Iranian Journal of Pathology

Vacuolating Cytotoxin A (VacA) and Extracellular Vesicles in Helicobacter pylori: Two Key Arms in Disease Development

Document Type : Review Article

Authors

Seyedeh Faride Alavi Rostami 1
Mansoor Khaledi 2, 3
Fatemeh Dalilian 4
Mahtab Mehboodi 5
Atefeh Akbari 6
Milad Shahini Shams Abadi 2
Pouria Khodaei Ataloo 7
Zeinab Mohsenipour 8
Samad Rastmanesh 9

1 Department of Microbiology, Faculty of Biological Sciences, Islamic Azad University Tehran-North Branch, Tehran, Iran

2 Department of Microbiology and Immunology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

3 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

4 Department of Microbiology, Mashhad University of Bacic science, Mashhad, Iran

5 Department of Medical Microbiology (Bacteriology & Virology), Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

6 Department of Microbiology, Faculty of Science, Qom branch, Islamic Azad University, Qom, Iran

7 Department of Microbiology, School of Medicine, Ardabil University of Medical Science, Ardabil, Iran

8 Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

9 Department of Bacteriology and Virology, School of Medicine, Tabriz University of Medical Science, Tabriz, Iran

https://doi.org/10.30699/ijp.2024.2031417.3312
Abstract
Extracellular vesicles (EVs) are cell-derived vesicles that play a critical role in host-pathogen interactions, facilitating intercellular communication and transporting both pathogen- and host-derived molecules during infection spread. To regulate their environment, for instance, by modulating innate and adaptive inflammatory immune responses, pathogens may alter the composition of EVs produced by infected cells. Gastric cancer is one of the leading causes of cancer-related deaths worldwide, and Helicobacter pylori infection is considered a significant risk factor for its development. This cancer is characterized by significant inflammation mediated by EVs generated from infected host cells. H. pylori contributes substantially to inflammation, promoting disease progression. Moreover, H. pylori produces and releases vesicles known as outer membrane vesicles (H. pylori-OMVs), which contribute to the shrinkage and cellular transformation of the gastric epithelium. Although the vacuolating cytotoxin A (VacA) plays a critical role in pathogenesis, its association with EVs in H. pylori has not been previously addressed. Understanding the roles of extracellular vesicles and VacA during H. pylori infection—whether they benefit the host or the pathogen—could pave the way for new treatment approaches. This review briefly discusses the role of VacA and extracellular vesicles in the growth and pathogenesis of H. pylori.

Keywords

Helicobacter disease
Extracellular vesicles، Disease development
Autophagy
Cell signaling
Immune cells

Subjects

  1. McClain MS, Beckett AC, Cover TL. Helicobacter pylori Vacuolating Toxin and Gastric Cancer. Toxins (Basel). 2017;9(10). [DOI:10.3390/toxins9100316] [PMID]
  2. Wroblewski LE, Peek RM, Jr., Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23(4):713-39. [DOI:10.1128/CMR.00011-10] [PMID]
  3. Kurokawa K, Itoh T, Kuwahara T, Oshima K, Toh H, Toyoda A, et al. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes. DNA Res. 2007;14(4):169-81. [DOI:10.1093/dnares/dsm018] [PMID]
  4. Sommer F, Backhed F. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol. 2013;11(4):227-38. [DOI:10.1038/nrmicro2974] [PMID]
  5. Tucci A, Bisceglia M, Rugge M, Tucci P, Marchegiani A, Papadopoli G, et al. Clinical usefulness of gastric-juice analysis in 2007: the stone that the builders rejected has become the cornerstone. Gastrointest Endosc. 2007;66(5):881-90. [DOI:10.1016/j.gie.2007.03.1052] [PMID]
  6. Yang Y, Shao Y, Zhu M, Li Q, Yang F, Lu X, et al. Using gastric juice lncRNA-ABHD11-AS1 as a novel type of biomarker in the screening of gastric cancer. Tumour Biol. 2016;37(1):1183-8. [DOI:10.1007/s13277-015-3903-3] [PMID]
  7. Kim JH, Lee J, Park J, Gho YS. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin Cell Dev Biol. 2015;40:97-104. [DOI:10.1016/j.semcdb.2015.02.006] [PMID]
  8. Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, Mantilla A, Torres J. Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep. 2014;4:4202. [DOI:10.1038/srep04202] [PMID] 
  9. Goldman CG, Loureiro JD, Matteo MJ, Catalano M, Gonzalez AB, Heredia SR, et al. Helicobacter spp. from gastric biopsies of stranded South American fur seals (Arctocephalus australis). Res Vet Sci. 2009;86(1):18-21. [DOI:10.1016/j.rvsc.2008.04.001] [PMID]
  10. Sause WE, Castillo AR, Ottemann KM. The Helicobacter pylori autotransporter ImaA (HP0289) modulates the immune response and contributes to host colonization. Infect Immun. 2012;80(7):2286-96. [DOI:10.1128/IAI.00312-12] [PMID]
  11. Eppinger M, Baar C, Linz B, Raddatz G, Lanz C, Keller H, et al. Who ate whom? Adaptive Helicobacter genomic changes that accompanied a host jump from early humans to large felines. PLoS Genet. 2006;2(7):e120. [DOI:10.1371/journal.pgen.0020120] [PMID]
  12. Gangwer KA, Shaffer CL, Suerbaum S, Lacy DB, Cover TL, Bordenstein SR. Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J Bacteriol. 2010;192(23):6126-35. [DOI:10.1128/JB.01081-10] [PMID]
  13. Fischer W, Buhrdorf R, Gerland E, Haas R. Outer membrane targeting of passenger proteins by the vacuolating cytotoxin autotransporter of Helicobacter pylori. Infect Immun. 2001;69(11):6769-75. [DOI:10.1128/IAI.69.11.6769-6775.2001] [PMID]
  14. Radin JN, Gaddy JA, Gonzalez-Rivera C, Loh JT, Algood HM, Cover TL. Flagellar localization of a Helicobacter pylori autotransporter protein. mBio. 2013;4(2):e00613-12. [DOI:10.1128/mBio.00613-12] [PMID]
  15. Kavermann H, Burns BP, Angermuller K, Odenbreit S, Fischer W, Melchers K, et al. Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J Exp Med. 2003;197(7):813-22. [DOI:10.1084/jem.20021531] [PMID]
  16. Voss BJ, Gaddy JA, McDonald WH, Cover TL. Analysis of surface-exposed outer membrane proteins in Helicobacter pylori. J Bacteriol. 2014;196(13):2455-71. [DOI:10.1128/JB.01768-14] [PMID]
  17. Forsyth MH, Cover TL. Mutational analysis of the vacA promoter provides insight into gene transcription in Helicobacter pylori. J Bacteriol. 1999;181(7):2261-6. [DOI:10.1128/JB.181.7.2261-2266.1999] [PMID]
  18. Czajkowsky DM, Iwamoto H, Cover TL, Shao Z. The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc Natl Acad Sci U S A. 1999;96(5):2001-6. [DOI:10.1073/pnas.96.5.2001] [PMID] 
  19. Terebiznik MR, Vazquez CL, Torbicki K, Banks D, Wang T, Hong W, et al. Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. Infect Immun. 2006;74(12):6599-614. [DOI:10.1128/IAI.01085-06] [PMID]
  20. Palframan SL, Kwok T, Gabriel K. Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Front Cell Infect Microbiol. 2012;2:92. [DOI:10.3389/fcimb.2012.00092] [PMID]
  21. McClain MS, Iwamoto H, Cao P, Vinion-Dubiel AD, Li Y, Szabo G, et al. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J Biol Chem. 2003;278(14): 12101-8. [DOI:10.1074/jbc.M212595200] [PMID]
  22. Tombola F, Morbiato L, Del Giudice G, Rappuoli R, Zoratti M, Papini E. The Helicobacter pylori VacA toxin is a urea permease that promotes urea diffusion across epithelia. J Clin Invest. 2001;108(6):929-37. [DOI:10.1172/JCI13045] [PMID]
  23. Kim S, Chamberlain AK, Bowie JU. Membrane channel structure of Helicobacter pylori vacuolating toxin: role of multiple GXXXG motifs in cylindrical channels. Proc Natl Acad Sci USA. 2004;101(16): 5988-91. [DOI:10.1073/pnas.0308694101] [PMID]
  24. Torres VJ, McClain MS, Cover TL. Interactions between p-33 and p-55 domains of the Helicobacter pylori vacuolating cytotoxin (VacA). J Biol Chem. 2004;279(3):2324-31. [DOI:10.1074/jbc.M310159200] [PMID]
  25. Gonzalez-Rivera C, Gangwer KA, McClain MS, Eli IM, Chambers MG, Ohi MD, et al. Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry. 2010;49(27):5743-52. [DOI:10.1021/bi100618g] [PMID]
  26. de Bernard M, Burroni D, Papini E, Rappuoli R, Telford J, Montecucco C. Identification of the Helicobacter pylori VacA toxin domain active in the cell cytosol. Infect Immun. 1998;66(12):6014-6. [DOI:10.1128/IAI.66.12.6014-6016.1998] [PMID]
  27. Junker M, Schuster CC, McDonnell AV, Sorg KA, Finn MC, Berger B, et al. Pertactin beta-helix folding mechanism suggests common themes for the secretion and folding of autotransporter proteins. Proc Natl Acad Sci U S A. 2006;103(13):4918-23. [DOI:10.1073/pnas.0507923103] [PMID] 
  28. Torres VJ, Ivie SE, McClain MS, Cover TL. Functional properties of the p33 and p55 domains of the Helicobacter pylori vacuolating cytotoxin. J Biol Chem. 2005;280(22):21107-14. [DOI:10.1074/jbc.M501042200] [PMID]
  29. de Bernard M, Arico B, Papini E, Rizzuto R, Grandi G, Rappuoli R, et al. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Microbiol. 1997;26(4):665-74. [DOI:10.1046/j.1365-2958.1997.5881952.x] [PMID]
  30. Ye D, Willhite DC, Blanke SR. Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J Biol Chem. 1999;274(14):9277-82. [DOI:10.1074/jbc.274.14.9277] [PMID]
  31. McClain MS, Cao P, Cover TL. Amino-terminal hydrophobic region of Helicobacter pylori vacuolating cytotoxin (VacA) mediates transmembrane protein dimerization. Infect Immun. 2001;69(2):1181-4. [DOI:10.1128/IAI.69.2.1181-1184.2001] [PMID] 
  32. Forsyth MH, Atherton JC, Blaser MJ, Cover TL. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun. 1998;66(7):3088-94. [DOI:10.1128/IAI.66.7.3088-3094.1998] [PMID]
  33. Ito Y, Azuma T, Ito S, Suto H, Miyaji H, Yamazaki Y, et al. Full-length sequence analysis of the vacA gene from cytotoxic and noncytotoxic Helicobacter pylori. J Infect Dis. 1998;178(5):1391-8. [DOI:10.1086/314435] [PMID]
  34. Duncan SS, Valk PL, McClain MS, Shaffer CL, Metcalf JA, Bordenstein SR, et al. Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes. PLoS One. 2013;8(1):e55120. [DOI:10.1371/journal.pone.0055120] [PMID] 
  35. Atherton JC, Cao P, Peek RM, Jr., Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 1995;270(30):17771-7. [DOI:10.1074/jbc.270.30.17771] [PMID]
  36. Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133(3):926-36. [DOI:10.1053/j.gastro.2007.06.056] [PMID]
  37. Letley DP, Atherton JC. Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J Bacteriol. 2000;182(11):3278-80. [DOI:10.1128/JB.182.11.3278-3280.2000] [PMID]
  38. Letley DP, Rhead JL, Twells RJ, Dove B, Atherton JC. Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J Biol Chem. 2003;278(29):26734-41. [DOI:10.1074/jbc.M304071200] [PMID]
  39. Pagliaccia C, de Bernard M, Lupetti P, Ji X, Burroni D, Cover TL, et al. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc Natl Acad Sci U S A. 1998;95(17):10212-7. [DOI:10.1073/pnas.95.17.10212] [PMID]
  40. Ji X, Fernandez T, Burroni D, Pagliaccia C, Atherton JC, Reyrat JM, et al. Cell specificity of Helicobacter pylori cytotoxin is determined by a short region in the polymorphic midregion. Infect Immun. 2000;68(6): 3754-7. [DOI:10.1128/IAI.68.6.3754-3757.2000] [PMID]
  41. Gonzalez-Rivera C, Algood HM, Radin JN, McClain MS, Cover TL. The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay. Infect Immun. 2012;80(8):2578-88. [DOI:10.1128/IAI.00052-12] [PMID]
  42. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94(22):1680-7. [DOI:10.1093/jnci/94.22.1680] [PMID]
  43. Cover TL. Helicobacter pylori Diversity and Gastric Cancer Risk. mBio. 2016;7(1):e01869-15. [DOI:10.1128/mBio.01869-15] [PMID] 
  44. Cover TL, Vaughn SG, Cao P, Blaser MJ. Potentiation of Helicobacter pylori vacuolating toxin activity by nicotine and other weak bases. J Infect Dis. 1992;166(5):1073-8. [DOI:10.1093/infdis/166.5.1073] [PMID]
  45. Papini E, de Bernard M, Milia E, Bugnoli M, Zerial M, Rappuoli R, et al. Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments. Proc Natl Acad Sci USA. 1994;91(21): 9720-4. [DOI:10.1073/pnas.91.21.9720] [PMID]
  46. Kern B, Jain U, Utsch C, Otto A, Busch B, Jimenez-Soto L, et al. Characterization of Helicobacter pylori VacA-containing vacuoles (VCVs), VacA intracellular trafficking and interference with calcium signalling in T lymphocytes. Cell Microbiol. 2015;17(12):1811-32. [DOI:10.1111/cmi.12474] [PMID]
  47. Szabo I, Brutsche S, Tombola F, Moschioni M, Satin B, Telford JL, et al. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. EMBO J. 1999;18(20):5517-27. [DOI:10.1093/emboj/18.20.5517] [PMID] 
  48. Ricci V, Sommi P, Fiocca R, Romano M, Solcia E, Ventura U. Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J Pathol. 1997;183(4):453-9. [DOI:10.1002/(SICI)1096-9896(199712)183:43.0.CO;2-2]
  49. Genisset C, Puhar A, Calore F, de Bernard M, Dell'Antone P, Montecucco C. The concerted action of the Helicobacter pylori cytotoxin VacA and of the v-ATPase proton pump induces swelling of isolated endosomes. Cell Microbiol. 2007;9(6):1481-90. [DOI:10.1111/j.1462-5822.2006.00886.x] [PMID]
  50. Satin B, Norais N, Telford J, Rappuoli R, Murgia M, Montecucco C, et al. Effect of helicobacter pylori vacuolating toxin on maturation and extracellular release of procathepsin D and on epidermal growth factor degradation. J Biol Chem. 1997;272(40):25022-8. [DOI:10.1074/jbc.272.40.25022] [PMID]
  51. Tan S, Noto JM, Romero-Gallo J, Peek RM, Jr., Amieva MR. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog. 2011;7(5):e1002050. [DOI:10.1371/journal.ppat.1002050] [PMID] 
  52. Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, et al. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med. 1998;187(1):135-40. [DOI:10.1084/jem.187.1.135] [PMID] 
  53. Terebiznik MR, Raju D, Vazquez CL, Torbricki K, Kulkarni R, Blanke SR, et al. Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy. 2009;5(3):370-9. [DOI:10.4161/auto.5.3.7663] [PMID]
  54. Yahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J, et al. Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J Biol Chem. 2012;287(37):31104-15. [DOI:10.1074/jbc.M112.387498] [PMID]
  55. Raju D, Hussey S, Ang M, Terebiznik MR, Sibony M, Galindo-Mata E, et al. Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology. 2012;142(5):1160-71. [DOI:10.1053/j.gastro.2012.01.043] [PMID] 
  56. Greenfield LK, Jones NL. Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol. 2013;21(11):602-12. [DOI:10.1016/j.tim.2013.09.004] [PMID]
  57. Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J, Nakayama M, et al. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J Biol Chem. 2006;281(16):11250-9. [DOI:10.1074/jbc.M509404200] [PMID]
  58. Willhite DC, Blanke SR. Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell Microbiol. 2004;6(2):143-54. [DOI:10.1046/j.1462-5822.2003.00347.x] [PMID]
  59. Willhite DC, Cover TL, Blanke SR. Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation. J Biol Chem. 2003;278(48):48204-9. [DOI:10.1074/jbc.M304131200] [PMID]
  60. Papini E, Satin B, Norais N, de Bernard M, Telford JL, Rappuoli R, et al. Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest. 1998;102(4): 813-20. [DOI:10.1172/JCI2764] [PMID]
  61. Pelicic V, Reyrat JM, Sartori L, Pagliaccia C, Rappuoli R, Telford JL, et al. Helicobacter pylori VacA cytotoxin associated with the bacteria increases epithelial permeability independently of its vacuolating activity. Microbiology (Reading). 1999;145 (Pt 8):2043-50. [DOI:10.1099/13500872-145-8-2043] [PMID]
  62. Foo JH, Culvenor JG, Ferrero RL, Kwok T, Lithgow T, Gabriel K. Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria. J Mol Biol. 2010;401(5): 792-8. [DOI:10.1016/j.jmb.2010.06.065] [PMID]
  63. Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, et al. Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells. Infect Immun. 2007;75(9):4472-81. [DOI:10.1128/IAI.00500-07] [PMID] 
  64. Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, et al. Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem. 2009;284(3):1612-9. [DOI:10.1074/jbc.M806981200] [PMID]
  65. Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, et al. Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet. 2003;33(3):375-81. [DOI:10.1038/ng1112] [PMID]
  66. Caputo R, Tuccillo C, Manzo BA, Zarrilli R, Tortora G, Blanco Cdel V, et al. Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an epidermal growth factor receptor-, cyclooxygenase-2-dependent mechanism. Clin Cancer Res. 2003;9(6): 2015-21.
  67. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300(5624):1430-4. [DOI:10.1126/science.1081919] [PMID]
  68. Yang Y, Du J, Liu F, Wang X, Li X, Li Y. Role of caspase-3/E-cadherin in helicobacter pylori-induced apoptosis of gastric epithelial cells. Oncotarget. 2017;8(35):59204-16. [DOI:10.18632/oncotarget.19471] [PMID]
  69. Radin JN, Gonzalez-Rivera C, Ivie SE, McClain MS, Cover TL. Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect Immun. 2011;79(7):2535-43. [DOI:10.1128/IAI.01370-10] [PMID] 
  70. Radin JN, Gonzalez-Rivera C, Frick-Cheng AE, Sheng J, Gaddy JA, Rubin DH, et al. Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect Immun. 2014;82(1):423-32. [DOI:10.1128/IAI.00827-13] [PMID]
  71. Kim IJ, Blanke SR. Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol. 2012;2:37. [DOI:10.3389/fcimb.2012.00037] [PMID] 
  72. Zheng PY, Jones NL. Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol. 2003;5(1):25-40. [DOI:10.1046/j.1462-5822.2003.00250.x] [PMID]
  73. Menaker RJ, Ceponis PJ, Jones NL. Helicobacter pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Infect Immun. 2004;72(5):2889-98. [DOI:10.1128/IAI.72.5.2889-2898.2004] [PMID]
  74. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med. 2003;198(12): 1887-97. [DOI:10.1084/jem.20030621] [PMID]
  75. Wang F, Xia P, Wu F, Wang D, Wang W, Ward T, et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem. 2008;283(39):26714-25. [DOI:10.1074/jbc.M800527200] [PMID] 
  76. Seto K, Hayashi-Kuwabara Y, Yoneta T, Suda H, Tamaki H. Vacuolation induced by cytotoxin from Helicobacter pylori is mediated by the EGF receptor in HeLa cells. FEBS Lett. 1998;431(3):347-50. [DOI:10.1016/S0014-5793(98)00788-1] [PMID]
  77. Gupta VR, Patel HK, Kostolansky SS, Ballivian RA, Eichberg J, Blanke SR. Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. PLoS Pathog. 2008;4(5):e1000073. [DOI:10.1371/journal.ppat.1000073] [PMID] 
  78. Geisse NA, Cover TL, Henderson RM, Edwardson JM. Targeting of Helicobacter pylori vacuolating toxin to lipid raft membrane domains analysed by atomic force microscopy. Biochem J. 2004;381(Pt 3):911-7. [DOI:10.1042/BJ20031719] [PMID]
  79. Sewald X, Gebert-Vogl B, Prassl S, Barwig I, Weiss E, Fabbri M, et al. Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microb. 2008;3(1):20-9. [DOI:10.1016/j.chom.2007.11.003] [PMID]
  80. Gauthier NC, Ricci V, Gounon P, Doye A, Tauc M, Poujeol P, et al. Glycosylphosphatidylinositol-anchored proteins and actin cytoskeleton modulate chloride transport by channels formed by the Helicobacter pylori vacuolating cytotoxin VacA in HeLa cells. J Biol Chem. 2004;279(10):9481-9. [DOI:10.1074/jbc.M312040200] [PMID]
  81. Schraw W, Li Y, McClain MS, van der Goot FG, Cover TL. Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J Biol Chem. 2002;277(37):34642-50. [DOI:10.1074/jbc.M203466200] [PMID]
  82. Salama NR, Otto G, Tompkins L, Falkow S. Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun. 2001;69(2):730-6. [DOI:10.1128/IAI.69.2.730-736.2001] [PMID] 
  83. Winter JA, Letley DP, Cook KW, Rhead JL, Zaitoun AA, Ingram RJ, et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J Infect Dis. 2014;210(6):954-63. [DOI:10.1093/infdis/jiu154] [PMID]
  84. Kim JM, Kim JS, Lee JY, Kim YJ, Youn HJ, Kim IY, et al. Vacuolating cytotoxin in Helicobacter pylori water-soluble proteins upregulates chemokine expression in human eosinophils via Ca2+ influx, mitochondrial reactive oxygen intermediates, and NF-kappaB activation. Infect Immun. 2007;75(7):3373-81. [DOI:10.1128/IAI.01940-06] [PMID]
  85. 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:10.1084/jem.192.11.1601] [PMID]
  86. Supajatura V, Ushio H, Wada A, Yahiro K, Okumura K, Ogawa H, et al. Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J Immunol. 2002;168(6):2603-7. [DOI:10.4049/jimmunol.168.6.2603] [PMID]
  87. Marchetti M, Arico B, Burroni D, Figura N, Rappuoli R, Ghiara P. Development of a mouse model of Helicobacter pylori infection that mimics human disease. Science. 1995;267(5204):1655-8. [DOI:10.1126/science.7886456] [PMID]
  88. Liu KY, Shi Y, Luo P, Yu S, Chen L, Zhao Z, et al. Therapeutic efficacy of oral immunization with attenuated Salmonella typhimurium expressing Helicobacter pylori CagA, VacA and UreB fusion proteins in mice model. Vaccine. 2011;29(38):6679-85. [DOI:10.1016/j.vaccine.2011.06.099] [PMID]
  89. Rossi G, Ruggiero P, Peppoloni S, Pancotto L, Fortuna D, Lauretti L, et al. Therapeutic vaccination against Helicobacter pylori in the beagle dog experimental model: safety, immunogenicity, and efficacy. Infect Immun. 2004;72(6):3252-9. [DOI:10.1128/IAI.72.6.3252-3259.2004] [PMID] 
  90. Ghiara P, Rossi M, Marchetti M, Di Tommaso A, Vindigni C, Ciampolini F, et al. Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection. Infect Immun. 1997;65(12):4996-5002. [DOI:10.1128/iai.65.12.4996-5002.1997] [PMID]
  91. Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology. 2009;136(6):1863-73. [DOI:10.1053/j.gastro.2009.01.073] [PMID]
  92. Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest. 2009;119(9):2475-87. [DOI:10.1172/JCI38605] [PMID]
  93. Oertli M, Sundquist M, Hitzler I, Engler DB, Arnold IC, Reuter S, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest. 2012;122(3):1082-96. [DOI:10.1172/JCI61029] [PMID]
  94. Engler DB, Reuter S, van Wijck Y, Urban S, Kyburz A, Maxeiner J, et al. Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc Natl Acad Sci USA. 2014;111(32):11810-5. [DOI:10.1073/pnas.1410579111] [PMID]
  95. Harris PR, Cover TL, Crowe DR, Orenstein JM, Graham MF, Blaser MJ, et al. Helicobacter pylori cytotoxin induces vacuolation of primary human mucosal epithelial cells. Infect Immun. 1996;64(11): 4867-71. [DOI:10.1128/iai.64.11.4867-4871.1996] [PMID]
  96. Fiocca R, Luinetti O, Villani L, Chiaravalli AM, Capella C, Solcia E. Epithelial cytotoxicity, immune responses, and inflammatory components of Helicobacter pylori gastritis. Scand J Gastroenterol Suppl. 1994;205:11-21. [DOI:10.3109/00365529409091404] [PMID]
  97. Jones KR, Whitmire JM, Merrell DS. A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease. Front Microbiol. 2010;1:115. [DOI:10.3389/fmicb.2010.00115] [PMID]
  98. Argent RH, Thomas RJ, Letley DP, Rittig MG, Hardie KR, Atherton JC. Functional association between the Helicobacter pylori virulence factors VacA and CagA. J Med Microbiol. 2008;57(Pt 2):145-50. [DOI:10.1099/jmm.0.47465-0] [PMID]
  99. Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microb. 2012;12(6):764-77. [DOI:10.1016/j.chom.2012.10.014] [PMID]
  100. Gu H. Role of Flagella in the Pathogenesis of Helicobacter pylori. Curr Microbiol. 2017;74(7):863-9. [DOI:10.1007/s00284-017-1256-4] [PMID]
  101. Saberi S, Esmaeili M, Saghiri R, Shekari F, Mohammadi M. Assessment of the mixed origin of the gastric epithelial extracellular vesicles in acellular transfer of Helicobacter pylori toxins and a systematic review. Microb Pathog. 2023;177:106024. [DOI:10.1016/j.micpath.2023.106024] [PMID]
  102. Kao CY, Sheu BS, Wu JJ. Helicobacter pylori infection: An overview of bacterial virulence factors and pathogenesis. Biomed J. 2016;39(1):14-23. [DOI:10.1016/j.bj.2015.06.002] [PMID]
  103. Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun. 2001;69(8):5080-7. [DOI:10.1128/IAI.69.8.5080-5087.2001] [PMID]
  104. Qiang L, Hu J, Tian M, Li Y, Ren C, Deng Y, et al. Extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles in atherosclerosis. Helicobacter. 2022;27(2):e12877. [DOI:10.1111/hel.12877] [PMID]
  105. Shiota S, Matsunari O, Watada M, Yamaoka Y. Serum Helicobacter pylori CagA antibody as a biomarker for gastric cancer in east-Asian countries. Future Microbiol. 2010;5(12):1885-93. [DOI:10.2217/fmb.10.135] [PMID] 
  106. Zahmatkesh ME, Jahanbakhsh M, Hoseini N, Shegefti S, Peymani A, Dabin H, et al. Effects of Exosomes Derived From Helicobacter pylori Outer Membrane Vesicle-Infected Hepatocytes on Hepatic Stellate Cell Activation and Liver Fibrosis Induction. Front Cell Infect Microbiol. 2022;12:857570. [DOI:10.3389/fcimb.2022.857570] [PMID] 
  107. Mikołajczyk-Chmiela M, Walczak N, Rudnicka K. Helicobacter pylori outer membranę vesicles involvement in the infection development and Helicobacter pylori-related diseases. J Biomed Sci. 2018;25. [DOI:10.1186/s12929-018-0480-y] [PMID]
  108. Wang C, Li W, Shao L, Zhou A, Zhao M, Li P, et al. Both extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles are involved in gastric/extragastric diseases. Euro J Med Res. 2023;28(1):484. [DOI:10.1186/s40001-023-01458-z] [PMID]
  109. Chmiela M, Kupcinskas J. Helicobacter pylori and non-malignant upper gastrointestinal diseases. HELICOBACTER. 2019;24. [DOI:10.1111/hel.12638] [PMID]
  110. Choi H-I, Choi J-P, Seo J, Kim BJ, Rho M, Han JK, et al. Helicobacter pylori-derived extracellular vesicles increased in the gastric juices of gastric adenocarcinoma patients and induced inflammation mainly via specific targeting of gastric epithelial cells. Exp Mol Med. 2017;49(5):e330-e. [DOI:10.1038/emm.2017.47] [PMID] 
  111. Gao H, Wang JY, Shen XZ, Liu JJ. Effect of Helicobacter pylori infection on gastric epithelial cell proliferation. World J Gastroenterol. 2000;6(3):442-4. [DOI:10.3748/wjg.v6.i3.442] [PMID]
  112. Park KS, Lee J, Jang SC, Kim SR, Jang MH, Lotvall J, et al. Pulmonary inflammation induced by bacteria-free outer membrane vesicles from Pseudomonas aeruginosa. Am J Respir Cell Mol Biol. 2013;49(4): 637-45. [DOI:10.1165/rcmb.2012-0370OC] [PMID]
  113. Tong WW, Tong GH, Kong H, Liu Y. The tumor promoting roles of HSP60 and HIF2alpha in gastric cancer cells. Tumour Biol. 2016;37(7):9849-54. [DOI:10.1007/s13277-015-4783-2] [PMID]
  114. Yang Y, Dong K, Shao S. The effect of Helicobacter pylori on the expression of FRA-1 in gastric epithelial cells and its mechanism. Microb Pathog. 2019;129:257-65. [DOI:10.1016/j.micpath.2019.02.022] [PMID]
  115. Ricci V, Chiozzi V, Necchi V, Oldani A, Romano M, Solcia E, et al. Free-soluble and outer membrane vesicle-associated VacA from Helicobacter pylori: Two forms of release, a different activity. Biochem Biophys Res Commun. 2005;337(1):173-8. [DOI:10.1016/j.bbrc.2005.09.035] [PMID]
  116. Zhang J, Ji X, Liu S, Sun Z, Cao X, Liu B, et al. Helicobacter pylori infection promotes liver injury through an exosome-mediated mechanism. Microb Pathog. 2024;195:106898. [DOI:10.1016/j.micpath.2024.106898] [PMID]
  117. Hong SW, Kim MR, Lee EY, Kim JH, Kim YS, Jeon SG, et al. Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy. 2011;66(3):351-9. [DOI:10.1111/j.1398-9995.2010.02483.x] [PMID]
  118. Salvatori S, Marafini I, Laudisi F, Monteleone G, Stolfi C. Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms. Int J Mol Sci. 2023;24(3): 2895. [DOI:10.3390/ijms24032895] [PMID]
  119. Liu AR, Yan ZW, Jiang LY, Lv Z, Li YK, Wang BG. The role of non-coding RNA in the diagnosis and treatment of Helicobacter pylori-related gastric cancer, with a focus on inflammation and immune response. Front Med (Lausanne). 2022;9:1009021. [DOI:10.3389/fmed.2022.1009021] [PMID] 
  120. Zhang W, Jiang X, Bao J, Wang Y, Liu H, Tang L. Exosomes in Pathogen Infections: A Bridge to Deliver Molecules and Link Functions. Front Immunol. 2018;9:90. [DOI:10.3389/fimmu.2018.00090] [PMID]
  121. Marzhoseyni Z, Mousavi MJ, Ghotloo S. Helicobacter pylori antigens as immunomodulators of immune system. Helicobacter. 2024;29(1):e13058. [DOI:10.1111/hel.13058] [PMID]
  122. Polakovicova I, Jerez S, Wichmann IA, Sandoval-Borquez A, Carrasco-Veliz N, Corvalan AH. Role of microRNAs and Exosomes in Helicobacter pylori and Epstein-Barr Virus Associated Gastric Cancers. Front Microbiol. 2018;9:636. [DOI:10.3389/fmicb.2018.00636] [PMID] 
  123. Tang B, Xiao B, Liu Z, Li N, Zhu E-D, Li B-S, et al. Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett. 2010;584(8):1481-6. [DOI:10.1016/j.febslet.2010.02.063] [PMID]
  124. Libanio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol. 2015;6(5):111-32. [DOI:10.5306/wjco.v6.i5.111] [PMID]
  125. Winter J, Letley D, Rhead J, Atherton J, Robinson K. Helicobacter pylori membrane vesicles stimulate innate pro- and anti-inflammatory responses and induce apoptosis in Jurkat T cells. Infect Immun. 2014;82(4): 1372-81. [DOI:10.1128/IAI.01443-13] [PMID]
  126. Zhou S, Li C, Liu L, Yuan Q, Miao J, Wang H, et al. Gastric microbiota: an emerging player in gastric cancer. Front Microbiol. 2023;14:1130001. [DOI:10.3389/fmicb.2023.1130001] [PMID]
  127. Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F, Karaoz U, Contreras M, Blaser MJ, et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 2011;5(4):574-9. [DOI:10.1038/ismej.2010.149] [PMID]
  128. Zhang C, Powell SE, Betel D, Shah MA. The Gastric Microbiome and Its Influence on Gastric Carcinogenesis: Current Knowledge and Ongoing Research. Hematol Oncol Clin North Am. 2017;31(3):389-408. [DOI:10.1016/j.hoc.2017.01.002] [PMID]
Iranian Journal of Pathology
Volume 20, Issue 1
Winter 2025
Pages 1-17

  • Receive Date 24 June 2024
  • Revise Date 08 October 2024
  • Accept Date 06 December 2024

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