Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

References

  1. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 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.

    CAS  PubMed  Article  Google Scholar 

  3. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  5. 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.

    CAS  PubMed  Article  Google Scholar 

  6. 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.

    CAS  PubMed  Article  Google Scholar 

  7. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 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.

    CAS  PubMed  Article  Google Scholar 

  9. 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.

    CAS  PubMed  Article  Google Scholar 

  10. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  13. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  15. 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.

    CAS  PubMed  Article  Google Scholar 

  16. 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.

    PubMed  Article  CAS  Google Scholar 

  17. 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 

  18. 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.

    CAS  PubMed  Article  Google Scholar 

  19. 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.

    CAS  PubMed  Article  Google Scholar 

  20. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 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.

    CAS  PubMed  Article  Google Scholar 

  24. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 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.

    CAS  PubMed  Article  Google Scholar 

  27. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  31. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  33. 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.

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  35. 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.

    CAS  PubMed  Article  Google Scholar 

  36. 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.

    CAS  PubMed  Article  Google Scholar 

  37. 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.

    CAS  PubMed  Article  Google Scholar 

  38. 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.

    CAS  PubMed  Article  Google Scholar 

  39. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 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.

    CAS  PubMed  Article  Google Scholar 

  43. 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.

    CAS  PubMed  Article  Google Scholar 

  44. 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.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

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

Author information

Affiliations

Authors

Corresponding authors

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

Additional information

Conflict of Interest

The authors have no conflicts of interest to report.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Helicobacter pylori
  • type IV secretion system
  • CagL
  • polymorphism