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.
Sundus Javed and Emma C. Skoog—These authors contributed equally.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
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.1004234
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.0020143
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.68.7.4155-4168.2000
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.20030381
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.20172049
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.2010.06.047
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.1098801
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
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
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
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_8
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/toxins9040115
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
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
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
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.1003189
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.2016.08.014
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/nature05762
Baumler AJ, Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85–93. https://doi.org/10.1038/nature18849
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.12158
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
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.8018146
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.01239-17
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
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.2017.02.013
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 35:1–7
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.40.12.4504-4511.2002
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.2005.07.023
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.2018.03.085
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.i26.4242
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.01815-09
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.00485-06
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
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
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.90.12.5791
Cover TL, Blaser MJ (1992) Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 267:10570–10575
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)01035-4
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.2016.09.014
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.0.45551-0
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/10.1086/508426
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.02321-16
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 65:3462–3464
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.1080857
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.x
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.02001-15
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.1004450
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.01271-12
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.01168-17
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.1086871
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.96.22.12778
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 63:4154–4160
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
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.m109.052738
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
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.x
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.1000073
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.00094-17
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.2007.11.006
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.2004.10.020
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.222375399
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/ftx113
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.279.5349.373
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.m111.233601
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.1105175108
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.01779-16
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
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.1000684
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.01640-14
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.00293-09
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/srep46499
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/cws076
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.1318093111
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.14299
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
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/nature06187
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-2013-305178
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.0000000000006620
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
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
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
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.96.12.7011
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-06-4746
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.m611178200
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.1069076
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/jci34324
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.x
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.2013.4350
McClain MS, Beckett AC, Cover TL (2017) Helicobacter pylori vacuolating toxin and gastric cancer. Toxins (Basel) 9:E316. https://doi.org/10.3390/toxins9100316
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.183.22.6499-6508.2001
Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335:936–941. https://doi.org/10.1126/science.1214935
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.39.7.2463-2465.2001
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.2015.12.004
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
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/jci61143
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.2010.04.005
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.2017.10.014
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.01233-15
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/jci64373
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/10.1078/1438-4221-00205
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.x
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.1211248110
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.192.11.1601
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.0711183105
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/jiq090
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.1001069
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.x
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.m113.513135
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/27.16.3325
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.50.3.295
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
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.2018.03.004
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-11-77
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 61:1903–1909
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.01951-06
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.2007.06.056
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.2007.137539
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.x
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/jiu239
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.69.2.730-736.2001
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):6775–8
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.70.2.665-671.2002
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.2009.03.004
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.01275-10
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)00788-1
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.2007.11.003
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.1002237
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/nature08756
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/fnw275
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/10.1101/294769
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/10.1086/423142
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.1006514
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.01297-09
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/srep36442
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.x
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.2012.00046
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.x
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.00375.2010
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.x
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.00947-11
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):1309–19
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.x
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
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.13707
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.2017.09.005
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.179.5.1653
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.2016.158
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/ni1131
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/jiu154
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.pm9322503
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.0007736
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.m112.387498
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.m300117200
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.2015.10.027
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.130079797
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.2005.083014
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/srep18594
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.0502529102
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.1007359
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
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.x
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/s41586-018-0433-3
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/10.1101/139998
Acknowledgements
Work in the Solnick laboratory is supported by Public Health Service Grant R01 AI08713 from the NIH to JVS.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Javed, S., Skoog, E.C., Solnick, J.V. (2019). Impact of Helicobacter pylori Virulence Factors on the Host Immune Response and Gastric Pathology. In: Backert, S. (eds) Molecular Mechanisms of Inflammation: Induction, Resolution and Escape by Helicobacter pylori. Current Topics in Microbiology and Immunology, vol 421. Springer, Cham. https://doi.org/10.1007/978-3-030-15138-6_2
Download citation
DOI: https://doi.org/10.1007/978-3-030-15138-6_2
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-15137-9
Online ISBN: 978-3-030-15138-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)