Advertisement

Activity and Functional Importance of Helicobacter pylori Virulence Factors

  • Dionyssios SgourasEmail author
  • Nicole Tegtmeyer
  • Silja Wessler
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1149)

Abstract

Helicobacter pylori is a very successful Gram-negative pathogen colonizing the stomach of humans worldwide. Infections with this bacterium can generate pathologies ranging from chronic gastritis and peptic ulceration to gastric cancer. The best characterized H. pylori virulence factors that cause direct cell damage include an effector protein encoded by the cytotoxin-associated gene A (CagA), a type IV secretion system (T4SS) encoded in the cag-pathogenicity island (cag PAI), vacuolating cytotoxin A (VacA), γ-glutamyl transpeptidase (GGT), high temperature requirement A (HtrA, a serine protease) and cholesterol glycosyl-transferase (CGT). Since these H. pylori factors are either surface-exposed, secreted or translocated, they can directly interact with host cell molecules and are able to hijack cellular functions. Studies on these bacterial factors have progressed substantially in recent years. Here, we review the current status in the characterization of signaling cascades by these factors in vivo and in vitro, which comprise the disruption of cell-to-cell junctions, induction of membrane rearrangements, cytoskeletal dynamics, proliferative, pro-inflammatory, as well as, pro-apoptotic and anti-apoptotic responses or immune evasion. The impact of these signal transduction modules in the pathogenesis of H. pylori infections is discussed.

Keywords

E-cadherin Protease CagA HtrA serine protease VacA UreA Adherens junction Tight junction Epithelial barrier Type IV secretion T4SS 

References

  1. 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(1):115–128CrossRefPubMedPubMedCentralGoogle Scholar
  2. Amieva MR, El-Omar EM (2008) Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology 134(1):306–323.  https://doi.org/10.1053/j.gastro.2007.11.009 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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(5624):1430–1434.  https://doi.org/10.1126/science.1081919 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC (2004) Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology 127(2):514–523CrossRefPubMedPubMedCentralGoogle Scholar
  5. Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, Tsubokawa M, Tohyama Y, Maeda S, Omata M, Suzuki T, Sasakawa C (2000) Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 191(4):593–602CrossRefPubMedPubMedCentralGoogle Scholar
  6. Atherton JC, Blaser MJ (2009) Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest 119(9):2475–2487.  https://doi.org/10.1172/JCI38605 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270(30):17771–17777CrossRefPubMedPubMedCentralGoogle Scholar
  8. Backert S, Blaser MJ (2016) The role of CagA in the gastric biology of Helicobacter pylori. Cancer Res 76(14):4028–4031.  https://doi.org/10.1158/0008-5472.CAN-16-1680 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Backert S, Tegtmeyer N (2017) Type IV secretion and signal transduction of Helicobacter pylori CagA through interactions with host cell receptors. Toxins (Basel) 9(4).  https://doi.org/10.3390/toxins9040115
  10. Backert S, Ziska E, Brinkmann V, Zimny-Arndt U, Fauconnier A, Jungblut PR, Naumann M, Meyer TF (2000) Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol 2(2):155–164CrossRefPubMedPubMedCentralGoogle Scholar
  11. Backert S, Tegtmeyer N, Selbach M (2010) The versatility of Helicobacter pylori CagA effector protein functions: the master key hypothesis. Helicobacter 15(3):163–176.  https://doi.org/10.1111/j.1523-5378.2010.00759.x CrossRefPubMedPubMedCentralGoogle Scholar
  12. Backert S, Clyne M, Tegtmeyer N (2011) Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal CCS 9:28.  https://doi.org/10.1186/1478-811X-9-28 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Backert S, Tegtmeyer N, Fischer W (2015) Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol 10(6):955–965.  https://doi.org/10.2217/fmb.15.32 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Barden S, Lange S, Tegtmeyer N, Conradi J, Sewald N, Backert S, Niemann HH (2013) A helical RGD motif promoting cell adhesion: crystal structures of the Helicobacter pylori type IV secretion system pilus protein CagL. Structure 21(11):1931–1941.  https://doi.org/10.1016/j.str.2013.08.018 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bauer B, Pang E, Holland C, Kessler M, Bartfeld S, Meyer TF (2012) The Helicobacter pylori virulence effector CagA abrogates human beta-defensin 3 expression via inactivation of EGFR signaling. Cell Host Microbe 11(6):576–586.  https://doi.org/10.1016/j.chom.2012.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Beigier-Bompadre M, Moos V, Belogolova E, Allers K, Schneider T, Churin Y, Ignatius R, Meyer TF, Aebischer T (2011) Modulation of the CD4+ T-cell response by Helicobacter pylori depends on known virulence factors and bacterial cholesterol and cholesterol alpha-glucoside content. J Infect Dis 204(9):1339–1348.  https://doi.org/10.1093/infdis/jir547 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Berge C, Terradot L (2017) Structural insights into Helicobacter pylori cag protein interactions with host cell factors. Curr Top Microbiol Immunol 400:129–147.  https://doi.org/10.1007/978-3-319-50520-6_6 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A (1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55(10):2111–2115PubMedPubMedCentralGoogle Scholar
  19. Boanca G, Sand A, Barycki JJ (2006) Uncoupling the enzymatic and autoprocessing activities of Helicobacter pylori gamma-glutamyltranspeptidase. J Biol Chem 281(28):19029–19037.  https://doi.org/10.1074/jbc.M603381200 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Bonsor DA, Zhao Q, Schmidinger B, Weiss E, Wang J, Deredge D, Beadenkopf R, Dow B, Fischer W, Beckett D, Wintrode PL, Haas R, Sundberg EJ (2018) The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. EMBO J  https://doi.org/10.15252/embj.201798664
  21. Bumann D, Aksu S, Wendland M, Janek K, Zimny-Arndt U, Sabarth N, Meyer TF, Jungblut PR (2002) Proteome analysis of secreted proteins of the gastric pathogen Helicobacter pylori. Infect Immun 70(7):3396–3403CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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(3):255–267CrossRefPubMedPubMedCentralGoogle Scholar
  23. Buti L, Spooner E, Van der Veen AG, Rappuoli R, Covacci A, Ploegh HL (2011) Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc Natl Acad Sci U S A 108(22):9238–9243.  https://doi.org/10.1073/pnas.1106200108 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Caputo R, Tuccillo C, Manzo BA, Zarrilli R, Tortora G, Blanco Cdel V, Ricci V, Ciardiello F, Romano M (2003) 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 9(6):2015–2021PubMedPubMedCentralGoogle Scholar
  25. Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J, Pinheiro H, Leite M, Melo S, Oliveira P, Simoes-Correia J, Oliveira MJ, Carneiro F, Figueiredo C, Paredes J, Oliveira C, Seruca R (2012) E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS Lett 586(18):2981–2989.  https://doi.org/10.1016/j.febslet.2012.07.045 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Chevalier C, Thiberge JM, Ferrero RL, Labigne A (1999) Essential role of Helicobacter pylori gamma-glutamyltranspeptidase for the colonization of the gastric mucosa of mice. Mol Microbiol 31(5):1359–1372CrossRefPubMedPubMedCentralGoogle Scholar
  27. Chey WD, Leontiadis GI, Howden CW, Moss SF (2017) ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol 112(2):212–239.  https://doi.org/10.1038/ajg.2016.563 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M (2003) Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 161(2):249–255.  https://doi.org/10.1083/jcb.200208039 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Covacci A, Rappuoli R (2000) Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med 191(4):587–592CrossRefPubMedPubMedCentralGoogle Scholar
  30. Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N et al (1993) Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci U S A 90(12):5791–5795CrossRefPubMedPubMedCentralGoogle Scholar
  31. Cover TL (2016) Helicobacter pylori diversity and gastric cancer risk. mBio 7(1):e01869–e01815.  https://doi.org/10.1128/mBio.01869-15
  32. Cover TL, Blaser MJ (1992) Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 267(15):10570–10575PubMedPubMedCentralGoogle Scholar
  33. Cover TL, Tummuru MK, Cao P, Thompson SA, Blaser MJ (1994) Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem 269(14):10566–10573PubMedPubMedCentralGoogle Scholar
  34. 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 U S A 96(5):2001–2006CrossRefPubMedPubMedCentralGoogle Scholar
  35. de Bernard M, Papini E, de Filippis V, Gottardi E, Telford J, Manetti R, Fontana A, Rappuoli R, Montecucco C (1995) Low pH activates the vacuolating toxin of Helicobacter pylori, which becomes acid and pepsin resistant. J Biol Chem 270(41):23937–23940CrossRefPubMedPubMedCentralGoogle Scholar
  36. Debellis L, Papini E, Caroppo R, Montecucco C, Curci S (2001) Helicobacter pylori cytotoxin VacA increases alkaline secretion in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 281(6):G1440–G1448.  https://doi.org/10.1152/ajpgi.2001.281.6.G1440 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Djekic A, Muller A (2016) The Immunomodulator VacA promotes immune tolerance and persistent Helicobacter pylori infection through its activities on T-cells and antigen-presenting cells. Toxins (Basel) 8(6).  https://doi.org/10.3390/toxins8060187
  38. Du SY, Wang HJ, Cheng HH, Chen SD, Wang LH, Wang WC (2016) Cholesterol glucosylation by Helicobacter pylori delays internalization and arrests phagosome maturation in macrophages. J Microbiol Immunol Infect Wei mian yu gan ran za zhi 49(5):636–645.  https://doi.org/10.1016/j.jmii.2014.05.011 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Dubois A, Borén T (2007) Helicobacter pylori is invasive and it may be a facultative intracellular organism. Cell Microbiol 9(5):1108–1116.  https://doi.org/10.1111/j.1462-5822.2007.00921.x
  40. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13(11):759–771.  https://doi.org/10.1038/nrc3611 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Engler DB, Reuter S, van Wijck Y, Urban S, Kyburz A, Maxeiner J, Martin H, Yogev N, Waisman A, Gerhard M, Cover TL, Taube C, Muller A (2014) Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc Natl Acad Sci U S A 111(32):11810–11815.  https://doi.org/10.1073/pnas.1410579111 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Fehri LF, Rechner C, Janssen S, Mak TN, Holland C, Bartfeld S, Bruggemann H, Meyer TF (2009) Helicobacter pylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation. Epigenetics 4(8):577–586CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386.  https://doi.org/10.1002/ijc.29210 CrossRefGoogle Scholar
  44. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn LJ, Carneiro F, Sobrinho-Simoes M (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94(22):1680–1687CrossRefGoogle Scholar
  45. Figueiredo C, Camargo MC, Leite M, Fuentes-Panana EM, Rabkin CS, Machado JC (2017) Pathogenesis of gastric Cancer: genetics and molecular classification. Curr Top Microbiol Immunol 400:277–304.  https://doi.org/10.1007/978-3-319-50520-6_12 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Flahou B, Haesebrouck F, Chiers K, Van Deun K, De Smet L, Devreese B, Vandenberghe I, Favoreel H, Smet A, Pasmans F, D’Herde K, Ducatelle R (2011) Gastric epithelial cell death caused by helicobacter suis and Helicobacter pylori gamma-glutamyl transpeptidase is mainly glutathione degradation-dependent. Cell Microbiol 13(12):1933–1955.  https://doi.org/10.1111/j.1462-5822.2011.01682.x CrossRefPubMedPubMedCentralGoogle Scholar
  47. Foegeding NJ, Caston RR, McClain MS, Ohi MD, Cover TL (2016) An overview of Helicobacter pylori VacA toxin biology. Toxins (Basel) 8(6).  https://doi.org/10.3390/toxins8060173
  48. Franco AT, Israel DA, Washington MK, Krishna U, Fox JG, Rogers AB, Neish AS, Collier-Hyams L, Perez-Perez GI, Hatakeyama M, Whitehead R, Gaus K, O’Brien DP, Romero-Gallo J, Peek RM Jr (2005) Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A 102(30):10646–10651.  https://doi.org/10.1073/pnas.0504927102 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Frick-Cheng AE, Pyburn TM, Voss BJ, McDonald WH, Ohi MD, Cover TL (2016) Molecular and structural analysis of the Helicobacter pylori cag type IV secretion system core complex. mBio 7(1):e02001–e02015.  https://doi.org/10.1128/mBio.02001-15
  50. Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, Shintani T, Wada A, Aoyama N, Hirayama T, Fukamachi H, Noda M (2003) Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 33(3):375–381.  https://doi.org/10.1038/ng1112 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Gall A, Gaudet RG, Gray-Owen SD (2017) TIFA signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori. Infection 8(4).  https://doi.org/10.1128/mBio.01168-17
  52. Gangwer KA, Shaffer CL, Suerbaum S, Lacy DB, Cover TL, Bordenstein SR (2010) Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J Bacteriol 192(23):6126–6135.  https://doi.org/10.1128/jb.01081-10 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301(5636):1099–1102.  https://doi.org/10.1126/science.1086871 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Geisse NA, Cover TL, Henderson RM, Edwardson JM (2004) Targeting of Helicobacter pylori vacuolating toxin to lipid raft membrane domains analysed by atomic force microscopy. Biochem J 381(Pt 3):911–917.  https://doi.org/10.1042/bj20031719 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Geppert T, Hoy B, Wessler S, Schneider G (2011) Context-based identification of protein-protein interfaces and “hot-spot” residues. Chem Biol 18(3):344–353.  https://doi.org/10.1016/j.chembiol.2011.01.005 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Gerhard M, Schmees C, Voland P, Endres N, Sander M, Reindl W, Rad R, Oelsner M, Decker T, Mempel M, Hengst L, Prinz C (2005) A secreted low-molecular-weight protein from Helicobacter pylori induces cell-cycle arrest of T cells. Gastroenterology 128(5):1327–1339CrossRefPubMedPubMedCentralGoogle Scholar
  57. Gobert AP, McGee DJ, Akhtar M, Mendz GL, Newton JC, Cheng Y, Mobley HL, Wilson KT (2001) Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc Natl Acad Sci U S A 98(24):13844–13849.  https://doi.org/10.1073/pnas.241443798 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Gong M, Ling SS, Lui SY, Yeoh KG, Ho B (2010) Helicobacter pylori gamma-glutamyl transpeptidase is a pathogenic factor in the development of peptic ulcer disease. Gastroenterology 139(2):564–573.  https://doi.org/10.1053/j.gastro.2010.03.050 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Grohmann E, Christie PJ, Waksman G, Backert S (2018) Type IV secretion in Gram-negative and Gram-positive bacteria. Mol Microbiol 107(4):455–471.  https://doi.org/10.1111/mmi.13896 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Gupta VR, Patel HK, Kostolansky SS, Ballivian RA, Eichberg J, Blanke SR (2008) Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. PLoS Pathog 4(5):e1000073.  https://doi.org/10.1371/journal.ppat.1000073 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Gupta VR, Wilson BA, Blanke SR (2010) Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA. Cell Microbiol 12(10):1517–1533.  https://doi.org/10.1111/j.1462-5822.2010.01487.x CrossRefPubMedPubMedCentralGoogle Scholar
  62. Hatakeyama M (2008) Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA. Oncogene 27(55):7047–7054.  https://doi.org/10.1038/onc.2008.353 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Hatakeyama M (2017) Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. Proc Jpn Acad Ser B Phys Biol Sci 93(4):196–219.  https://doi.org/10.2183/pjab.93.013 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Hayashi T, Senda M, Morohashi H, Higashi H, Horio M, Kashiba Y, Nagase L, Sasaya D, Shimizu T, Venugopalan N, Kumeta H, Noda NN, Inagaki F, Senda T, Hatakeyama M (2012) Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA. Cell Host Microbe 12(1):20–33.  https://doi.org/10.1016/j.chom.2012.05.010 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Hayashi T, Morohashi H, Hatakeyama M (2013) Bacterial EPIYA effectors--where do they come from? What are they? Where are they going? Cell Microbiol 15(3):377–385.  https://doi.org/10.1111/cmi.12040 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M (2002) SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science (New York NY) 295(5555):683–686CrossRefGoogle Scholar
  67. Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, Inoue H, Han J, Sap J, Yahiro K, Moss J, Hirayama T (2007) Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells. Infect Immun 75(9):4472–4481.  https://doi.org/10.1128/iai.00500-07 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Hoy B, Lower M, Weydig C, Carra G, Tegtmeyer N, Geppert T, Schroder P, Sewald N, Backert S, Schneider G, Wessler S (2010) Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep 11(10):798–804.  https://doi.org/10.1038/embor.2010.114 CrossRefPubMedPubMedCentralGoogle Scholar
  69. Hoy B, Brandstetter H, Wessler S (2013) The stability and activity of recombinant Helicobacter pylori HtrA under stress conditions. J Basic Microbiol 53(5):402–409.  https://doi.org/10.1002/jobm.201200074 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Huang JY, Sweeney EG, Sigal M, Zhang HC, Remington SJ, Cantrell MA, Kuo CJ, Guillemin K, Amieva MR (2015) Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Cell Host Microbe 18(2):147–156.  https://doi.org/10.1016/j.chom.2015.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Iwamoto H, Czajkowsky DM, Cover TL, Szabo G, Shao Z (1999) VacA from Helicobacter pylori: a hexameric chloride channel. FEBS Lett 450(1-2):101–104CrossRefPubMedPubMedCentralGoogle Scholar
  72. Jang S, Su H, Blum FC, Bae S, Choi YH, Kim A, Hong YA, Kim J, Kim JH, Gunawardhana N, Jeon YE, Yoo YJ, Merrell DS, Ge L, Cha JH (2017) Dynamic expansion and contraction of cagA copy number in Helicobacter pylori impact development of gastric disease. mBio 8(1).  https://doi.org/10.1128/mBio.01779-16
  73. Javaheri A, Kruse T, Moonens K, Mejias-Luque R, Debraekeleer A, Asche CI, Tegtmeyer N, Kalali B, Bach NC, Sieber SA, Hill DJ, Koniger V, Hauck CR, Moskalenko R, Haas R, Busch DH, Klaile E, Slevogt H, Schmidt A, Backert S, Remaut H, Singer BB, Gerhard M (2016) Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat Microbiol 2:16189.  https://doi.org/10.1038/nmicrobiol.2016.189 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Jimenez-Soto LF, Kutter S, Sewald X, Ertl C, Weiss E, Kapp U, Rohde M, Pirch T, Jung K, Retta SF, Terradot L, Fischer W, Haas R (2009) Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog 5(12):e1000684.  https://doi.org/10.1371/journal.ppat.1000684 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Jones KR, Joo YM, Jang S, Yoo YJ, Lee HS, Chung IS, Olsen CH, Whitmire JM, Merrell DS, Cha JH (2009) Polymorphism in the CagA EPIYA motif impacts development of gastric cancer. J Clin Microbiol 47(4):959–968.  https://doi.org/10.1128/JCM.02330-08 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Kabisch R, Semper RP, Mejias-Luque R, Wustner S, Gerhard M (2016) Helicobacter pylori gamma-Glutamyltranspeptidase induces tolerogenic human dendritic cells by activation of glutamate receptors. J Immunol 196(10):4246–4252.  https://doi.org/10.4049/jimmunol.1501062 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Kaplan-Turkoz B, Jimenez-Soto LF, Dian C, Ertl C, Remaut H, Louche A, Tosi T, Haas R, Terradot L (2012) Structural insights into Helicobacter pylori oncoprotein CagA interaction with beta1 integrin. Proc Natl Acad Sci U S A 109(36):14640–14645.  https://doi.org/10.1073/pnas.1206098109 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Keates S, Sougioultzis S, Keates AC, Zhao D, Peek RM Jr, Shaw LM, Kelly CP (2001) cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem 276(51):48127–48134.  https://doi.org/10.1074/jbc.M107630200 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Kim JM, Kim JS, Lee JY, Kim YJ, Youn HJ, Kim IY, Chee YJ, Oh YK, Kim N, Jung HC, Song IS (2007) 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 75(7):3373–3381.  https://doi.org/10.1128/iai.01940-06 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Kim JM, Kim JS, Lee JY, Sim YS, Kim YJ, Oh YK, Yoon HJ, Kang JS, Youn J, Kim N, Jung HC, Kim S (2010a) Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation. Eur J Immunol 40(6):1651–1662.  https://doi.org/10.1002/eji.200939882 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Kim KM, Lee SG, Kim JM, Kim DS, Song JY, Kang HL, Lee WK, Cho MJ, Rhee KH, Youn HS, Baik SC (2010b) Helicobacter pylori gamma-glutamyltranspeptidase induces cell cycle arrest at the G1-S phase transition. J Microbiol (Seoul, Korea) 48(3):372–377.  https://doi.org/10.1007/s12275-010-9293-8 CrossRefGoogle Scholar
  82. Kim JM, Kim JS, Yoo DY, Ko SH, Kim N, Kim H, Kim YJ (2011) Stimulation of dendritic cells with Helicobacter pylori vacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1. Clin Exp Immunol 166(1):34–45.  https://doi.org/10.1111/j.1365-2249.2011.04447.x CrossRefPubMedPubMedCentralGoogle Scholar
  83. Klenner A, Hahnke V, Geppert T, Schneider P, Zettl H, Haller S, Rodrigues T, Reisen F, Hoy B, Schaible AM, Werz O, Wessler S, Schneider G (2012) From virtual screening to bioactive compounds by visualizing and clustering of chemical space. Mol Inform 31(1):21–26.  https://doi.org/10.1002/minf.201100147 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Kobayashi H, Kamiya S, Suzuki T, Kohda K, Muramatsu S, Kurumada T, Ohta U, Miyazawa M, Kimura N, Mutoh N, Shirai T, Takagi A, Harasawa S, Tani N, Miwa T (1996) 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 31(5):428–433CrossRefPubMedPubMedCentralGoogle Scholar
  85. Koniger V, Holsten L, Harrison U, Busch B, Loell E, Zhao Q, Bonsor DA, Roth A, Kengmo-Tchoupa A, Smith SI, Mueller S, Sundberg EJ, Zimmermann W, Fischer W, Hauck CR, Haas R (2016) Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat Microbiol 2:16188.  https://doi.org/10.1038/nmicrobiol.2016.188 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Krueger S, Hundertmark T, Kuester D, Kalinski T, Peitz U, Roessner A (2007) Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract 203(6):433–444.  https://doi.org/10.1016/j.prp.2007.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Kusters JG, van Vliet AH, Kuipers EJ (2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19(3):449–490.  https://doi.org/10.1128/CMR.00054-05 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, Konig W, Backert S (2007) Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449(7164):862–866.  https://doi.org/10.1038/nature06187 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Kyburz A, Urban S, Altobelli A, Floess S, Huehn J, Cover TL, Muller A (2017) Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. Clin Exp Allergy 47(10):1331–1341.  https://doi.org/10.1111/cea.12996 CrossRefPubMedPubMedCentralGoogle Scholar
  90. Lebrun AH, Wunder C, Hildebrand J, Churin Y, Zahringer U, Lindner B, Meyer TF, Heinz E, Warnecke D (2006) Cloning of a cholesterol-alpha-glucosyltransferase from Helicobacter pylori. J Biol Chem 281(38):27765–27772.  https://doi.org/10.1074/jbc.M603345200 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Lee IO, Kim JH, Choi YJ, Pillinger MH, Kim SY, Blaser MJ, Lee YC (2010) Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. J Biol Chem 285(21):16042–16050.  https://doi.org/10.1074/jbc.M110.111054 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Lee DG, Kim HS, Lee YS, Kim S, Cha SY, Ota I, Kim NH, Cha YH, Yang DH, Lee Y, Park GJ, Yook JI, Lee YC (2014) Helicobacter pylori CagA promotes snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. Nat Commun 5:4423.  https://doi.org/10.1038/ncomms5423 CrossRefPubMedPubMedCentralGoogle Scholar
  93. 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(11):3278–3280CrossRefPubMedPubMedCentralGoogle Scholar
  94. 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(29):26734–26741.  https://doi.org/10.1074/jbc.M304071200 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR (1988) Cytotoxic activity in broth-culture filtrates of campylobacter pylori. J Med Microbiol 26(2):93–99.  https://doi.org/10.1099/00222615-26-2-93 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Li Q, Liu J, Gong Y, Yuan Y (2017) Association of CagA EPIYA-D or EPIYA-C phosphorylation sites with peptic ulcer and gastric cancer risks: a meta-analysis. Medicine 96(17):e6620.  https://doi.org/10.1097/md.0000000000006620 CrossRefPubMedPubMedCentralGoogle Scholar
  97. Liu X, Chu KM (2014) E-cadherin and gastric cancer: cause, consequence, and applications. Biomed Res Int 2014:637308.  https://doi.org/10.1155/2014/637308 CrossRefPubMedPubMedCentralGoogle Scholar
  98. Lower M, Weydig C, Metzler D, Reuter A, Starzinski-Powitz A, Wessler S, Schneider G (2008) Prediction of extracellular proteases of the human pathogen Helicobacter pylori reveals proteolytic activity of the Hp1018/19 protein HtrA. PLoS One 3(10):e3510.  https://doi.org/10.1371/journal.pone.0003510 CrossRefPubMedPubMedCentralGoogle Scholar
  99. Lower M, Geppert T, Schneider P, Hoy B, Wessler S, Schneider G (2011) Inhibitors of Helicobacter pylori protease HtrA found by ‘virtual ligand’ screening combat bacterial invasion of epithelia. PLoS One 6(3):e17986.  https://doi.org/10.1371/journal.pone.0017986 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Malfertheiner P, Megraud F, O’Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt R, Moayyedi P, Rokkas T, Rugge M, Selgrad M, Suerbaum S, Sugano K, El-Omar EM, European H, Microbiota Study G, Consensus panel (2017) Management of Helicobacter pylori infection-the Maastricht V/Florence consensus report. Gut 66(1):6–30.  https://doi.org/10.1136/gutjnl-2016-312288 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM, Honjo T, Chiba T (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13(4):470–476.  https://doi.org/10.1038/nm1566 CrossRefPubMedPubMedCentralGoogle Scholar
  102. Matsumoto A, Isomoto H, Nakayama M, Hisatsune J, Nishi Y, Nakashima Y, Matsushima K, Kurazono H, Nakao K, Hirayama T, Kohno S (2011) 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 56(4):999–1006.  https://doi.org/10.1007/s10620-010-1420-1 CrossRefPubMedPubMedCentralGoogle Scholar
  103. McClain MS, Schraw W, Ricci V, Boquet P, Cover TL (2000) Acid activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells. Mol Microbiol 37(2):433–442CrossRefPubMedPubMedCentralGoogle Scholar
  104. McClain MS, Cao P, Iwamoto H, Vinion-Dubiel AD, Szabo G, Shao Z, Cover TL (2001) 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(22):6499–6508.  https://doi.org/10.1128/jb.183.22.6499-6508.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 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 Chem 278(14):12101–12108.  https://doi.org/10.1074/jbc.M212595200 CrossRefPubMedPubMedCentralGoogle Scholar
  106. McGovern KJ, Blanchard TG, Gutierrez JA, Czinn SJ, Krakowka S, Youngman P (2001) Gamma-glutamyltransferase is a Helicobacter pylori virulence factor but is not essential for colonization. Infect Immun 69(6):4168–4173.  https://doi.org/10.1128/iai.69.6.4168-4173.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  107. Mejias-Luque R, Gerhard M (2017) Immune evasion strategies and persistence of Helicobacter pylori. Curr Top Microbiol Immunol 400:53–71.  https://doi.org/10.1007/978-3-319-50520-6_3 CrossRefPubMedPubMedCentralGoogle Scholar
  108. Mishra JP, Cohen D, Zamperone A, Nesic D, Muesch A, Stein M (2015) CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2. Cell Microbiol 17(11):1670–1682.  https://doi.org/10.1111/cmi.12464 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 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(2):334–340.  https://doi.org/10.1006/bbrc.1998.8808 CrossRefPubMedPubMedCentralGoogle Scholar
  110. 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(1):135–140CrossRefPubMedPubMedCentralGoogle Scholar
  111. Moodley Y, Linz B (2009) Helicobacter pylori sequences reflect past human migrations. Genome Dyn 6:62–74.  https://doi.org/10.1159/000235763 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Moonens K, Remaut H (2017) Evolution and structural dynamics of bacterial glycan binding adhesins. Curr Opin Struct Biol 44:48–58.  https://doi.org/10.1016/j.sbi.2016.12.003 CrossRefPubMedPubMedCentralGoogle Scholar
  113. Morbiato L, Tombola F, Campello S, Del Giudice G, Rappuoli R, Zoratti M, Papini E (2001) Vacuolation induced by VacA toxin of Helicobacter pylori requires the intracellular accumulation of membrane permeant bases, Cl and water. FEBS Lett 508(3):479–483.  https://doi.org/10.1016/S0014-5793(01)03133-7 CrossRefPubMedPubMedCentralGoogle Scholar
  114. Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf HJ, Schlaermann P, Meyer TF (2017) Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory response. Gastroenterology.  https://doi.org/10.1053/j.gastro.2017.12.008
  115. Mueller D, Tegtmeyer N, Brandt S, Yamaoka Y, De Poire E, Sgouras D, Wessler S, Torres J, Smolka A, Backert S (2012) c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122(4):1553–1566.  https://doi.org/10.1172/JCI61143 CrossRefPubMedPubMedCentralGoogle Scholar
  116. Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, Aburatani H, Akiyama T, Peek RM, Jr., Azuma T, Hatakeyama M (2007) Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 26 (32):4617-4626. doi: https://doi.org/10.1038/sj.onc.1210251
  117. Murata-Kamiya N, Kikuchi K, Hayashi T, Higashi H, Hatakeyama M (2010) Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 7(5):399–411.  https://doi.org/10.1016/j.chom.2010.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  118. Nakayama M, Kimura M, Wada A, Yahiro K, Ogushi K, Niidome T, Fujikawa A, Shirasaka D, Aoyama N, Kurazono H, Noda M, Moss J, Hirayama T (2004) Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells. J Biol Chem 279(8):7024–7028.  https://doi.org/10.1074/jbc.M308898200 CrossRefPubMedPubMedCentralGoogle Scholar
  119. Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T (2009) Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem 284(3):1612–1619.  https://doi.org/10.1074/jbc.M806981200 CrossRefPubMedPubMedCentralGoogle Scholar
  120. Naumann M, Sokolova O, Tegtmeyer N, Backert S (2017) Helicobacter pylori: a paradigm pathogen for subverting host cell signal transmission. Trends Microbiol 25(4):316–328.  https://doi.org/10.1016/j.tim.2016.12.004 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Neal JT, Peterson TS, Kent ML, Guillemin K (2013) H. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model. Dis Model Mech 6(3):802–810.  https://doi.org/10.1242/dmm.011163 CrossRefPubMedPubMedCentralGoogle Scholar
  122. Odenbreit S, Puls 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(5457):1497–1500CrossRefPubMedPubMedCentralGoogle Scholar
  123. Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J, Gerhard M, Taube C, Muller A (2013) Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci U S A 110(8):3047–3052.  https://doi.org/10.1073/pnas.1211248110 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, Yamada G, Azuma T, Hatakeyama M (2008) Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A 105(3):1003–1008.  https://doi.org/10.1073/pnas.0711183105 CrossRefPubMedPubMedCentralGoogle Scholar
  125. Oliveira MJ, Costa AC, Costa AM, Henriques L, Suriano G, Atherton JC, Machado JC, Carneiro F, Seruca R, Mareel M, Leroy A, Figueiredo C (2006) Helicobacter pylori induces gastric epithelial cell invasion in a c-Met and type IV secretion system-dependent manner. J Biol Chem 281(46):34888–34896.  https://doi.org/10.1074/jbc.M607067200 CrossRefGoogle Scholar
  126. Oliveira MJ, Costa AM, Costa AC, Ferreira RM, Sampaio P, Machado JC, Seruca R, Mareel M, Figueiredo C (2009) CagA associates with c-Met, E-cadherin, and p120-catenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. J Infect Dis 200(5):745–755.  https://doi.org/10.1086/604727 CrossRefPubMedPubMedCentralGoogle Scholar
  127. Pachathundikandi SK, Muller A, Backert S (2016) Inflammasome activation by Helicobacter pylori and its implications for persistence and immunity. Curr Top Microbiol Immunol 397:117–131.  https://doi.org/10.1007/978-3-319-41171-2_6 CrossRefPubMedPubMedCentralGoogle Scholar
  128. Panayotopoulou EG, Sgouras DN, Papadakos KS, Petraki K, Breurec S, Michopoulos S, Mantzaris G, Papatheodoridis G, Mentis A, Archimandritis A (2010) CagA and VacA polymorphisms are associated with distinct pathological features in Helicobacter pylori-infected adults with peptic ulcer and non-peptic ulcer disease. J Clin Microbiol 48(6):2237–2239.  https://doi.org/10.1128/jcm.00662-10 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 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(4):813–820.  https://doi.org/10.1172/jci2764 CrossRefPubMedPubMedCentralGoogle Scholar
  130. Parsonnet J, Friedman GD, Orentreich N, Vogelman H (1997) Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40(3):297–301CrossRefPubMedPubMedCentralGoogle Scholar
  131. 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):2043–2050.  https://doi.org/10.1099/13500872-145-8-2043 CrossRefPubMedPubMedCentralGoogle Scholar
  132. Perna AM, Reisen F, Schmidt TP, Geppert T, Pillong M, Weisel M, Hoy B, Simister PC, Feller SM, Wessler S, Schneider G (2014) Inhibiting Helicobacter pylori HtrA protease by addressing a computationally predicted allosteric ligand binding site. Chem Sci 5:3583–3590.  https://doi.org/10.1039/c4sc01443j CrossRefPubMedPubMedCentralGoogle Scholar
  133. Perna AM, Rodrigues T, Schmidt TP, Bohm M, Stutz K, Reker D, Pfeiffer B, Altmann KH, Backert S, Wessler S, Schneider G (2015) Fragment-based De novo design reveals a small-molecule inhibitor of Helicobacter pylori HtrA. Angew Chem Int Ed Engl 54(35):10244–10248.  https://doi.org/10.1002/anie.201504035 CrossRefPubMedPubMedCentralGoogle Scholar
  134. Phadnis SH, Ilver D, Janzon L, Normark S, Westblom TU (1994) Pathological significance and molecular characterization of the vacuolating toxin gene of Helicobacter pylori. Infect Immun 62(5):1557–1565PubMedPubMedCentralGoogle Scholar
  135. Polk DB, Peek RM, Jr. (2010) Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 10 (6):403-414. doi: https://doi.org/10.1038/nrc2857
  136. Poppe M, Feller SM, Romer G, Wessler S (2007) Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility. Oncogene 26(24):3462–3472.  https://doi.org/10.1038/sj.onc.1210139 CrossRefPubMedPubMedCentralGoogle Scholar
  137. Posselt G, Backert S, Wessler S (2013) The functional interplay of Helicobacter pylori factors with gastric epithelial cells induces a multi-step process in pathogenesis. Cell Commun Signal CCS 11:77.  https://doi.org/10.1186/1478-811X-11-77 CrossRefPubMedPubMedCentralGoogle Scholar
  138. Raghunathan K, Foegeding NJ, Campbell AM, Cover TL, Ohi MD, Kenworthy AK (2018) Determinants of raft partitioning of the Helicobacter pylori pore-forming toxin VacA. Infect Immun 86(5).  https://doi.org/10.1128/IAI.00872-17
  139. 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(6):1389–1404CrossRefPubMedPubMedCentralGoogle Scholar
  140. Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, Atherton JC (2007) A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 133(3):926–936.  https://doi.org/10.1053/j.gastro.2007.06.056 CrossRefPubMedPubMedCentralGoogle Scholar
  141. Ricci V, Sommi P, Fiocca R, Romano M, Solcia E, Ventura U (1997) Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J Pathol 183(4):453–459.  https://doi.org/10.1002/(sici)1096-9896(199712)183:4<453::aid-path950>3.0.co;2-2 CrossRefPubMedPubMedCentralGoogle Scholar
  142. Robinson K, Letley DP, Kaneko K (2017) The human stomach in health and disease: infection strategies by Helicobacter pylori. Curr Top Microbiol Immunol 400:1–26.  https://doi.org/10.1007/978-3-319-50520-6_1 CrossRefPubMedPubMedCentralGoogle Scholar
  143. Roche N, Ilver D, Angstrom J, Barone S, Telford JL, Teneberg S (2007) Human gastric glycosphingolipids recognized by Helicobacter pylori vacuolating cytotoxin VacA. Microbes Infect 9(5):605–614.  https://doi.org/10.1016/j.micinf.2007.01.023 CrossRefPubMedPubMedCentralGoogle Scholar
  144. Rossi M, Bolz C, Revez J, Javed S, El-Najjar N, Anderl F, Hyytiainen H, Vuorela P, Gerhard M, Hanninen ML (2012) Evidence for conserved function of gamma-glutamyltranspeptidase in helicobacter genus. PLoS One 7(2):e30543.  https://doi.org/10.1371/journal.pone.0030543 CrossRefPubMedPubMedCentralGoogle Scholar
  145. Roure S, Bonis M, Chaput C, Ecobichon C, Mattox A, Barriere C, Geldmacher N, Guadagnini S, Schmitt C, Prevost MC, Labigne A, Backert S, Ferrero RL, Boneca IG (2012) Peptidoglycan maturation enzymes affect flagellar functionality in bacteria. Mol Microbiol 86(4):845–856.  https://doi.org/10.1111/mmi.12019 CrossRefPubMedPubMedCentralGoogle Scholar
  146. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, Lu H, Ohnishi N, Azuma T, Suzuki A, Ohno S, Hatakeyama M (2007) Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447(7142):330–333.  https://doi.org/10.1038/nature05765 CrossRefPubMedPubMedCentralGoogle Scholar
  147. Saha A, Backert S, Hammond CE, Gooz M, Smolka AJ (2010) Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology 139(1):239–248.  https://doi.org/10.1053/j.gastro.2010.03.036 CrossRefPubMedPubMedCentralGoogle Scholar
  148. Salama NR, Shepherd B, Falkow S (2004) Global transposon mutagenesis and essential gene analysis of Helicobacter pylori. J Bacteriol 186(23):7926–7935.  https://doi.org/10.1128/jb.186.23.7926-7935.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  149. 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(40):25022–25028CrossRefPubMedPubMedCentralGoogle Scholar
  150. Schmees C, Prinz C, Treptau T, Rad R, Hengst L, Voland P, Bauer S, Brenner L, Schmid RM, Gerhard M (2007) Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase. Gastroenterology 132(5):1820–1833.  https://doi.org/10.1053/j.gastro.2007.02.031 CrossRefPubMedPubMedCentralGoogle Scholar
  151. Schmidt TP, Goetz C, Huemer M, Schneider G, Wessler S (2016a) Calcium binding protects E-cadherin from cleavage by Helicobacter pylori HtrA. Gut Pathogens 8:29.  https://doi.org/10.1186/s13099-016-0112-6 CrossRefPubMedPubMedCentralGoogle Scholar
  152. Schmidt TP, Perna AM, Fugmann T, Bohm M, Jan H, Haller S, Gotz C, Tegtmeyer N, Hoy B, Rau TT, Neri D, Backert S, Schneider G, Wessler S (2016b) Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Sci Rep 6:23264.  https://doi.org/10.1038/srep23264 CrossRefPubMedPubMedCentralGoogle Scholar
  153. 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(2):307–319CrossRefPubMedPubMedCentralGoogle Scholar
  154. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS (1999) Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A 96(25):14559–14564CrossRefPubMedPubMedCentralGoogle Scholar
  155. Selbach M, Moese S, Hurwitz R, Hauck CR, Meyer TF, Backert S (2003) The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J 22(3):515–528.  https://doi.org/10.1093/emboj/cdg050 CrossRefPubMedPubMedCentralGoogle Scholar
  156. Selbach M, Paul FE, Brandt S, Guye P, Daumke O, Backert S, Dehio C, Mann M (2009) Host cell interactome of tyrosine-phosphorylated bacterial proteins. Cell Host Microbe 5(4):397–403.  https://doi.org/10.1016/j.chom.2009.03.004 CrossRefPubMedPubMedCentralGoogle Scholar
  157. Senda Y, Hatakeyama M (2016) CagA. In: Suzuki H, Warren R, Marshall B (eds) Helicobacter pylori. Springer, Tokyo, pp 33–47.  https://doi.org/10.1007/978-4-431-55705-0_3 CrossRefGoogle Scholar
  158. 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(3):347–350CrossRefPubMedPubMedCentralGoogle Scholar
  159. Sgouras DN, Panayotopoulou EG, Papadakos K, Martinez-Gonzalez B, Roumbani A, Panayiotou J, van Vliet-Constantinidou C, Mentis AF, Roma-Giannikou E (2009) CagA and VacA polymorphisms do not correlate with severity of histopathological lesions in Helicobacter pylori-infected Greek children. J Clin Microbiol 47(8):2426–2434.  https://doi.org/10.1128/jcm.00159-09 CrossRefPubMedPubMedCentralGoogle Scholar
  160. Shaffer CL, Gaddy JA, Loh JT, Johnson EM, Hill S, Hennig EE, McClain MS, McDonald WH, Cover TL (2011) Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog 7(9):e1002237.  https://doi.org/10.1371/journal.ppat.1002237 CrossRefPubMedPubMedCentralGoogle Scholar
  161. Shibayama K, Kamachi K, Nagata N, Yagi T, Nada T, Doi Y, Shibata N, Yokoyama K, Yamane K, Kato H, Iinuma Y, Arakawa Y (2003) A novel apoptosis-inducing protein from Helicobacter pylori. Mol Microbiol 47(2):443–451CrossRefPubMedPubMedCentralGoogle Scholar
  162. Shibayama K, Wachino J, Arakawa Y, Saidijam M, Rutherford NG, Henderson PJ (2007) Metabolism of glutamine and glutathione via gamma-glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism. Mol Microbiol 64(2):396–406.  https://doi.org/10.1111/j.1365-2958.2007.05661.x CrossRefPubMedPubMedCentralGoogle Scholar
  163. Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67(7):1247–1260.  https://doi.org/10.1136/gutjnl-2016-312888
  164. Sougleri IS, Papadakos KS, Zadik MP, Mavri-Vavagianni M, Mentis AF, Sgouras DN (2016) Helicobacter pylori CagA protein induces factors involved in the epithelial to mesenchymal transition (EMT) in infected gastric epithelial cells in an EPIYA- phosphorylation-dependent manner. FEBS J 283(2):206–220.  https://doi.org/10.1111/febs.13592 CrossRefPubMedPubMedCentralGoogle Scholar
  165. Stein M, Rappuoli R, Covacci A (2000) Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A 97(3):1263–1268CrossRefPubMedPubMedCentralGoogle Scholar
  166. Stein SC, Faber E, Bats SH, Murillo T, Speidel Y, Coombs N, Josenhans C (2017) Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis. PLoS Pathog 13(7):e1006514.  https://doi.org/10.1371/journal.ppat.1006514 CrossRefPubMedPubMedCentralGoogle Scholar
  167. Suzuki M, Mimuro H, Kiga K, Fukumatsu M, Ishijima N, Morikawa H, Nagai S, Koyasu S, Gilman RH, Kersulyte D, Berg DE, Sasakawa C (2009) Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 5(1):23–34.  https://doi.org/10.1016/j.chom.2008.11.010 CrossRefPubMedPubMedCentralGoogle Scholar
  168. Tammer I, Brandt S, Hartig R, Konig W, Backert S (2007) Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 132(4):1309–1319.  https://doi.org/10.1053/j.gastro.2007.01.050 CrossRefPubMedPubMedCentralGoogle Scholar
  169. Tan S, Noto JM, Romero-Gallo J, Peek RM, Jr., Amieva MR (2011) Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog 7 (5):e1002050. doi: https://doi.org/10.1371/journal.ppat.1002050
  170. Tegtmeyer N, Hartig R, Delahay RM, Rohde M, Brandt S, Conradi J, Takahashi S, Smolka AJ, Sewald N, Backert S (2010) A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J Biol Chem 285(30):23515–23526.  https://doi.org/10.1074/jbc.M109.096214 CrossRefPubMedPubMedCentralGoogle Scholar
  171. Tegtmeyer N, Wittelsberger R, Hartig R, Wessler S, Martinez-Quiles N, Backert S (2011) Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. Cell Host Microbe 9(6):520–531.  https://doi.org/10.1016/j.chom.2011.05.007 CrossRefPubMedPubMedCentralGoogle Scholar
  172. Tegtmeyer N, Moodley Y, Yamaoka Y, Pernitzsch SR, Schmidt V, Traverso FR, Schmidt TP, Rad R, Yeoh KG, Bow H, Torres J, Gerhard M, Schneider G, Wessler S, Backert S (2016) Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA. Mol Microbiol 99(5):925–944.  https://doi.org/10.1111/mmi.13276 CrossRefPubMedPubMedCentralGoogle Scholar
  173. Tegtmeyer N, Neddermann M, Asche CI, Backert S (2017a) Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA. Mol Microbiol 105(3):358–372.  https://doi.org/10.1111/mmi.13707 CrossRefPubMedPubMedCentralGoogle Scholar
  174. Tegtmeyer N, Wessler S, Necchi V, Rohde M, Harrer A, Rau TT, Asche CI, Boehm M, Loessner H, Figueiredo C, Naumann M, Palmisano R, Solcia E, Ricci V, Backert S (2017b) Helicobacter pylori employs a unique Basolateral type IV secretion mechanism for CagA delivery. Cell Host Microbe 22 (4):552-560.e555. doi: https://doi.org/10.1016/j.chom.2017.09.005
  175. Telford JL, Ghiara P, Dell’Orco M, Comanducci M, Burroni D, Bugnoli M, Tecce MF, Censini S, Covacci A, Xiang Z et al (1994) Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med 179(5):1653–1658CrossRefPubMedPubMedCentralGoogle Scholar
  176. Terebiznik MR, Raju D, Vazquez CL, Torbricki K, Kulkarni R, Blanke SR, Yoshimori T, Colombo MI, Jones NL (2009) Effect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy 5(3):370–379CrossRefPubMedPubMedCentralGoogle Scholar
  177. Tombola F, Carlesso C, Szabò I, de Bernard M, Reyrat JM, Telford JL, Rappuoli R, Montecucco C, Papini E, Zoratti M (1999) Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: possible implications for the mechanism of cellular vacuolation. Biophys J 76(3):1401–1409.  https://doi.org/10.1016/S0006-3495(99)77301-7 CrossRefPubMedPubMedCentralGoogle Scholar
  178. 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(6):929–937.  https://doi.org/10.1172/jci13045 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Torres VJ, VanCompernolle SE, Sundrud MS, Unutmaz D, Cover TL (2007) Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets. J Immunol 179(8):5433–5440CrossRefPubMedPubMedCentralGoogle Scholar
  180. Tsang YH, Lamb A, Romero-Gallo J, Huang B, Ito K, Peek RM, Jr., Ito Y, Chen LF (2010) Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 29 (41):5643-5650. doi: https://doi.org/10.1038/onc.2010.304
  181. Tsutsumi R, Higashi H, Higuchi M, Okada M, Hatakeyama M (2003) Attenuation of Helicobacter pylori CagA x SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem 278(6):3664–3670.  https://doi.org/10.1074/jbc.M208155200 CrossRefPubMedPubMedCentralGoogle Scholar
  182. Tummuru MK, Cover TL, Blaser MJ (1993) Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun 61(5):1799–1809PubMedPubMedCentralGoogle Scholar
  183. Utsch C, Haas R (2016) VacA’s induction of VacA-containing vacuoles (VCVs) and their immunomodulatory activities on human T cells. Toxins (Basel) 8(6).  https://doi.org/10.3390/toxins8060190
  184. Utt M, Danielsson B, Wadstrom T (2001) Helicobacter pylori vacuolating cytotoxin binding to a putative cell surface receptor, heparan sulfate, studied by surface plasmon resonance. FEMS Immunol Med Microbiol 30(2):109–113CrossRefPubMedPubMedCentralGoogle Scholar
  185. Varga MG, Shaffer CL, Sierra JC, Suarez G, Piazuelo MB, Whitaker ME, Romero-Gallo J, Krishna US, Delgado A, Gomez MA, Good JA, Almqvist F, Skaar EP, Correa P, Wilson KT, Hadjifrangiskou M, Peek RM (2016) Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35(48):6262–6269.  https://doi.org/10.1038/onc.2016.158 CrossRefPubMedPubMedCentralGoogle Scholar
  186. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL (2004) Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5(11):1166–1174.  https://doi.org/10.1038/ni1131 CrossRefPubMedPubMedCentralGoogle Scholar
  187. Vinion-Dubiel AD, McClain MS, Czajkowsky DM, Iwamoto H, Ye D, Cao P, Schraw W, Szabo G, Blanke SR, Shao Z, Cover TL (1999) A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J Biol Chem 274(53):37736–37742CrossRefPubMedPubMedCentralGoogle Scholar
  188. Wandler AM, Guillemin K (2012) Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila. PLoS Pathog 8(10):e1002939.  https://doi.org/10.1371/journal.ppat.1002939 CrossRefPubMedPubMedCentralGoogle Scholar
  189. Wang F, Xia P, Wu F, Wang D, Wang W, Ward T, Liu Y, Aikhionbare F, Guo Z, Powell M, Liu B, Bi F, Shaw A, Zhu Z, Elmoselhi A, Fan D, Cover TL, Ding X, Yao X (2008) Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem 283(39):26714–26725.  https://doi.org/10.1074/jbc.M800527200 CrossRefPubMedPubMedCentralGoogle Scholar
  190. Wang G, Romero-Gallo J, Benoit SL, Piazuelo MB, Dominguez RL, Morgan DR, Peek RM, Jr., Maier RJ (2016) Hydrogen metabolism in Helicobacter pylori plays a role in gastric carcinogenesis through facilitating CagA translocation. mBio 7 (4). doi: https://doi.org/10.1128/mBio.01022-16
  191. Wei J, Nagy TA, Vilgelm A, Zaika E, Ogden SR, Romero-Gallo J, Piazuelo MB, Correa P, Washington MK, El-Rifai W, Peek RM, Zaika A (2010) Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 139(4):1333–1343.  https://doi.org/10.1053/j.gastro.2010.06.018 CrossRefPubMedPubMedCentralGoogle Scholar
  192. Wei J, Noto JM, Zaika E, Romero-Gallo J, Piazuelo MB, Schneider B, El-Rifai W, Correa P, Peek RM, Zaika AI (2015) Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut 64(7):1040–1048.  https://doi.org/10.1136/gutjnl-2014-307295 CrossRefPubMedPubMedCentralGoogle Scholar
  193. Wessler S, Backert S (2017) A novel basolateral type IV secretion model for the CagA oncoprotein of Helicobacter pylori. Microbial cell (Graz, Austria) 5(1):60–62.  https://doi.org/10.15698/mic2018.01.611 CrossRefGoogle Scholar
  194. Wiedemann T, Hofbaur S, Tegtmeyer N, Huber S, Sewald N, Wessler S, Backert S, Rieder G (2012) Helicobacter pylori CagL dependent induction of gastrin expression via a novel alphavbeta5-integrin-integrin linked kinase signalling complex. Gut 61(7):986–996.  https://doi.org/10.1136/gutjnl-2011-300525 CrossRefPubMedPubMedCentralGoogle Scholar
  195. 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(2):143–154CrossRefPubMedPubMedCentralGoogle Scholar
  196. Winter JA, Letley DP, Cook KW, Rhead JL, Zaitoun AA, Ingram RJ, Amilon KR, Croxall NJ, Kaye PV, Robinson K, Atherton JC (2014) A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J Infect Dis 210(6):954–963.  https://doi.org/10.1093/infdis/jiu154 CrossRefPubMedPubMedCentralGoogle Scholar
  197. Wroblewski LE, Peek RM, Jr. (2007) Orchestration of dysregulated epithelial turnover by a manipulative pathogen. Cell Host Microbe 2 (4):209-211. doi: https://doi.org/10.1016/j.chom.2007.09.011
  198. Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B, Zahringer U, Mollenkopf HJ, Heinz E, Meyer TF (2006) Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. Nat Med 12(9):1030–1038.  https://doi.org/10.1038/nm1480 CrossRefPubMedPubMedCentralGoogle Scholar
  199. Wustner S, Anderl F, Wanisch A, Sachs C, Steiger K, Nerlich A, Vieth M, Mejias-Luque R, Gerhard M (2017) Helicobacter pylori gamma-glutamyl transferase contributes to colonization and differential recruitment of T cells during persistence. Sci Rep 7(1):13636.  https://doi.org/10.1038/s41598-017-14028-1 CrossRefPubMedPubMedCentralGoogle Scholar
  200. Xia Y, Yamaoka Y, Zhu Q, Matha I, Gao X (2009) A comprehensive sequence and disease correlation analyses for the C-terminal region of CagA protein of Helicobacter pylori. PLoS One 4(11):e7736.  https://doi.org/10.1371/journal.pone.0007736 CrossRefPubMedPubMedCentralGoogle Scholar
  201. Yahiro K, Niidome T, Kimura M, Hatakeyama T, Aoyagi H, Kurazono H, Imagawa K, Wada A, Moss J, Hirayama T (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(51):36693–36699CrossRefPubMedPubMedCentralGoogle Scholar
  202. Yahiro K, Wada A, Nakayama M, Kimura T, Ogushi K, Niidome T, Aoyagi H, Yoshino K, Yonezawa K, Moss J, Hirayama T (2003) Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. J Biol Chem 278(21):19183–19189.  https://doi.org/10.1074/jbc.M300117200 CrossRefPubMedPubMedCentralGoogle Scholar
  203. Yahiro K, Wada A, Yamasaki E, Nakayama M, Nishi Y, Hisatsune J, Morinaga N, Sap J, Noda M, Moss J, Hirayama T (2004) Essential domain of receptor tyrosine phosphatase beta (RPTPbeta) for interaction with Helicobacter pylori vacuolating cytotoxin. J Biol Chem 279(49):51013–51021.  https://doi.org/10.1074/jbc.M406473200 CrossRefPubMedPubMedCentralGoogle Scholar
  204. Yahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J, Suzuki H, Nomura F, Noda M, Moss J, Hirayama T (2012) Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J Biol Chem 287(37):31104–31115.  https://doi.org/10.1074/jbc.M112.387498 CrossRefPubMedPubMedCentralGoogle Scholar
  205. Yamaoka Y, Graham DY (2014) Helicobacter pylori virulence and cancer pathogenesis. Future Oncol 10(8):1487–1500.  https://doi.org/10.2217/fon.14.29 CrossRefPubMedPubMedCentralGoogle Scholar
  206. Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J, Nakayama M, Hisatsune J, Kimura M, Moss J, Hirayama T (2006) 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 281(16):11250–11259.  https://doi.org/10.1074/jbc.M509404200 CrossRefPubMedPubMedCentralGoogle Scholar
  207. Zeaiter Z, Cohen D, Musch A, Bagnoli F, Covacci A, Stein M (2008) Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity. Cell Microbiol 10(3):781–794.  https://doi.org/10.1111/j.1462-5822.2007.01084.x CrossRefPubMedPubMedCentralGoogle Scholar
  208. Zhang XS, Tegtmeyer N, Traube L, Jindal S, Perez-Perez G, Sticht H, Backert S, Blaser MJ (2015) A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interactions. PLoS Pathog 11(2):e1004621.  https://doi.org/10.1371/journal.ppat.1004621 CrossRefPubMedPubMedCentralGoogle Scholar
  209. 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(1):25–40CrossRefPubMedPubMedCentralGoogle Scholar
  210. Zimmermann S, Pfannkuch L, Al-Zeer MA, Bartfeld S, Koch M, Liu J, Rechner C, Soerensen M, Sokolova O, Zamyatina A, Kosma P, Maurer AP, Glowinski F, Pleissner KP, Schmid M, Brinkmann V, Karlas A, Naumann M, Rother M, Machuy N, Meyer TF (2017) ALPK1- and TIFA-dependent innate immune response triggered by the Helicobacter pylori type IV secretion system. Cell Rep 20(10):2384–2395.  https://doi.org/10.1016/j.celrep.2017.08.039 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Dionyssios Sgouras
    • 1
    Email author
  • Nicole Tegtmeyer
    • 2
  • Silja Wessler
    • 3
  1. 1.Laboratory of Medical MicrobiologyHellenic Pasteur InstituteAthensGreece
  2. 2.Division of Microbiology, Department of BiologyFriedrich Alexander University Erlangen-NurembergErlangenGermany
  3. 3.Division of Microbiology, Department of BiosciencesParis-Lodron University of SalzburgSalzburgAustria

Personalised recommendations