Archives of Clinical Infectious Diseases

Published by: Kowsar

Functional Cytotoxin Associated Gene A in Helicobacter pylori Strains and Its Association with Integrity of Cag-pathogenicity Island and Histopathological Changes of Gastric Tissue

Zeinab Fazeli 1 , Masoud Alebouyeh 2 , 3 , * , Mostafa Rezaei Tavirani 1 , ** , Abbas Yadegar 2 , Nastaran Farzi 2 and Mohammad Reza Zali 2 , 3
Authors Information
1 Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Corresponding Authors:
Article information
  • Archives of Clinical Infectious Diseases: July 2017, 12 (3); e62955
  • Published Online: July 31, 2017
  • Article Type: Research Article
  • Received: August 9, 2016
  • Revised: February 17, 2017
  • Accepted: March 14, 2017
  • DOI: 10.5812/archcid.62955

To Cite: Fazeli Z, Alebouyeh M, Rezaei Tavirani M, Yadegar A, Farzi N, et al. Functional Cytotoxin Associated Gene A in Helicobacter pylori Strains and Its Association with Integrity of Cag-pathogenicity Island and Histopathological Changes of Gastric Tissue, Arch Clin Infect Dis. 2017 ; 12(3):e62955. doi: 10.5812/archcid.62955.

Copyright © 2017, Archives of Clinical Infectious Diseases. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
2. Methods
4. Results
5. Discussion
  • 1. Hatakeyama M. Helicobacter pylori and gastric carcinogenesis. J Gastroenterol. 2009; 44(4): 239-48[DOI][PubMed]
  • 2. Nagini S. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 2012; 4(7): 156-69[DOI][PubMed]
  • 3. Peek RJ, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002; 2(1): 28-37[DOI][PubMed]
  • 4. Farinha P, Gascoyne RD. Helicobacter pylori and MALT lymphoma. Gastroenterology. 2005; 128(6): 1579-605[DOI][PubMed]
  • 5. Wroblewski LE, Peek RJ, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010; 23(4): 713-39[DOI][PubMed]
  • 6. Aviles-Jimenez F, Reyes-Leon A, Nieto-Patlan E, Hansen LM, Burgueno J, Ramos IP, et al. In vivo expression of Helicobacter pylori virulence genes in patients with gastritis, ulcer, and gastric cancer. Infect Immun. 2012; 80(2): 594-601[DOI][PubMed]
  • 7. Chiurillo MA, Moran Y, Canas M, Valderrama E, Granda N, Sayegh M, et al. Genotyping of Helicobacter pylori virulence-associated genes shows high diversity of strains infecting patients in western Venezuela. Int J Infect Dis. 2013; 17(9)-6[DOI][PubMed]
  • 8. Cover TL. Helicobacter pylori Diversity and Gastric Cancer Risk. MBio. 2016; 7(1)-15[DOI][PubMed]
  • 9. Saribasak H, Salih BA, Yamaoka Y, Sander E. Analysis of Helicobacter pylori genotypes and correlation with clinical outcome in Turkey. J Clin Microbiol. 2004; 42(4): 1648-51[DOI][PubMed]
  • 10. Azuma T, Yamakawa A, Yamazaki S, Ohtani M, Ito Y, Muramatsu A, et al. Distinct diversity of the cag pathogenicity island among Helicobacter pylori strains in Japan. J Clin Microbiol. 2004; 42(6): 2508-17[DOI][PubMed]
  • 11. Olbermann P, Josenhans C, Moodley Y, Uhr M, Stamer C, Vauterin M, et al. A global overview of the genetic and functional diversity in the Helicobacter pylori cag pathogenicity island. PLoS Genet. 2010; 6(8)[DOI][PubMed]
  • 12. Brenner H, Arndt V, Stegmaier C, Ziegler H, Rothenbacher D. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer? Am J Epidemiol. 2004; 159(3): 252-8[DOI][PubMed]
  • 13. Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology. 2004; 127(2): 514-23[DOI][PubMed]
  • 14. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A. 1996; 93(25): 14648-53[DOI][PubMed]
  • 15. Terry CE, McGinnis LM, Madigan KC, Cao P, Cover TL, Liechti GW, et al. Genomic Comparison of cag pathogenicity island (PAI)-positive and -negative Helicobacter pylori strains: identification of novel markers for cag PAI-positive strains. Infect Immun. 2005; 73(6): 3794-8[DOI][PubMed]
  • 16. Fischer W, Puls J, Buhrdorf R, Gebert B, Odenbreit S, Haas R. Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol. 2001; 42(5): 1337-48[DOI][PubMed]
  • 17. Kauser F, Khan AA, Hussain MA, Carroll IM, Ahmad N, Tiwari S, et al. The cag pathogenicity island of Helicobacter pylori is disrupted in the majority of patient isolates from different human populations. J Clin Microbiol. 2004; 42(11): 5302-8[DOI][PubMed]
  • 18. Nguyen LT, Uchida T, Tsukamoto Y, Trinh TD, Ta L, Mai HB, et al. Clinical relevance of cagPAI intactness in Helicobacter pylori isolates from Vietnam. Eur J Clin Microbiol Infect Dis. 2010; 29(6): 651-60[DOI][PubMed]
  • 19. Busler VJ, Torres VJ, McClain MS, Tirado O, Friedman DB, Cover TL. Protein-protein interactions among Helicobacter pylori cag proteins. J Bacteriol. 2006; 188(13): 4787-800[DOI][PubMed]
  • 20. Kutter S, Buhrdorf R, Haas J, Schneider-Brachert W, Haas R, Fischer W. Protein subassemblies of the Helicobacter pylori Cag type IV secretion system revealed by localization and interaction studies. J Bacteriol. 2008; 190(6): 2161-71[DOI][PubMed]
  • 21. Selbach M, Moese S, Meyer TF, Backert S. Functional analysis of the Helicobacter pylori cag pathogenicity island reveals both VirD4-CagA-dependent and VirD4-CagA-independent mechanisms. Infect Immun. 2002; 70(2): 665-71[DOI][PubMed]
  • 22. Vannini A, Roncarati D, Spinsanti M, Scarlato V, Danielli A. In depth analysis of the Helicobacter pylori cag pathogenicity island transcriptional responses. PLoS One. 2014; 9(6)[DOI][PubMed]
  • 23. Kumar S, Kumar A, Dixit VK. Diversity in the cag pathogenicity island of Helicobacter pylori isolates in populations from North and South India. J Med Microbiol. 2010; 59: 32-40[DOI][PubMed]
  • 24. Nilsson C, Sillen A, Eriksson L, Strand ML, Enroth H, Normark S, et al. Correlation between cag pathogenicity island composition and Helicobacter pylori-associated gastroduodenal disease. Infect Immun. 2003; 71(11): 6573-81[DOI][PubMed]
  • 25. Backert S, Schwarz T, Miehlke S, Kirsch C, Sommer C, Kwok T, et al. Functional analysis of the cag pathogenicity island in Helicobacter pylori isolates from patients with gastritis, peptic ulcer, and gastric cancer. Infect Immun. 2004; 72(2): 1043-56[DOI][PubMed]
  • 26. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002; 295(5555): 683-6[DOI][PubMed]
  • 27. Kauser F, Hussain MA, Ahmed I, Ahmad N, Habeeb A, Khan AA, et al. Comparing genomes of Helicobacter pylori strains from the high-altitude desert of Ladakh, India. J Clin Microbiol. 2005; 43(4): 1538-45[DOI][PubMed]
  • 28. Vaziri F, Najar Peerayeh S, Alebouyeh M, Molaei M, Maghsoudi N, Zali MR. Determination of Helicobacter pylori CagA EPIYA types in Iranian isolates with different gastroduodenal disorders. Infect Genet Evol. 2013; 17: 101-5[DOI][PubMed]
  • 29. Yadegar A, Alebouyeh M, Zali MR. Analysis of the intactness of Helicobacter pylori cag pathogenicity island in Iranian strains by a new PCR-based strategy and its relationship with virulence genotypes and EPIYA motifs. Infect Genet Evol. 2015; 35: 19-26[DOI][PubMed]
  • 30. Mukhopadhyay AK, Kersulyte D, Jeong JY, Datta S, Ito Y, Chowdhury A, et al. Distinctiveness of genotypes of Helicobacter pylori in Calcutta, India. J Bacteriol. 2000; 182(11): 3219-27[DOI][PubMed]
  • 31. Schuelein R, Everingham P, Kwok T. Integrin-mediated type IV secretion by Helicobacter: what makes it tick? Trends Microbiol. 2011; 19(5): 211-6[DOI][PubMed]
  • 32. Tegtmeyer N, Wessler S, Backert S. Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J. 2011; 278(8): 1190-202[DOI][PubMed]
  • 33. Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 2006; 19(3): 449-90[DOI][PubMed]
  • 34. Ahmadzadeh A, Ghalehnoei H, Farzi N, Yadegar A, Alebouyeh M, Aghdaei HA, et al. Association of CagPAI integrity with severeness of Helicobacter pylori infection in patients with gastritis. Pathol Biol (Paris). 2015; 63(6): 252-7[DOI][PubMed]
  • 35. Matteo MJ, Granados G, Perez CV, Olmos M, Sanchez C, Catalano M. Helicobacter pylori cag pathogenicity island genotype diversity within the gastric niche of a single host. J Med Microbiol. 2007; 56: 664-9[DOI][PubMed]
  • 36. Gzyl A, Augustynowicz E, Dzierzanowska D, Rozynek E, Dura W, Celinska-Cedro D, et al. Genotypes of Helicobacter pylori in Polish population. Acta Microbiol Pol. 1999; 48(3): 261-75[PubMed]
  • 37. Gressmann H, Linz B, Ghai R, Pleissner KP, Schlapbach R, Yamaoka Y, et al. Gain and loss of multiple genes during the evolution of Helicobacter pylori. PLoS Genet. 2005; 1(4)[DOI][PubMed]
  • 38. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, et al. Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis. 2002; 186(11): 1621-30[DOI][PubMed]
  • 39. Ikenoue T, Maeda S, Ogura K, Akanuma M, Mitsuno Y, Imai Y, et al. Determination of Helicobacter pylori virulence by simple gene analysis of the cag pathogenicity island. Clin Diagn Lab Immunol. 2001; 8(1): 181-6[DOI][PubMed]
  • 40. Jenks PJ, Megraud F, Labigne A. Clinical outcome after infection with Helicobacter pylori does not appear to be reliably predicted by the presence of any of the genes of the cag pathogenicity island. Gut. 1998; 43(6): 752-8[DOI][PubMed]
  • 41. Kidd M, Lastovica AJ, Atherton JC, Louw JA. Conservation of the cag pathogenicity island is associated with vacA alleles and gastroduodenal disease in South African Helicobacter pylori isolates. Gut. 2001; 49(1): 11-7[DOI][PubMed]
  • 42. Maeda S, Yoshida H, Ikenoue T, Ogura K, Kanai F, Kato N, et al. Structure of cag pathogenicity island in Japanese Helicobacter pylori isolates. Gut. 1999; 44(3): 336-41[DOI][PubMed]
  • 43. Peters TM, Owen RJ, Slater E, Varea R, Teare EL, Saverymuttu S. Genetic diversity in the Helicobacter pylori cag pathogenicity island and effect on expression of anti-CagA serum antibody in UK patients with dyspepsia. J Clin Pathol. 2001; 54(3): 219-23[DOI][PubMed]
  • 44. Audibert C, Burucoa C, Janvier B, Fauchere JL. implication of the structure of the Helicobacter pylori cag pathogenicity island in induction of interleukin-8 secretion. Infect Immun. 2001; 69(3): 1625-9[DOI][PubMed]
  • 45. Ali M, Khan AA, Tiwari SK, Ahmed N, Rao LV, Habibullah CM. Association between cag-pathogenicity island in Helicobacter pylori isolates from peptic ulcer, gastric carcinoma, and non-ulcer dyspepsia subjects with histological changes. World J Gastroenterol. 2005; 11(43): 6815-22[PubMed]
  • 46. Lai CH, Perng CL, Lan KH, Lin HJ. Association of IS605 and cag-PAI of Helicobacter pylori Isolated from Patients with Gastrointestinal Diseases in Taiwan. Gastroenterol Res Pract. 2013; 2013: 356217[DOI][PubMed]
  • 47. Kawamura O, Murakami M, Araki O, Yamada T, Tomizawa S, Shimoyama Y, et al. Relationship between gastric disease and deletion of cag pathogenicity island genes of Helicobacter pylori in gastric juice. Dig Dis Sci. 2003; 48(1): 47-53[DOI][PubMed]
  • 48. Wang MY, Chen C, Gao XZ, Li J, Yue J, Ling F, et al. Distribution of Helicobacter pylori virulence markers in patients with gastroduodenal diseases in a region at high risk of gastric cancer. Microb Pathog. 2013; 59-60: 13-8[DOI][PubMed]
  • 49. Tegtmeyer N, Lind J, Schmid B, Backert S. Helicobacter pylori CagL Y58/E59 mutation turns-off type IV secretion-dependent delivery of CagA into host cells. PLoS One. 2014; 9(6)[DOI][PubMed]
  • 50. Loh JT, Shaffer CL, Piazuelo MB, Bravo LE, McClain MS, Correa P, et al. Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity. Cancer Epidemiol Biomarkers Prev. 2011; 20(10): 2237-49[DOI][PubMed]
  • 51. Szkaradkiewicz A, Karpinski TM, Linke K, Majewski P, Rozkiewicz D, Goslinska-Kuzniarek O. Expression of cagA, virB/D Complex and/or vacA Genes in Helicobacter pylori Strains Originating from Patients with Gastric Diseases. PLoS One. 2016; 11(2)[DOI][PubMed]
  • 52. Fajardo CA, Quiroga AJ, Coronado A, Labrador K, Acosta N, Delgado P, et al. CagA EPIYA polymorphisms in Colombian Helicobacter pylori strains and their influence on disease-associated cellular responses. World J Gastrointest Oncol. 2013; 5(3): 50-9[DOI][PubMed]
  • 53. Hayashi T, Morohashi H, Hatakeyama M. Bacterial EPIYA effectors--where do they come from? What are they? Where are they going? Cell Microbiol. 2013; 15(3): 377-85[DOI][PubMed]
  • 54. Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol. 2002; 43(4): 971-80[PubMed]
  • 55. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, et al. 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. 2002; 99(22): 14428-33[DOI][PubMed]
  • 56. Sheu SM, Hung KH, Sheu BS, Yang HB, Wu JJ. Association of nonsynonymous substitutions in the intermediate region of the vacA gene of Helicobacter pylori with gastric diseases in Taiwan. J Clin Microbiol. 2009; 47(1): 249-51[DOI][PubMed]
  • 57. Shokrzadeh L, Baghaei K, Yamaoka Y, Dabiri H, Jafari F, Sahebekhtiari N, et al. Analysis of 3'-end variable region of the cagA gene in Helicobacter pylori isolated from Iranian population. J Gastroenterol Hepatol. 2010; 25(1): 172-7[DOI][PubMed]
  • 58. Peek RJ. Pathogenesis of Helicobacter pylori infection. Springer Semin Immunopathol. 2005; 27(2): 197-215[DOI][PubMed]
  • 59. Ogura K, Maeda S, Nakao M, Watanabe T, Tada M, Kyutoku T, et al. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med. 2000; 192(11): 1601-10[DOI][PubMed]
  • 60. You WC, Zhang L, Gail MH, Chang YS, Liu WD, Ma JL, et al. Gastric dysplasia and gastric cancer: Helicobacter pylori, serum vitamin C, and other risk factors. J Natl Cancer Inst. 2000; 92(19): 1607-12[DOI][PubMed]
Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .

Search Relations:



Create Citiation Alert
via Google Reader

Readers' Comments