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CagL polymorphisms between East Asian and Western Helicobacter pylori are associated with different abilities to induce IL-8 secretion

  • Microbial Pathogenesis and Host-Microbe Interaction
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Abstract

Helicobacter pylori colonizes human gastric mucosa. Its infection is associated with gastric diseases including gastric cancer. CagA is one of the most important toxins produced by H. pylori. It is related to gastric cancer which can be injected into host cells via a type IV secretion system (T4SS). CagL is a structural component of T4SS apparatus, which triggers host cell signaling pathway. It has been reported that CagL polymorphisms may influence the severity of disease development. To explore the contribution of CagL polymorphisms between East Asian and Western H. pylori in pathogenesis, cagL gene in G27 H. pylori was swapped by K74 cagL which is identical to East Asian CagL consensus sequence and by Western 26695 H. pylori, resulting in G27 ΔcagL/cagLK74 and G27 ΔcagL/cagL26695, respectively. Intriguingly, G27 ΔcagL/cagLK74 showed significantly less ability of IL-8 induction than G27 ΔcagL/cagL26695 while displayed similar abilities of CagA phosphorylation, and cell elongation. Taken together, this study suggests that the CagL polymorphism may influence IL-8 induction, and K74 CagL has less ability to induce IL-8 secretion than G27 or 26695 CagL. Further research should address how the different capabilities of IL-8 induction between intraspecies-CagL are associated with the large differences of the incidence of gastric cancer between East Asian and Western countries.

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References

  • Backert, S., Clyne, M., and Tegtmeyer, N. 2011. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun. Signal. 9, 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Backert, S., Moese, S., Selbach, M., Brinkmann, V., and Meyer, T.F. 2001. Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Mol. Microbiol. 42, 631–644.

    Article  CAS  PubMed  Google Scholar 

  • Backert, S., Schwarz, T., Miehlke, S., Kirsch, C., Sommer, C., Kwok, T., Gerhard, M., Goebel, U.B., Lehn, N., Koenig, W., et al. 2004. Functional analysis of the cag pathogenicity island in Helicobacter pylori isolates from patients with gastritis, peptic ulcer, and gastric cancer. Infect. Immun. 72, 1043–1056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Backert, S. and Selbach, M. 2008. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell. Microbiol. 10, 1573–1581.

    Article  CAS  PubMed  Google Scholar 

  • Barden, S., Lange, S., Tegtmeyer, N., Conradi, J., Sewald, N., Backert, S., and Niemann, H.H. 2013. A helical RGD motif promoting cell adhesion: crystal structures of the Helicobacter pylori type IV secretion system pilus protein CagL. Structure 21, 1931–1941.

    Article  CAS  PubMed  Google Scholar 

  • Barden, S. and Niemann, H.H. 2015. Adhesion of several cell lines to Helicobacter pylori CagL is mediated by integrin αvβ6via an RGDLXXL motif. J. Mol. Biol. 427, 1304–1315.

    Article  CAS  PubMed  Google Scholar 

  • Brandt, S., Kwok, T., Hartig, R., König, W., and Backert, S. 2005. NF-κB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc. Natl. Acad. Sci. USA 102, 9300–9305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi, J.M., Choi, Y.H., Sudhanva, M.S., Devakumar, S., Lee, K.H., Cha, J.H., and Lee, S.H. 2015. Crystal structure of CagL from Helicobacter pylori K74 strain. Biochem. Biophys. Res. Commun. 460, 964–970.

    Article  CAS  PubMed  Google Scholar 

  • Conradi, J., Huber, S., Gaus, K., Mertink, F., Royo Gracia, S., Strijowski, U., Backert, S., and Sewald, N. 2012a. Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins αvβ3 and α5β1. Amino Acids 43, 219–232.

    Article  CAS  PubMed  Google Scholar 

  • Conradi, J., Tegtmeyer, N., Woźna, M., Wissbrock, M., Michalek, C., Gagell, C., Cover, T.L., Frank, R., Sewald, N., and Backert, S. 2012b. An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA. Front. Cell. Infect. Microbiol. 2, 70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Copass, M., Grandi, G., and Rappuoli, R. 1997. Introduction of unmarked mutations in the Helicobacter pylori vacA gene with a sucrose sensitivity marker. Infect. Immun. 65, 1949–1952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cover, T.L. 2012. Role of Helicobacter pylori CagL in modulating gastrin expression. Gut 61, 965–966.

    Article  CAS  PubMed  Google Scholar 

  • Duncan, S.S., Valk, P.L., McClain, M.S., Shaffer, C.L., Metcalf, J.A., Bordenstein, S.R., and Cover, T.L. 2013. Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes. PLoS ONE 8, e55120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eusebi, L.H., Zagari, R.M., and Bazzoli, F. 2014. Epidemiology of Helicobacter pylori infection. Helicobacter 19, 1–5.

    Article  PubMed  Google Scholar 

  • Fu, H.Y., Asahi, K., Hayashi, Y., Eguchi, H., Murata, H., Tsujii, M., Tsuji, S., Azuma, T., and Kawano, S. 2007. East Asian-type Helicobacter pylori cytotoxin-associated gene A protein has a more significant effect on growth of rat gastric mucosal cells than the Western type. J. Gastroenterol. Hepatol. 22, 355–362.

    Article  CAS  PubMed  Google Scholar 

  • Gunawardhana, N., Jang, S., Choi, Y.H., Hong, Y.A., Jeon, Y.E., Kim, A., Su, H., Kim, J.H., Yoo, Y.J., Merrell, D.S., et al. 2017. Helicobacter pylori-induced HB-EGF upregulates gastrin expression via the EGF Receptor, C-Raf, Mek1, and Erk2 in the MAPK pathway. Front. Cell. Infect. Microbiol. 7, 541.

    Article  PubMed  CAS  Google Scholar 

  • International Agency for Research on Cancer, IARC. 1994. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evalucation of Carcinogenic Risks to Humans. Lyon, 7–14 June. IARC Monogr. Eval. Carcinog. Risks Hum. 61, 1–241.

    Google Scholar 

  • Jang, S., Jones, K.R., Olsen, C.H., Joo, Y.M., Yoo, Y.J., Chung, I.S., Cha, J.H., and Merrell, D.S. 2010. Epidemiological link between gastric disease and polymorphisms in VacA and CagA. J. Clin. Microbiol. 48, 559–567.

    Article  CAS  PubMed  Google Scholar 

  • Jones, K.R., Jang, S., Chang, J.Y., Kim, J., Chung, I.S., Olsen, C.H., Merrell, D.S., and Cha, J.H. 2011. Polymorphisms in the intermediate region of VacA impact Helicobacter pylori-induced disease development. J. Clin. Microbiol. 49, 101–110.

    Article  CAS  PubMed  Google Scholar 

  • Jones, K.R., Joo, Y.M., Jang, S., Yoo, Y.J., Lee, H.S., Chung, I.S., Olsen, C.H., Whitmire, J.M., Merrell, D.S., and Cha, J.H. 2009. Polymorphism in the CagA EPIYA motif impacts development of gastric cancer. J. Clin. Microbiol. 47, 959–968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang, J., Jones, K.R., Jang, S., Olsen, C.H., Yoo, Y.J., Merrell, D.S., and Cha, J.H. 2012. The geographic origin of Helicobacter pylori influences the association of the homB gene with gastric cancer. J. Clin. Microbiol. 50, 1082–1085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, A., Servetas, S.L., Kang, J., Kim, J., Jang, S., Cha, H.J., Lee, W.J., Kim, J., Romero-Gallo, J., Peek, R.M.Jr., et al. 2015. Helicobacter pylori bab paralog distribution and association with cagA, vacA, and homA/B genotypes in American and South Korean clinical isolates. PLoS ONE 10, e0137078.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R., Wessler, S., Misselwitz, R., Berger, J., Sewald, N., König, W., et al. 2007. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449, 862–866.

    Article  CAS  PubMed  Google Scholar 

  • Moese, S., Selbach, M., Kwok, T., Brinkmann, V., König, W., Meyer, T.F., and Backert, S. 2004. Helicobacter pylori induces AGS cell motility and elongation via independent signaling pathways. Infect. Immun. 72, 3646–3649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moodley, Y., Linz, B., Bond, R.P., Nieuwoudt, M., Soodyall, H., Schlebusch, C.M., Bernhöft, S., Hale, J., Suerbaum, S., Mugisha, L., et al. 2012. Age of the association between Helicobacter pylori and man. PLoS Pathog. 8, e1002693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Odenbreit, S., Püls, J., Sedlmaier, B., Gerland, E., Fischer, W., and Haas, R. 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287, 1497–1500.

    Article  CAS  PubMed  Google Scholar 

  • Ogawa, H., Iwamoto, A., Tanahashi, T., Okada, R., Yamamoto, K., Nishiumi, S., Yoshida, M., and Azuma, T.J. 2017. Genetic variants of Helicobacter pylori type IV secretion system components CagL and CagI and their association with clinical outcomes. Gut Pathog. 9, 21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Olbermann, P., Josenhans, C., Moodley, Y., Uhr, M., Stamer, C., Vauterin, M., Suerbaum, S., Achtman, M., and Linz, B. 2010. A global overview of the genetic and functional diversity in the Helicobacter pylori cag pathogenicity island. PLoS Genet. 6, e1001069.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Posselt, G., Backert, S., and 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rahman, R., Asombang, A.W., and Ibdah, J.A. 2014. Characteristics of gastric cancer in Asia. World J. Gastroenterol. 20, 4483–4490.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rieder, G., Hatz, R.A., Moran, A.P., Walz, A., Stolte, M., and Enders, G. 1997. Role of adherence in interleukin-8 induction in Helicobacter pylori-associated gastritis. Infect. Immun. 65, 3622–3630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Russo, A.E. and Strong, V.E. 2019. Gastric cancer etiology and management in Asia and the West. Annu. Rev. Med. 70, 353–367.

    Article  CAS  PubMed  Google Scholar 

  • Servetas, S.L., Kim, A., Su, H., Cha, J.H., and Merrell, D.S. 2018. Comparative analysis of the Hom family of outer membrane proteins in isolates from two geographically distinct regions: The United States and South Korea. Helicobacter 23, e12461.

    Article  PubMed  CAS  Google Scholar 

  • Shin, A., Kim, J., and Park, S. 2011. Gastric cancer epidemiology in Korea. J. Gastric. Cancer 11, 135–140.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shukla, S.K., Prasad, K.N., Tripathi, A., Jaiswal, V., Khatoon, J., Ghsohal, U.C., Krishnani, N., and Husain, N. 2013. Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases. Gastric Cancer 16, 435–439.

    Article  CAS  PubMed  Google Scholar 

  • Sokolova, O., Borgmann, M., Rieke, C., Schweitzer, K., Rothkötter, H.J., and Naumann, M. 2013. Helicobacter pylori induces type 4 secretion system-dependent, but CagA-independent activation of IκBs and NF-κB/RelA at early time points. Int. J. Med. Microbiol. 303, 548–552.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki, M., Mimuro, H., Kiga, K., Fukumatsu, M., Ishijima, N., Morikawa, H., Nagai, S., Koyasu, S., Gilman, R.H., Kersulyte, D., et al. 2009. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 5, 23–34.

    Article  CAS  PubMed  Google Scholar 

  • Tammer, I., Brandt, S., Hartig, R., König, W., and Backert, S. 2007. Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 132, 1309–1319.

    Article  CAS  PubMed  Google Scholar 

  • Tegtmeyer, N., Hartig, R., Delahay, R.M., Rohde, M., Brandt, S., Conradi, J., Takahashi, S., Smolka, A.J., Sewald, N., and Backert, S. 2010. A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J. Biol. Chem. 285, 23515–23526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tegtmeyer, N., Lind, J., Schmid, B., and Backert, S. 2014. Helicobacter pylori CagL Y58/E59 mutation turns-off type IV secretion-dependent delivery of CagA into host cells. PLoS ONE 9, e97782.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tegtmeyer, N., Wessler, S., and Backert, S. 2011. Role of the cag pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J. 278, 1190–1202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tegtmeyer, N., Zabler, D., Schmidt, D., Hartig, R., Brandt, S., and Backert, S. 2009. Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol. 11, 488–505.

    Article  CAS  PubMed  Google Scholar 

  • Wiedemann, T., Hofbaur, S., Tegtmeyer, N., Huber, S., Sewald, N., Wessler, S., Backert, S., and Rieder, G. 2012. Helicobacter pylori CagL dependent induction of gastrin expression via a novel αvβ5-integrin-integrin linked kinase signalling complex. Gut 61, 986–996.

    Article  CAS  PubMed  Google Scholar 

  • Yeh, Y.C., Chang, W.L., Yang, H.B., Cheng, H.C., Wu, J.J., and Sheu, B.S. 2011. H. pylori cagL amino acid sequence polymorphism Y58E59 induces a corpus shift of gastric integrin α5β1 related with gastric carcinogenesis. Mol. Carcinog. 50, 751–759.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Korean College of Helicobacter and Upper Gastrointestinal Research Foundation Grant KCHUGR-202001005.

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Correspondence to Hanfu Su, Linhu Ge or Jeong-Heon Cha.

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Choi, Y.H., Lai, J., Kim, MA. et al. CagL polymorphisms between East Asian and Western Helicobacter pylori are associated with different abilities to induce IL-8 secretion. J Microbiol. 59, 763–770 (2021). https://doi.org/10.1007/s12275-021-1136-2

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  • DOI: https://doi.org/10.1007/s12275-021-1136-2

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