9277–9282PubMedGoogle Scholar
  105. Zheng PY, Jones NL (2003) Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol 5:25–40PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Max von Pettenkofer Institut für Hygiene und Medizinische MikrobiologieMünchenGermany

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