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Impact of Helicobacter pylori Virulence Factors on the Host Immune Response and Gastric Pathology

  • Sundus Javed
  • Emma C. Skoog
  • Jay V. SolnickEmail author
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 421)

Abstract

Helicobacter pylori chronically infects nearly half the world’s population, yet most of those infected remain asymptomatic throughout their lifetime. The outcome of infection—peptic ulcer disease or gastric cancer versus asymptomatic colonization—is a product of host genetics, environmental influences, and differences in bacterial virulence factors. Here, we review the current understanding of the cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and a large family of outer membrane proteins (OMPs), which are among the best understood H. pylori virulence determinants that contribute to disease. Each of these virulence factors is characterized by allelic and phenotypic diversity that is apparent within and across individuals, as well as over time, and modulates inflammation. From the bacterial perspective, inflammation is probably a necessary evil because it promotes nutrient acquisition, but at the cost of reduction in bacterial load and therefore decreases the chance of transmission to a new host. The general picture that emerges is one of a chronic bacterial infection that is dependent on both inducing and carefully regulating the host inflammatory response. A better understanding of these regulatory mechanisms may have implications for the control of chronic inflammatory diseases that are increasingly common causes of human morbidity and mortality.

Keywords

Virulence Inflammation cagPAI OMPs VacA 

Notes

Acknowledgements

Work in the Solnick laboratory is supported by Public Health Service Grant R01 AI08713 from the NIH to JVS.

References

  1. Aberg A, Gideonsson P, Vallstrom A, Olofsson A, Ohman C, Rakhimova L, Boren T, Engstrand L, Brannstrom K, Arnqvist A (2014) A repetitive DNA element regulates expression of the Helicobacter pylori sialic acid binding adhesin by a rheostat-like mechanism. PLoS Pathog 10:e1004234.  https://doi.org/10.1371/journal.ppat.1004234CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alm E, Huang K, Arkin A (2006) The evolution of two-component systems in bacteria reveals different strategies for niche adaptation. PLoS Comput Biol 2:e143.  https://doi.org/10.1371/journal.pcbi.0020143CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alm RA, Bina J, Andrews BM, Doig P, Hancock RE, Trust TJ (2000) Comparative genomics of Helicobacter pylori: analysis of the outer membrane protein families. Infect Immun 68:4155–4168.  https://doi.org/10.1128/iai.68.7.4155-4168.2000CrossRefPubMedPubMedCentralGoogle Scholar
  4. Aras RA, Fischer W, Perez-Perez GI, Crosatti M, Ando T, Haas R, Blaser MJ (2003) Plasticity of repetitive DNA sequences within a bacterial (Type IV) secretion system component. J Exp Med 198:1349–1360.  https://doi.org/10.1084/jem.20030381CrossRefPubMedPubMedCentralGoogle Scholar
  5. Arnold IC, Artola-Boran M, Tallon de Lara P, Kyburz A, Taube C, Ottemann K, van den Broek M, Yousefi S, Simon HU, Muller A (2018) Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation. J Exp Med 215:2055–2072.  https://doi.org/10.1084/jem.20172049CrossRefPubMedPubMedCentralGoogle Scholar
  6. Arnold IC, Lee JY, Amieva MR, Roers A, Flavell RA, Sparwasser T, Muller A (2011) Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia. Gastroenterology 140:199–209.  https://doi.org/10.1053/j.gastro.2010.06.047CrossRefPubMedGoogle Scholar
  7. Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikstrom S, Sjostrom R, Linden S, Backstrom A, Lundberg C, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatino B, Gilman RH, Gerhard M, Alarcon T, Lopez-Brea M, Nakazawa T, Fox JG, Correa P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE, Boren T (2004) Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science 305:519–522.  https://doi.org/10.1126/science.1098801CrossRefPubMedGoogle Scholar
  8. Aspholm M, Olfat FO, Norden J, Sonden B, Lundberg C, Sjostrom R, Altraja S, Odenbreit S, Haas R, Wadstrom T, Engstrand L, Semino-Mora C, Liu H, Dubois A, Teneberg S, Arnqvist A, Boren T (2006) SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans. PLoS Pathog 2: e110.  https://doi.org/10.1371/journal.ppat.0020110
  9. Backert S, Feller SM, Wessler S (2008) Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci 33(2):80–90.  https://doi.org/10.1016/j.tibs.2007.10.006
  10. 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
  11. Backert S, Haas R, Gerhard M, Naumann M (2017) The Helicobacter pylori type IV secretion system encoded by the cag pathogenicity Island: architecture, function, and signaling. Curr Top Microbiol Immunol 413:187–220.  https://doi.org/10.1007/978-3-319-75241-9_8CrossRefPubMedGoogle Scholar
  12. Backert S, Tegtmeyer N (2017) Type IV secretion and signal transduction of Helicobacter pylori CagA through interactions with host cell receptors. Toxins (Basel) 9:115.  https://doi.org/10.3390/toxins9040115CrossRefGoogle 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 10:955–965.  https://doi.org/10.2217/fmb.15.32
  14. 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
  15. 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
  16. Barrozo RM, Cooke CL, Hansen LM, Lam AM, Gaddy JA, Johnson EM, Cariaga TA, Suarez G, Peek RM Jr, Cover TL, Solnick JV (2013) Functional plasticity in the type IV secretion system of Helicobacter pylori. PLoS Pathog 9:e1003189.  https://doi.org/10.1371/journal.ppat.1003189CrossRefPubMedPubMedCentralGoogle Scholar
  17. Barrozo RM, Hansen LM, Lam AM, Skoog EC, Martin ME, Cai LP, Lin Y, Latoscha A, Suerbaum S, Canfield DR, Solnick JV (2016) CagY is an immune-sensitive regulator of the Helicobacter pylori type IV secretion system. Gastroenterology 151:1164–1175.  https://doi.org/10.1053/j.gastro.2016.08.014CrossRefPubMedPubMedCentralGoogle Scholar
  18. Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, Diamond MS, Miller VL, Virgin HW (2007) Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447:326–329.  https://doi.org/10.1038/nature05762CrossRefPubMedGoogle Scholar
  19. Baumler AJ, Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85–93.  https://doi.org/10.1038/nature18849CrossRefPubMedPubMedCentralGoogle Scholar
  20. Belogolova E, Bauer B, Pompaiah M, Asakura H, Brinkman V, Ertl C, Bartfeld S, Nechitaylo TY, Haas R, Machuy N, Salama N, Churin Y, Meyer TF (2013) Helicobacter pylori outer membrane protein HopQ identified as a novel T4SS-associated virulence factor. Cell Microbiol 15:1896–1912.  https://doi.org/10.1111/cmi.12158CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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 37:e98664.  https://doi.org/10.15252/embj.201798664
  22. Borén T, Falk P, Roth KA, Larson G, Normark S (1993) Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 262:1892–1895.  https://doi.org/10.1126/science.8018146CrossRefPubMedGoogle Scholar
  23. Borozan I, Zapatka M, Frappier L, Ferretti V (2018) Analysis of Epstein-Barr virus genomes and expression profiles in gastric adenocarcinoma. J Virol 92:e01239–01217.  https://doi.org/10.1128/jvi.01239-17CrossRefPubMedPubMedCentralGoogle Scholar
  24. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancer in 185 countries. CA Cancer J Clin 68:394–424.  https://doi.org/10.3322/caac.21492
  25. Bugaytsova JA, Björnham O, Chernov YA, Gideonsson P, Henriksson S, Mendez M, Sjöström R, Mahdavi J, Shevtsova A, Ilver D, Moonens K, Quintana-Hayashi MP, Moskalenko R, Aisenbrey C, Bylund G, Schmidt A, Åberg A, Brännström K, Königer V, Vikström S, Rakhimova L, Hofer A, Ögren J, Liu H, Goldman MD, Whitmire JM, Ådén J, Younson J, Kelly CG, Gilman RH, Chowdhury A, Mukhopadhyay AK, Nair GB, Papadakos KS, Martinez-Gonzalez B, Sgouras DN, Engstrand L, Unemo M, Danielsson D, Suerbaum S, Oscarson S, Morozova-Roche LA, Olofsson A, Gröbner G, Holgersson J, Esberg A, Strömberg N, Landström M, Eldridge AM, Chromy BA, Hansen LM, Solnick JV, Lindén SK, Haas R, Dubois A, Merrell DS, Schedin S, Remaut H, Arnqvist A, Berg DE, Borén T (2017) Helicobacter pylori adapts to chronic infection and gastric disease via pH-responsive BabA-mediated adherence. Cell Host Microbe 21:376–389.  https://doi.org/10.1016/j.chom.2017.02.013CrossRefPubMedPubMedCentralGoogle Scholar
  26. Byndloss MX, Rivera-Chavez F, Tsolis R, Baumler AJ (2017) How bacterial pathogens use type III and type IV secretion systems to facilitate their transmission. Curr Opin Microbiol 35:1–7CrossRefGoogle Scholar
  27. Cao P, Cover TL (2002) Two different families of hopQ alleles in Helicobacter pylori. J Clin Microbiol 40:4504–4511.  https://doi.org/10.1128/jcm.40.12.4504-4511.2002CrossRefPubMedPubMedCentralGoogle Scholar
  28. Cao P, Lee KJ, Blaser MJ, Cover TL (2005) Analysis of hopQ alleles in East Asian and Western strains of Helicobacter pylori. FEMS Microbiol Lett 251:37–43.  https://doi.org/10.1016/j.femsle.2005.07.023CrossRefPubMedGoogle Scholar
  29. Chang YW, Shaffer CL, Rettberg LA, Ghosal D, Jensen GJ (2018) In Vivo structures of the Helicobacter pylori cag Type IV secretion system. Cell Rep 23:673–681.  https://doi.org/10.1016/j.celrep.2018.03.085CrossRefPubMedPubMedCentralGoogle Scholar
  30. Chen MY, He CY, Meng X, Yuan Y (2013) Association of Helicobacter pylori babA2 with peptic ulcer disease and gastric cancer. World J Gastroenterol 19:4242–4251.  https://doi.org/10.3748/wjg.v19.i26.4242CrossRefPubMedPubMedCentralGoogle Scholar
  31. Chung C, Olivares A, Torres E, Yilmaz O, Cohen H, Perez-Perez G (2010) Diversity of VacA intermediate region among Helicobacter pylori strains from several regions of the world. J Clin Microbiol 48:690–696.  https://doi.org/10.1128/jcm.01815-09CrossRefPubMedPubMedCentralGoogle Scholar
  32. Colbeck JC, Hansen LM, Fong JM, Solnick JV (2006) Genotypic profile of the outer membrane proteins BabA and BabB in clinical isolates of Helicobacter pylori. Infect Immun 74:4375–4378.  https://doi.org/10.1128/iai.00485-06CrossRefPubMedPubMedCentralGoogle Scholar
  33. Conradi J, Tegtmeyer N, Woźna M, Wissbrock M, Michalek C, Gagell C, Cover TL, Frank R, Sewald N, Backert S (2012) An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Front Cell Infect Microbiol. 2:70.  https://doi.org/10.3389/fcimb.2012.00070
  34. Coppens F, Castaldo G, Debraekeleer A, Subedi S, Moonens K, Lo A, Remaut H (2018) Hop-family Helicobacter outer membrane adhesins form a novel class of Type 5-like secretion proteins with an interrupted beta-barrel domain. Mol Microbiol  https://doi.org/10.1111/mmi.14075
  35. Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N (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 90:5791–5795.  https://doi.org/10.1073/pnas.90.12.5791CrossRefPubMedPubMedCentralGoogle Scholar
  36. Cover TL, Blaser MJ (1992) Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 267:10570–10575PubMedGoogle Scholar
  37. Covacci A, Falkow S, Berg DE, Rappuoli R (1997) Did the inheritance of a pathogenicity Island modify the virulence of Helicobacter pylori? Trends Microbiol 5:205–208.  https://doi.org/10.1016/S0966-842X(97)01035-4CrossRefPubMedGoogle Scholar
  38. Cronan MR, Beerman RW, Rosenberg AF, Saelens JW, Johnson MG, Oehlers SH, Sisk DM, Jurcic Smith KL, Medvitz NA, Miller SE, Trinh LA, Fraser SE, Madden JF, Turner J, Stout JE, Lee S, Tobin DM (2016) Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection. Immunity 45:861–876.  https://doi.org/10.1016/j.immuni.2016.09.014CrossRefPubMedPubMedCentralGoogle Scholar
  39. de Jonge R, Durrani Z, Rijpkema SG, Kuipers EJ, van Vliet AH, Kusters JG (2004) Role of the Helicobacter pylori outer-membrane proteins AlpA and AlpB in colonization of the guinea pig stomach. J Med Microbiol 53:375–379.  https://doi.org/10.1099/jmm.0.45551-0CrossRefPubMedGoogle Scholar
  40. Dossumbekova A, Prinz C, Mages J, Lang R, Kusters JG, Van Vliet AH, Reindl W, Backert S, Saur D, Schmid RM, Rad R (2006) Helicobacter pylori HopH (OipA) and bacterial pathogenicity: genetic and functional genomic analysis of hopH gene polymorphisms. J Infect Dis 194:1346–1355.  https://doi.org/10.1086/508426CrossRefPubMedGoogle Scholar
  41. Draper JL, Hansen LM, Bernick DL, Abedrabbo S, Underwood JG, Kong N, Huang BC, Weis AM, Weimer BC, van Vliet AH, Pourmand N, Solnick JV, Karplus K, Ottemann KM (2017) Fallacy of the unique genome: sequence diversity within single Helicobacter pylori strains. MBio 8:e02321–16.  https://doi.org/10.1128/mbio.02321-16CrossRefPubMedPubMedCentralGoogle Scholar
  42. Eaton KA, Cover TL, Tummuru MK, Blaser MJ, Krakowka S (1997) Role of vacuolating cytotoxin in gastritis due to Helicobacter pylori in gnotobiotic piglets. Infect Immun 65:3462–3464PubMedPubMedCentralGoogle Scholar
  43. Falush D, Wirth T, Linz B, Pritchard JK, Stephens M, Kidd M, Blaser MJ, Graham DY, Vacher S, Perez-Perez GI, Yamaoka Y, Mégraud F, Otto K, Reichard U, Katzowitsch E, Wang X, Achtman M, Suerbaum S (2003) Traces of human migrations in Helicobacter pylori populations. Science 299:1582–1585.  https://doi.org/10.1126/science.1080857CrossRefPubMedGoogle Scholar
  44. Fischer W, Püls J, Buhrdorf R, Gebert B, Odenbreit S, Haas R (2001) Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol 42:1337–1348.  https://doi.org/10.1046/j.1365-2958.2001.02714.xCrossRefPubMedGoogle Scholar
  45. 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:e02001–02015.  https://doi.org/10.1128/mbio.02001-15CrossRefPubMedPubMedCentralGoogle Scholar
  46. Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM (2014) The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration. PLoS Pathog 10:e1004450.  https://doi.org/10.1371/journal.ppat.1004450CrossRefPubMedPubMedCentralGoogle Scholar
  47. Gaddy JA, Radin JN, Loh JT, Zhang F, Washington MK, Peek RM, Algood HM, Cover TL (2013) High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect Immun 81:2258–2267.  https://doi.org/10.1128/iai.01271-12CrossRefPubMedPubMedCentralGoogle Scholar
  48. Gall A, Gaudet RG, Gray-Owen SD, Salama NR (2017) TIFA signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori Infection. MBio 8:e01168–17.  https://doi.org/10.1128/mbio.01168-17CrossRefPubMedPubMedCentralGoogle Scholar
  49. Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301:1099–1102.  https://doi.org/10.1126/science.1086871CrossRefPubMedGoogle Scholar
  50. Gerhard M, Lehn N, Neumayer N, Boren T, Rad R, Schepp W, Miehlke S, Classen M, Prinz C (1999) Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci U S A 96:12778–12783.  https://doi.org/10.1073/pnas.96.22.12778CrossRefPubMedPubMedCentralGoogle Scholar
  51. Ghiara P, Marchetti M, Blaser MJ, Tummuru MK, Cover TL, Segal ED, Tompkins LS, Rappuoli R (1995) Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease. Infect Immun 63:4154–4160PubMedPubMedCentralGoogle Scholar
  52. Ghosal D, Chang YW, Jeong KC, Vogel JP, Jensen GJ (2017) In situ structure of the Legionella Dot/Icm type IV secretion system by electron cryotomography. EMBO Rep 18:726–732.  https://doi.org/10.15252/embr.201643598
  53. Giannakis M, Backhed HK, Chen SL, Faith JJ, Wu M, Guruge JL, Engstrand L, Gordon JI (2009) Response of gastric epithelial progenitors to Helicobacter pylori Isolates obtained from Swedish patients with chronic atrophic gastritis. J Biol Chem 284:30383–30394.  https://doi.org/10.1074/jbc.m109.052738CrossRefPubMedPubMedCentralGoogle Scholar
  54. Grohmann E, Christie PJ, Waksman G, Backert S (2018) Type IV secretion in Gram-negative and Gram-positive bacteria. Mol Microbiol 107:455–471.  https://doi.org/10.1111/mmi.13896
  55. Grubman A, Kaparakis M, Viala J, Allison C, Badea L, Karrar A, Boneca IG, Le Bourhis L, Reeve S, Smith IA, Hartland EL, Philpott DJ, Ferrero RL (2010) The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell Microbiol 12:626–639.  https://doi.org/10.1111/j.1462-5822.2009.01421.xCrossRefPubMedGoogle Scholar
  56. 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:e1000073.  https://doi.org/10.1371/journal.ppat.1000073CrossRefPubMedPubMedCentralGoogle Scholar
  57. Hansen LM, Gideonsson P, Canfield DR, Boren T, Solnick JV (2017) Dynamic expression of the BabA adhesin and Its BabB paralog during Helicobacter pylori infection in rhesus macaques. Infect Immun 85:e00094–00017.  https://doi.org/10.1128/iai.00094-17CrossRefPubMedPubMedCentralGoogle Scholar
  58. Harris PR, Wright SW, Serrano C, Riera F, Duarte I, Torres J, Pena A, Rollan A, Viviani P, Guiraldes E, Schmitz JM, Lorenz RG, Novak L, Smythies LE, Smith PD (2008) Helicobacter pylori gastritis in children is associated with a regulatory T-cell response. Gastroenterology 134:491–499.  https://doi.org/10.1053/j.gastro.2007.11.006CrossRefPubMedGoogle Scholar
  59. Hennig EE, Godlewski MM, Butruk E, Ostrowski J (2005) Helicobacter pylori VacA cytotoxin interacts with fibronectin and alters HeLa cell adhesion and cytoskeletal organization in vitro. FEMS Immunol Med Microbiol 44:143–150.  https://doi.org/10.1016/j.femsim.2004.10.020CrossRefPubMedGoogle Scholar
  60. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, Hatakeyama M (2002) Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A 99:14428–14433.  https://doi.org/10.1073/pnas.222375399CrossRefPubMedPubMedCentralGoogle Scholar
  61. Horridge DN, Begley AA, Kim J, Aravindan N, Fan K, Forsyth MH (2017) Outer inflammatory protein a (OipA) of Helicobacter pylori is regulated by host cell contact and mediates CagA translocation and interleukin-8 response only in the presence of a functional cag pathogenicity island type IV secretion system. Pathog Dis 75:113.  https://doi.org/10.1093/femspd/ftx113CrossRefGoogle Scholar
  62. Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, Berg DE, Covacci A, Engstrand L, Borén T (1998) Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science 279:373–377.  https://doi.org/10.1126/science.279.5349.373CrossRefPubMedPubMedCentralGoogle Scholar
  63. Ishijima N, Suzuki M, Ashida H, Ichikawa Y, Kanegae Y, Saito I, Boren T, Haas R, Sasakawa C, Mimuro H (2011) BabA-mediated adherence is a potentiator of the Helicobacter pylori Type IV secretion system activity. J Biol Chem 286:25256–25264.  https://doi.org/10.1074/jbc.m111.233601CrossRefPubMedPubMedCentralGoogle Scholar
  64. Jain P, Luo ZQ, Blanke SR (2011) Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc Natl Acad Sci U S A 108:16032–16037.  https://doi.org/10.1073/pnas.1105175108CrossRefPubMedPubMedCentralGoogle Scholar
  65. 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:e01779–16.  https://doi.org/10.1128/mbio.01779-16CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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.2016.189CrossRefPubMedGoogle Scholar
  67. 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 β1 integrin in a novel RGD-independent manner. PLoS Pathog 5:e1000684.  https://doi.org/10.1371/journal.ppat.1000684CrossRefPubMedPubMedCentralGoogle Scholar
  68. Johnson EM, Gaddy JA, Voss BJ, Hennig EE, Cover TL (2014) Genes required for assembly of pili associated with the Helicobacter pylori cag type IV secretion system. Infect Immun 82:3457–3470.  https://doi.org/10.1128/iai.01640-14CrossRefPubMedPubMedCentralGoogle Scholar
  69. Jung SW, Sugimoto M, Graham DY, Yamaoka Y (2009) The homB status of Helicobacter pylori as a novel marker to distinguish gastric cancer from duodenal ulcer. J Clin Microbiol 37:3241–3245.  https://doi.org/10.1128/jcm.00293-09CrossRefGoogle Scholar
  70. Kable ME, Hansen LM, Styer CM, Deck SL, Rakhimova O, Shevtsova A, Eaton KA, Martin ME, Gideonsson P, Boren T, Solnick JV (2017) Host determinants of expression of the Helicobacter pylori BabA adhesin. Sci Rep 7:46499.  https://doi.org/10.1038/srep46499CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kenny DT, Skoog EC, Linden SK, Struwe WB, Rudd PM, Karlsson NG (2012) Presence of terminal N-acetylgalactosaminebeta1-4 N-acetylglucosamine Residues on O-linked oligosaccharides from gastric MUC5AC: involvement in Helicobacter pylori colonization? Glycobiology 22:1077–1085.  https://doi.org/10.1093/glycob/cws076CrossRefPubMedGoogle Scholar
  72. Kodaman N, Pazos A, Schneider BG, Piazuelo MB, Mera R, Sobota RS, Sicinschi LA, Shaffer CL, Romero-Gallo J, de Sablet T, Harder RH, Bravo LE, Peek RM, Wilson KT, Cover TL, Williams SM, Correa P (2014) Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A 111:1455–1460.  https://doi.org/10.1073/pnas.1318093111CrossRefPubMedPubMedCentralGoogle Scholar
  73. Koelblen T, Bergé C, Cherrier MV, Brillet K, Jimenez-Soto L, Ballut L, Takagi J, Montserret R, Rousselle P, Fischer W, Haas R, Fronzes R, Terradot L (2017) Molecular dissection of protein-protein interactions between integrin α5β1 and the Helicobacter pylori Cag type IV secretion system. FEBS J 284:4143–4157.  https://doi.org/10.1111/febs.14299CrossRefPubMedGoogle Scholar
  74. 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.2016.188CrossRefPubMedGoogle Scholar
  75. 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 449:862–866.  https://doi.org/10.1038/nature06187CrossRefPubMedGoogle Scholar
  76. Lertpiriyapong K, Whary MT, Muthupalani S, Lofgren JL, Gamazon ER, Feng Y, Ge Z, Wang TC, Fox JG (2014) Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. Gut 63:54–63.  https://doi.org/10.1136/gutjnl-2013-305178CrossRefPubMedGoogle Scholar
  77. 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 (Baltimore) 96:e6620.  https://doi.org/10.1097/md.0000000000006620CrossRefGoogle Scholar
  78. Lind J, Backert S, Pfleiderer K, Berg DE, Yamaoka Y, Sticht H, Tegtmeyer N (2014) Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of Western-type Helicobacter pylori strains. PLoS One 9(5):e96488.  https://doi.org/10.1371/journal.pone.0096488
  79. Lind J, Backert S, Hoffmann R, Eichler J, Yamaoka Y, Perez-Perez GI, Torres J, Sticht H, Tegtmeyer N (2016) Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of East Asian-type Helicobacter pylori strains. BMC Microbiol 16(1):201.  https://doi.org/10.1186/s12866-016-0820-6
  80. Linden S, Mahdavi J, Semino-Mora C, Olsen C, Carlstedt I, Boren T, Dubois A (2008) Role of ABO secretor status in mucosal innate immunity and H. pylori infection. PLoS Pathog 4:e2.  https://doi.org/10.1371/journal.ppat.0040002
  81. Liu G, McDaniel TK, Falkow S, Karlin S (1999) Sequence anomalies in the Cag7 gene of the Helicobacter pylori pathogenicity island. Proc Natl Acad Sci U S A 96:7011–7016.  https://doi.org/10.1073/pnas.96.12.7011CrossRefPubMedPubMedCentralGoogle Scholar
  82. Loh JT, Torres VJ, Cover TL (2007) Regulation of Helicobacter pylori cagA expression in response to salt. Cancer Res 67:4709–4715.  https://doi.org/10.1158/0008-5472.can-06-4746CrossRefPubMedGoogle Scholar
  83. Lu H, Wu JY, Beswick EJ, Ohno T, Odenbreit S, Haas R, Reyes VE, Kita M, Graham DY, Yamaoka Y (2007) Functional and intracellular signaling differences associated with the Helicobacter pylori AlpAB adhesin from Western and East Asian strains. J Biol Chem 282:6242–6254.  https://doi.org/10.1074/jbc.m611178200CrossRefPubMedPubMedCentralGoogle Scholar
  84. Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA, Altraja S, Wadstrom T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson KE, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarstrom L, Boren T (2002) Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297:573–578.  https://doi.org/10.1126/science.1069076CrossRefPubMedPubMedCentralGoogle Scholar
  85. Marcos NT, Magalhaes A, Ferreira B, Oliveira MJ, Carvalho AS, Mendes N, Gilmartin T, Head SR, Figueiredo C, David L, Santos-Silva F, Reis CA (2008) Helicobacter pylori induces beta3GnT5 in human gastric cell lines, modulating expression of the SabA ligand sialyl-Lewis x. J Clin Invest 118:2325–2336.  https://doi.org/10.1172/jci34324CrossRefPubMedPubMedCentralGoogle Scholar
  86. Mattar R, dos Santos AF, Eisig JN, Rodrigues TN, Silva FM, Lupinacci RM, Iriya K, Carrilho FJ (2005) No correlation of babA2 with vacA and cagA genotypes of Helicobacter pylori and grading of gastritis from peptic ulcer disease patients in Brazil. Helicobacter 10:601–608.  https://doi.org/10.1111/j.1523-5378.2005.00360.xCrossRefPubMedGoogle Scholar
  87. Mayerle J, den Hoed CM, Schurmann C, Stolk L, Homuth G, Peters MJ, Capelle LG, Zimmermann K, Rivadeneira F, Gruska S, Völzke H, de Vries AC, Völker U, Teumer A, van Meurs JB, Steinmetz I, Nauck M, Ernst F, Weiss FU, Hofman A, Zenker M, Kroemer HK, Prokisch H, Uitterlinden AG, Lerch MM, Kuipers EJ (2013) Identification of genetic loci associated with Helicobacter pylori serologic status. J Am Med Assoc 309:1012–1920.  https://doi.org/10.1001/jama.2013.4350CrossRefGoogle Scholar
  88. McClain MS, Beckett AC, Cover TL (2017) Helicobacter pylori vacuolating toxin and gastric cancer. Toxins (Basel) 9:E316.  https://doi.org/10.3390/toxins9100316CrossRefGoogle Scholar
  89. 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 183:6499–6508.  https://doi.org/10.1128/jb.183.22.6499-6508.2001CrossRefPubMedPubMedCentralGoogle Scholar
  90. Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335:936–941.  https://doi.org/10.1126/science.1214935CrossRefPubMedPubMedCentralGoogle Scholar
  91. Mizushima T, Sugiyama T, Komatsu Y, Ishizuka J, Kato M, Asaka M (2001) Clinical relevance of the babA2 genotype of Helicobacter pylori in Japanese clinical isolates. J Clin Microbiol 39:2463–2465.  https://doi.org/10.1128/jcm.39.7.2463-2465.2001CrossRefPubMedPubMedCentralGoogle Scholar
  92. Moonens K, Gideonsson P, Subedi S, Bugaytsova J, Romao E, Mendez M, Norden J, Fallah M, Rakhimova L, Shevtsova A, Lahmann M, Castaldo G, Brannstrom K, Coppens F, Lo AW, Ny T, Solnick JV, Vandenbussche G, Oscarson S, Hammarstrom L, Arnqvist A, Berg DE, Muyldermans S, Boren T, Remaut H (2016) Structural Insights into polymorphic ABO glycan binding by Helicobacter pylori. Cell Host Microbe 19:55–66.  https://doi.org/10.1016/j.chom.2015.12.004CrossRefPubMedPubMedCentralGoogle Scholar
  93. Moonens K, Hamway Y, Neddermann M, Reschke M, Tegtmeyer N, Kruse T, Kammerer R, Mejías-Luque R, Singer BB, Backert S, Gerhard M, Remaut H (2018) Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAMs. EMBO J 37(13):e98665.  https://doi.org/10.15252/embj.201798665
  94. 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 122:1553–1566.  https://doi.org/10.1172/jci61143CrossRefPubMedPubMedCentralGoogle Scholar
  95. 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 7:399–411.  https://doi.org/10.1016/j.chom.2010.04.005CrossRefPubMedGoogle Scholar
  96. Nell S, Estibariz I, Krebes J, Bunk B, Graham DY, Overmann J, Song Y, Sproer C, Yang I, Wex T, Korlach J, Malfertheiner P, Suerbaum S (2018) Genome and methylome variation in Helicobacter pylori with a cag pathogenicity Island during early stages of human infection. Gastroenterology 154:612–623.e617.  https://doi.org/10.1053/j.gastro.2017.10.014CrossRefPubMedGoogle Scholar
  97. Nell S, Kennemann L, Schwarz S, Josenhans C, Suerbaum S (2014) Dynamics of Lewis b binding and sequence variation of the babA adhesin gene during chronic Helicobacter pylori infection in humans. MBio 5:e02281–02214.  https://doi.org/10.1128/mbio.01233-15CrossRefPubMedPubMedCentralGoogle Scholar
  98. Noto JM, Gaddy JA, Lee JY, Piazuelo MB, Friedman DB, Colvin DC, Romero-Gallo J, Suarez G, Loh J, Slaughter JC, Tan S, Morgan DR, Wilson KT, Bravo LE, Correa P, Cover TL, Amieva MR, Peek RM Jr (2013) Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J Clin Invest 123:479–492.  https://doi.org/10.1172/jci64373CrossRefPubMedGoogle Scholar
  99. Odenbreit S, Kavermann H, Puls J, Haas R (2002) CagA tyrosine phosphorylation and interleukin-8 induction by Helicobacter pylori are independent from AlpAB, HopZ and Bab group outer membrane proteins. Int J Med Microbiol 292:257–266.  https://doi.org/10.1078/1438-4221-00205CrossRefPubMedGoogle Scholar
  100. Odenbreit S, Till M, Hofreuter D, Faller G, Haas R (1999) Genetic and functional characterization of the AlpAB gene locus essential for the adhesion of Helicobacter pylori to human gastric tissue. Mol Microbiol 31:1537–1548.  https://doi.org/10.1046/j.1365-2958.1999.01300.xCrossRefPubMedGoogle Scholar
  101. 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 110:3047–3052.  https://doi.org/10.1073/pnas.1211248110CrossRefPubMedPubMedCentralGoogle Scholar
  102. 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 192:1601–1610.  https://doi.org/10.1084/jem.192.11.1601CrossRefPubMedPubMedCentralGoogle Scholar
  103. 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 105:1003–1008.  https://doi.org/10.1073/pnas.0711183105CrossRefPubMedPubMedCentralGoogle Scholar
  104. Ohno T, Vallstrom A, Rugge M, Ota H, Graham DY, Arnqvist A, Yamaoka Y (2011) Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils. J Infect Dis 203:726–735.  https://doi.org/10.1093/infdis/jiq090CrossRefPubMedPubMedCentralGoogle Scholar
  105. Olbermann P, Josenhans C, Moodley Y, Uhr M, Stamer C, Vauterin M, Suerbaum S, Achtman M, Linz B (2010) A global overview of the genetic and functional diversity in the Helicobacter pylori cag pathogenicity Island. PLoS Genet 6:e1001069.  https://doi.org/10.1371/journal.pgen.1001069CrossRefPubMedPubMedCentralGoogle Scholar
  106. Olofsson A, Vallstrom A, Petzold K, Tegtmeyer N, Schleucher J, Carlsson S, Haas R, Backert S, Wai SN, Grobner G, Arnqvist A (2010) Biochemical and functional characterization of Helicobacter pylori vesicles. Mol Microbiol 77:1539–1555.  https://doi.org/10.1111/j.1365-2958.2010.07307.xCrossRefPubMedPubMedCentralGoogle Scholar
  107. Pang SS, Nguyen ST, Perry AJ, Day CJ, Panjikar S, Tiralongo J, Whisstock JC, Kwok T (2014) The three-dimensional structure of the extracellular adhesion domain of the sialic acid-binding adhesin SabA from Helicobacter pylori. J Biol Chem 289:6332–6340.  https://doi.org/10.1074/jbc.m113.513135CrossRefPubMedGoogle Scholar
  108. Peck B, Ortkamp M, Diehl KD, Hundt E, Knapp B (1999) Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori. Nucleic Acids Res 27:3325–3333.  https://doi.org/10.1093/nar/27.16.3325CrossRefPubMedPubMedCentralGoogle Scholar
  109. Perez-Perez GI, Salomaa A, Kosunen TU, Daverman B, Rautelin H, Aromaa A, Knekt P, Blaser MJ (2002) Evidence that cagA(+) Helicobacter pylori strains are disappearing more rapidly than cagA(−) strains. Gut 50:295–298.  https://doi.org/10.1136/gut.50.3.295CrossRefPubMedPubMedCentralGoogle Scholar
  110. Pfannkuch L, Hurwitz R, Traulsen J, Kosma P, Schmid M, Meyer TF (2018) ADP heptose, a novel pathogen-associated moledular pattern associated with Helicobacter pylori type 4 secretion. bioRxiv  https://doi.org/10.1101/405951
  111. Pormohammad A, Ghotaslou R, Leylabadlo HE, Nasiri MJ, Dabiri H, Hashemi A (2018) Risk of gastric cancer in association with Helicobacter pylori different virulence factors: a systematic review and meta-analysis. Microb Pathog 118:214–219.  https://doi.org/10.1016/j.micpath.2018.03.004CrossRefPubMedGoogle Scholar
  112. 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 11:77.  https://doi.org/10.1186/1478-811X-11-77CrossRefPubMedPubMedCentralGoogle Scholar
  113. Prinz C, Schoniger M, Rad R, Becker I, Keiditsch E, Wagenpfeil S, Classen M, Rosch T, Schepp W, Gerhard M (2001) Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation. Cancer Res 61:1903–1909PubMedGoogle Scholar
  114. Reyes-Leon A, Atherton JC, Argent RH, Puente JL, Torres J (2007) Heterogeneity in the activity of Mexican Helicobacter pylori strains in gastric epithelial cells and its association with diversity in the cagA gene. Infect Immun 75:3445–3454.  https://doi.org/10.1128/iai.01951-06CrossRefPubMedPubMedCentralGoogle Scholar
  115. 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 133:926–936.  https://doi.org/10.1053/j.gastro.2007.06.056CrossRefPubMedGoogle Scholar
  116. Robinson K, Kenefeck R, Pidgeon EL, Shakib S, Patel S, Polson RJ, Zaitoun AM, Atherton JC (2008) Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses. Gut 57:1375–1385.  https://doi.org/10.1136/gut.2007.137539CrossRefPubMedGoogle Scholar
  117. Rohde M, Puls J, Buhrdorf R, Fischer W, Haas R (2003) A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system. Mol Microbiol 49:219–234.  https://doi.org/10.1046/j.1365-2958.2003.03549.xCrossRefPubMedGoogle Scholar
  118. Rossez Y, Gosset P, Boneca IG, Magalhaes A, Ecobichon C, Reis CA, Cieniewski-Bernard C, Chevalier Curt MJ, Leonard R, Maes E, Sperandio B, Slomianny C, Sansonetti PJ, Michalski JC, Robbe-Masselot C (2014) The LacdiNAc specific adhesin LabA mediates adhesion of Helicobacter pylori to human gastric mucosa. J Infect Dis 210:1286–1295.  https://doi.org/10.1093/infdis/jiu239CrossRefPubMedGoogle Scholar
  119. 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 69:730–736.  https://doi.org/10.1128/iai.69.2.730-736.2001CrossRefPubMedPubMedCentralGoogle Scholar
  120. Selbach M, Moese S, Hauck CR, Meyer TF, Backert S (2002a) Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem 277(9):6775–8CrossRefGoogle Scholar
  121. Selbach M, Moese S, Meyer TF, Backert S (2002b) Functional analysis of the Helicobacter pylori cag pathogenicity island reveals both VirD4-CagA-dependent and VirD4-CagA-independent mechanisms. Infect Immun 70:665–671.  https://doi.org/10.1128/iai.70.2.665-671.2002CrossRefPubMedPubMedCentralGoogle Scholar
  122. 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 5:397–403.  https://doi.org/10.1016/j.chom.2009.03.004CrossRefPubMedGoogle Scholar
  123. Senkovich OA, Yin J, Ekshyyan V, Conant C, Traylor J, Adegboyega P, McGee DJ, Rhoads RE, Slepenkov S, Testerman TL (2011) Helicobacter pylori AlpA and AlpB bind host laminin and influence gastric inflammation in gerbils. Infect Immun 79:3106–3116.  https://doi.org/10.1128/iai.01275-10CrossRefPubMedPubMedCentralGoogle Scholar
  124. 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 431:347–350.  https://doi.org/10.1016/s0014-5793(98)00788-1CrossRefPubMedGoogle Scholar
  125. Sewald X, Gebert-Vogl B, Prassl S, Barwig I, Weiss E, Fabbri M, Osicka R, Schiemann M, Busch DH, Semmrich M, Holzmann B, Sebo P, Haas R (2008) Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 3:20–29.  https://doi.org/10.1016/j.chom.2007.11.003CrossRefPubMedGoogle Scholar
  126. 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:e1002237.  https://doi.org/10.1371/journal.ppat.1002237CrossRefPubMedPubMedCentralGoogle Scholar
  127. Sharma CM, Hoffmann S, Darfeuille F, Reignier J, Findeiss S, Sittka A, Chabas S, Reiche K, Hackermüller J, Reinhardt R, Stadler PF, Vogel J (2010) The primary transcriptome of the major human pathogen Helicobacter pylori. Nature 464:250–255.  https://doi.org/10.1038/nature08756CrossRefPubMedGoogle Scholar
  128. Skoog EC, Deck SL, Entwistle HD, Hansen LM, Solnick JV (2016) Characterization of the Cag pathogenicity island in Helicobacter pylori from naturally infected rhesus macaques. FEMS Microbiol Lett 363:275.  https://doi.org/10.1093/femsle/fnw275CrossRefGoogle Scholar
  129. Skoog EC, Morikis VA, Martin ME, Foster GA, Cai LP, Hansen LM, Li B, Gaddy JA, Simon SI, Solnick JV (2018) CagY-dependent regulation of type IV secretion in Helicobacter pylori is associated with alterations in integrin binding. MBio 9:e00717–00718.  https://doi.org/10.1101/294769CrossRefPubMedPubMedCentralGoogle Scholar
  130. Solnick JV, Hansen LM, Salama NR, Boonjakuakul JK, Syvanen M (2004) Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc Natl Acad Sci U S A 101:2106–2111.  https://doi.org/10.1086/423142CrossRefPubMedPubMedCentralGoogle Scholar
  131. 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:e1006514.  https://doi.org/10.1371/journal.ppat.1006514CrossRefPubMedPubMedCentralGoogle Scholar
  132. Styer CM, Hansen LM, Cooke CL, Gundersen AM, Choi SS, Berg DE, Benghezal M, Marshall BJ, Peek RM Jr, Boren T, Solnick JV (2010) Expression of the BabA adhesin during experimental infection with Helicobacter pylori. Infect Immun 78:1593–1600.  https://doi.org/10.1128/iai.01297-09CrossRefPubMedPubMedCentralGoogle Scholar
  133. Su YL, Huang HL, Huang BS, Chen PC, Chen CS, Wang HL, Lin PH, Chieh MS, Wu JJ, Yang JC, Chow LP (2016) Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer. Sci Rep 6:36442.  https://doi.org/10.1038/srep36442CrossRefPubMedPubMedCentralGoogle Scholar
  134. Sugimoto M, Ohno T, Graham DY, Yamaoka Y (2011) Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils. J Gastroenterol Hepatol 26:1677–1684.  https://doi.org/10.1111/j.1440-1746.2011.06817.xCrossRefPubMedPubMedCentralGoogle Scholar
  135. Ta LH, Hansen LM, Sause WE, Shiva O, Millstein A, Ottemann KM, Castillo AR, Solnick JV (2012) Conserved transcriptional unit organization of the cag pathogenicity island among Helicobacter pylori strains. Front Cell Infect Microbiol 2:46.  https://doi.org/10.3389/fcimb.2012.00046CrossRefPubMedPubMedCentralGoogle Scholar
  136. Tabassam FH, Graham DY, Yamaoka Y (2008) OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization. Cell Microbiol 10:1008–1020.  https://doi.org/10.1111/j.1462-5822.2007.01104.xCrossRefPubMedGoogle Scholar
  137. Tabassam FH, Graham DY, Yamaoka Y (2011) Paxillin is a novel cellular target for converging Helicobacter pylori-induced cellular signaling. Am J Physiol Gastrointest Liver Physiol 301:G601–611.  https://doi.org/10.1152/ajpgi.00375.2010CrossRefPubMedPubMedCentralGoogle Scholar
  138. Talarico S, Whitefield SE, Fero J, Haas R, Salama NR (2012) Regulation of Helicobacter pylori adherence by gene conversion. Mol Microbiol 84:1050–1061.  https://doi.org/10.1111/j.1365-2958.2012.08073.xCrossRefPubMedPubMedCentralGoogle Scholar
  139. Talebi Bezmin Abadi A, Rafiei A, Ajami A, Hosseini V, Taghvaei T, Jones KR, Merrell DS (2011) Helicobacter pylori homB, but not cagA, is associated with gastric cancer in Iran. J Clin Microbiol 49:3191–3197.  https://doi.org/10.1128/jcm.00947-11CrossRefPubMedPubMedCentralGoogle Scholar
  140. Tammer I, Brandt S, Hartig R, König 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):1309–19CrossRefGoogle Scholar
  141. Tanaka J, Suzuki T, Mimuro H, Sasakawa C (2003) Structural definition on the surface of Helicobacter pylori type IV secretion apparatus. Cell Microbiol 5:395–404.  https://doi.org/10.1046/j.1462-5822.2003.00286.xCrossRefPubMedGoogle Scholar
  142. Tegtmeyer N, Harrer A, Schmitt V, Singer BB, Backert S (2019) Expression of CEACAM1 or CEACAM5 in AZ-521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori. Cell Microbiol 21:e12965.  https://doi.org/10.1111/cmi.12965
  143. 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 105:358–372.  https://doi.org/10.1111/mmi.13707CrossRefPubMedGoogle Scholar
  144. 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 22:552–560.e555.  https://doi.org/10.1016/j.chom.2017.09.005CrossRefPubMedGoogle Scholar
  145. 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 179:1653–1658.  https://doi.org/10.1084/jem.179.5.1653CrossRefPubMedGoogle Scholar
  146. 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 35:6262–6269.  https://doi.org/10.1038/onc.2016.158CrossRefPubMedPubMedCentralGoogle Scholar
  147. 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 5:1166–1174.  https://doi.org/10.1038/ni1131CrossRefPubMedGoogle Scholar
  148. 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 210:954–963.  https://doi.org/10.1093/infdis/jiu154CrossRefPubMedPubMedCentralGoogle Scholar
  149. Wirth HP, Beins MH, Yang M, Tham KT, Blaser MJ (1998) Experimental infection of Mongolian gerbils with wild-type and mutant Helicobacter pylori strains. Infect Immun 66:4856–4866.  https://doi.org/10.1053/gast.1997.v113.pm9322503CrossRefPubMedPubMedCentralGoogle Scholar
  150. 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:e7736.  https://doi.org/10.1371/journal.pone.0007736CrossRefPubMedPubMedCentralGoogle Scholar
  151. 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 287:31104–31115.  https://doi.org/10.1074/jbc.m112.387498CrossRefPubMedPubMedCentralGoogle Scholar
  152. 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 278:19183–19189.  https://doi.org/10.1074/jbc.m300117200CrossRefPubMedGoogle Scholar
  153. Yakoob J, Abbas Z, Khan R, Salim SA, Awan S, Abrar A, Jafri W (2016) Helicobacter pylori outer membrane protein Q allele distribution is associated with distinct pathologies in Pakistan. Infect Genet Evol 37:57–62.  https://doi.org/10.1016/j.meegid.2015.10.027CrossRefPubMedGoogle Scholar
  154. Yamaoka Y, Kwon DH, Graham DY (2000) A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci U S A 97:7533–7538.  https://doi.org/10.1073/pnas.130079797CrossRefPubMedPubMedCentralGoogle Scholar
  155. Yamaoka Y, Ojo O, Fujimoto S, Odenbreit S, Haas R, Gutierrez O, El-Zimaity HM, Reddy R, Arnqvist A, Graham DY (2006) Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut 55:775–781.  https://doi.org/10.1136/gut.2005.083014CrossRefPubMedPubMedCentralGoogle Scholar
  156. Yang I, Woltemate S, Piazuelo MB, Bravo LE, Yepez MC, Romero-Gallo J, Delgado AG, Wilson KT, Peek RM, Correa P, Josenhans C, Fox JG, Suerbaum S (2016) Different gastric microbiota compositions in two human populations with high and low gastric cancer risk in Colombia. Sci Rep 6:18594.  https://doi.org/10.1038/srep18594CrossRefPubMedPubMedCentralGoogle Scholar
  157. Yokoyama K, Higashi H, Ishikawa S, Fujii Y, Kondo S, Kato H, Azuma T, Wada A, Hirayama T, Aburatani H, Hatakeyama M (2005) Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci U S A 102:9661–9666.  https://doi.org/10.1073/pnas.0502529102CrossRefPubMedPubMedCentralGoogle Scholar
  158. Zhao Q, Busch B, Jimenez-Soto LF, Ishikawa-Ankerhold H, Massberg S, Terradot L, Fischer W, Haas R (2018) Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation. PLoS Pathog 14:e1007359.  https://doi.org/10.1371/journal.ppat.1007359CrossRefPubMedPubMedCentralGoogle Scholar
  159. 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 interaction. PloS Pathog 11:e1004621.  https://doi.org/10.1371/journal.ppat.1004621
  160. 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 5:25–40.  https://doi.org/10.1046/j.1462-5822.2003.00250.xCrossRefPubMedGoogle Scholar
  161. Zhou P, She Y, Dong N, Li P, He H, Borio A, Wu Q, Lu S, Ding X, Cao Y, Xu Y, Gao W, Dong M, Ding J, Wang D-C, Zamyatina A, Shao F (2018) Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561:122–126.  https://doi.org/10.1038/s41586-018-0433-3CrossRefPubMedGoogle Scholar
  162. Zimmermann S, Pfannkuch L, Al-Zeer MA, Bartfeld S, Koch M, Liu J, Rechner C, Soerensen M, Sokolova O, Zamyatina A, Kosma P, Mäurer 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 20:2384–2395.  https://doi.org/10.1101/139998CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sundus Javed
    • 1
    • 3
  • Emma C. Skoog
    • 1
  • Jay V. Solnick
    • 1
    • 2
    Email author
  1. 1.Department of Medicine, Department of Microbiology & Immunology, Center for Comparative MedicineUniversity of California, Davis School of MedicineDavisUSA
  2. 2.Center for Comparative MedicineUniversity of California, DavisDavisUSA
  3. 3.Department of BiosciencesCOMSATS Institute of Information TechnologyIslamabadPakistan

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