Helicobacter pylori vacuolating toxin and gastric cancer

Toxins

Volumn 9, Issue 10, 2017, Pages

  McClain, Mark S ^a   Beckett, Amber C ^b   Cover, Timothy L ^a,b,c  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Gastric cancer; Helicobacter pylori; Pore forming toxins

Indexed keywords

VACUOLATING TOXIN; BACTERIAL PROTEIN; VACA PROTEIN, HELICOBACTER PYLORI;

AMINO ACID SEQUENCE; BACTERIUM ADHERENCE; CANCER RISK; CARCINOGENESIS; CELL MEMBRANE; ENZYME ACTIVITY; GENE; GOLGI COMPLEX; HELICOBACTER PYLORI; HYDROPHOBICITY; NONHUMAN; PEPTIC ULCER; PROTEIN EXPRESSION; REVIEW; STOMACH CANCER; VACA GENE; ALLELE; ANIMAL; DISEASE MODEL; GENETICS; HUMAN; MICROBIOLOGY; PATHOLOGY; PHYSIOLOGY; RISK FACTOR; STOMACH; STOMACH TUMOR; VIRULENCE;

ALLELES; ANIMALS; BACTERIAL PROTEINS; DISEASE MODELS, ANIMAL; HELICOBACTER PYLORI; HUMANS; RISK FACTORS; STOMACH; STOMACH NEOPLASMS; VIRULENCE;

EID: 85032857622     PISSN: None     EISSN: 20726651     Source Type: Journal    
DOI: 10.3390/toxins9100316     Document Type: Review

References (173)

1. Leunk, R.D., Johnson, P.T., David, B.C., Kraft, W.G., Morgan, D.R. Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J. Med. Microbiol. 1988, 26, 93-99.
2. Cover, T.L., Blaser, M.J. Purification and characterization of the vacuolating toxin from Helicobacter pylori. J. Biol. Chem. 1992, 267, 10570-10575.
3. Cover, T.L., Blanke, S.R. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat. Rev. Microbiol. 2005, 3, 320-332.
4. Boquet, P., Ricci, V. Intoxication strategy of Helicobacter pylori VacA toxin. Trends Microbiol. 2012, 20, 165-174.
5. Kim, I.J., Blanke, S.R. Remodeling the host environment: Modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front. Cell. Infect. Microbiol. 2012, 2, 37.
6. Foegeding, N.J., Caston, R.R., McClain, M.S., Ohi, M.D., Cover, T.L. An overview of Helicobacter pylori VacA toxin biology. Toxins 2016, 8, 173.
7. Smoot, D.T., Resau, J.H., Earlington, M.H., Simpson, M., Cover, T.L. Effects of Helicobacter pylori vacuolating cytotoxin on primary cultures of human gastric epithelial cells. Gut 1996, 39, 795-799.
8. Harris, P.R., Cover, T.L., Crowe, D.R., Orenstein, J.M., Graham, M.F., Blaser, M.J., Smith, P.D. Helicobacter pylori cytotoxin induces vacuolation of primary human mucosal epithelial cells. Infect. Immun. 1996, 64, 4867-4871.
9. Ricci, V. Relationship between VacA Toxin and Host Cell Autophagy in Helicobacter pylori Infection of the Human Stomach: A Few Answers, Many Questions. Toxins (Basel) 2016, 8, 203.
10. Utsch, C., Haas, R. VacA’s Induction of VacA-Containing Vacuoles (VCVs) and Their Immunomodulatory Activities on Human T Cells. Toxins (Basel) 2016, 8, 190.
11. Djekic, A., Muller, A. The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins (Basel) 2016, 8, 187.
12. Gangwer, K.A., Mushrush, D.J., Stauff, D.L., Spiller, B., McClain, M.S., Cover, T.L., Lacy, D.B. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc. Natl. Acad. Sci. USA 2007, 104, 16293-16298.
13. Gonzalez-Rivera, C., Campbell, A.M., Rutherford, S.A., Pyburn, T.M., Foegeding, N.J., Barke, T.L., Spiller, B.W., McClain, M.S., Ohi, M.D., Lacy, D.B., et al. A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain. Infect. Immun. 2016, 84, 2662-2670.
14. El-Bez, C., Adrian, M., Dubochet, J., Cover, T.L. High resolution structural analysis of Helicobacter pylori VacA toxin oligomers by cryo-negative staining electron microscopy. J. Struct. Biol. 2005, 151, 215-228.
15. Chambers, M.G., Pyburn, T.M., Gonzalez-Rivera, C., Collier, S.E., Eli, I., Yip, C.K., Takizawa, Y., Lacy, D.B., Cover, T.L., Ohi, M.D. Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin. J. Mol. Biol. 2013, 425, 524-535.
16. Cover, T.L., Tummuru, M.K.R., Cao, P., Thompson, S.A., Blaser, M.J. Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J. Biol. Chem. 1994, 269, 10566-10573.
17. Schmitt, W., Haas, R. Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: Structural similarities with the IgA protease type of exported protein. Mol. Microbiol. 1994, 12, 307-319.
18. Telford, J.L., Ghiara, P., Dell’Orco, M., Comanducci, M., Burroni, D., Bugnoli, M., Tecce, M.F., Censini, S., Covacci, A., Xiang, Z., et al. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J. Exp. Med. 1994, 179, 1653-1658.
19. Phadnis, S.H., Ilver, D., Janzon, L., Normark, S., Westblom, T.U. Pathological significance and molecular characterization of the vacuolating toxin gene of Helicobacter pylori. Infect. Immun. 1994, 62, 1557-1565.
20. 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, 6769-6775.
21. Voss, B.J., Gaddy, J.A., McDonald, W.H., Cover, T.L. Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori. J. Bacteriol. 2014, 196, 2455-2471.
22. Snider, C.A., Voss, B.J., McDonald, W.H., Cover, T.L. Growth phase-dependent composition of the Helicobacter pylori exoproteome. J. Proteom. 2016, 130, 94-107.
23. Lupetti, P., Heuser, J.E., Manetti, R., Massari, P., Lanzavecchia, S., Bellon, P.L., Dallai, R., Rappuoli, R., Telford, J.L. Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J. Cell Biol. 1996, 133, 801-807.
24. Nguyen, V.Q., Caprioli, R.M., Cover, T.L. Carboxy-terminal proteolytic processing of Helicobacter pylori vacuolating toxin. Infect. Immun. 2001, 69, 543-546.
25. Cover, T.L., Hanson, P.I., Heuser, J.E. Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J. Cell Biol. 1997, 138, 759-769.
26. Torres, V.J., McClain, M.S., Cover, T.L. Interactions between p-33 and p-55 domains of the Helicobacter pylori vacuolating cytotoxin (VacA). J. Biol. Chem. 2004, 279, 2324-2331.
27. Torres, V.J., Ivie, S.E., McClain, M.S., Cover, T.L. Functional properties of the p33 and p55 domains of the Helicobacter pylori vacuolating cytotoxin. J. Biol. Chem. 2005, 280, 21107-21114.
28. Gonzalez-Rivera, C., Gangwer, K.A., McClain, M.S., Eli, I.M., Chambers, M.G., Ohi, M.D., Lacy, D.B., Cover, T.L. Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry 2010, 49, 5743-5752.
29. Ye, D., Willhite, D.C., Blanke, S.R. Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J. Biol. Chem. 1999, 274, 9277-9282.
30. De Bernard, M., Arico, B., Papini, E., Rizzuto, R., Grandi, G., Rappuoli, R., Montecucco, C. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol. Microbiol. 1997, 26, 665-674.
31. 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, 6014-6016.
32. Schraw, W., Li, Y., McClain, M.S., van der Goot, F.G., Cover, T.L. Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J. Biol. Chem. 2002, 277, 34642-34650.
33. Patel, H.K., Willhite, D.C., Patel, R.M., Ye, D., Williams, C.L., Torres, E.M., Marty, K.B., MacDonald, R.A., Blanke, S.R. Plasma membrane cholesterol modulates cellular vacuolation induced by the Helicobacter pylori vacuolating cytotoxin. Infect. Immun. 2002, 70, 4112-4123.
34. Geisse, N.A., Cover, T.L., Henderson, R.M., Edwardson, J.M. Targeting of Helicobacter pylori vacuolating toxin to lipid raft membrane domains analysed by atomic force microscopy. Biochem. J. 2004, 381, 911-917.
35. Gupta, V.R., Patel, H.K., Kostolansky, S.S., Ballivian, R.A., Eichberg, J., Blanke, S.R. Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. PLoS Pathog. 2008, 4, e1000073.
36. Gupta, V.R., Wilson, B.A., Blanke, S.R. Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA. Cell. Microbiol. 2010, 12, 1517-1533.
37. Yahiro, K., Hirayama, T., Moss, J., Noda, M. New Insights into VacA Intoxication Mediated through Its Cell Surface Receptors. Toxins (Basel) 2016, 8.
38. Sewald, X., Gebert-Vogal, B., Prassl, S., Barwig, I., Weiss, E., Fabbri, M., Osicka, R., Schiemann, M., Busch, D.H., Semmrich, M., et al. CD18 is the T-lymphocyte receptor of the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 2008, 3, 20-29.
39. Garner, J.A., Cover, T.L. Binding and internalization of the Helicobacter pylori vacuolating cytotoxin by epithelial cells. Infect. Immun. 1996, 64, 4197-4203.
40. 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, 453-459.
41. McClain, M.S., Schraw, W., Ricci, V., Boquet, P., Cover, T.L. Acid-activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells. Mol. Microbiol. 2000, 37, 433-442.
42. Gauthier, N.C., Monzo, P., Gonzalez, T., Doye, A., Oldani, A., Gounon, P., Ricci, V., Cormont, M., Boquet, P. Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin. J. Cell Biol. 2007, 177, 343-354.
43. Gauthier, N.C., Monzo, P., Kaddai, V., Doye, A., Ricci, V., Boquet, P. Helicobacter pylori VacA cytotoxin: A probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol. Biol. Cell. 2005, 16, 4852-4866.
44. Li, Y., Wandinger-Ness, A., Goldenring, J.R., Cover, T.L. Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin. Mol. Biol. Cell 2004, 15, 1946-1959.
45. Galmiche, A., Rassow, J., Doye, A., Cagnol, S., Chambard, J.C., Contamin, S., de Thillot, V., Just, I., Ricci, V., Solcia, E., et al. The N-terminal 34 kDa fragment of helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J. 2000, 19, 6361-6370.
46. Willhite, D.C., Cover, T.L., Blanke, S.R. 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, 48204-48209.
47. Willhite, D.C., Blanke, S.R. 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, 143-154.
48. Calore, F., Genisset, C., Casellato, A., Rossato, M., Codolo, G., Esposti, M.D., Scorrano, L., de Bernard, M. Endosome-mitochondria juxtaposition during apoptosis induced by H. pylori VacA. Cell Death Differ. 2010, 17, 1707-1716.
49. Kern, B., Jain, U., Utsch, C., Otto, A., Busch, B., Jimenez-Soto, L., Becher, D., Haas, R. Characterization of Helicobacter pylori VacA-containing vacuoles (VCVs), VacA intracellular trafficking and interference with calcium signalling in T lymphocytes. Cell. Microbiol. 2015, 17, 1811-1832.
50. Czajkowsky, D.M., Iwamoto, H., Cover, T.L., Shao, Z. The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc. Natl. Acad. Sci. USA 1999, 96, 2001-2006.
51. Iwamoto, H., Czajkowsky, D.M., Cover, T.L., Szabo, G., Shao, Z. VacA from Helicobacter pylori: A hexameric chloride channel. FEBS Lett. 1999, 450, 101-104.
52. Tombola, F., Carlesso, C., Szabo, I., de Bernard, M., Reyrat, J.M., Telford, J.L., Rappuoli, R., Montecucco, C., Papini, E., Zoratti, M. Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: Possible implications for the mechanism of cellular vacuolation. Biophys. J. 1999, 76, 1401-1409.
53. Szabo, I., Brutsche, S., Tombola, F., Moschioni, M., Satin, B., Telford, J.L., Rappuoli, R., Montecucco, C., Papini, E., Zoratti, M. 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, 5517-5527.
54. Vinion-Dubiel, A.D., McClain, M.S., Czajkowsky, D.M., Iwamoto, H., Ye, D., Cao, P., Schraw, W., Szabo, G., Blanke, S.R., Shao, Z., et al. A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J. Biol. Chem. 1999, 274, 37736-37742.
55. McClain, M.S., Iwamoto, H., Cao, P., Vinion-Dubiel, A.D., Li, Y., Szabo, G., Shao, Z., Cover, T.L. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J. Biol. Chem. 2003, 278, 12101-12108.
56. Adrian, M., Cover, T.L., Dubochet, J., Heuser, J.E. Multiple oligomeric states of the Helicobacter pylori vacuolating toxin demonstrated by cryo-electron microscopy. J. Mol. Biol. 2002, 318, 121-133.
57. Czajkowsky, D.M., Iwamoto, H., Szabo, G., Cover, T.L., Shao, Z. Mimicry of a host anion channel by a Helicobacter pylori pore-forming toxin. Biophys. J. 2005, 89, 3093-3101.
58. Pyburn, T.M., Foegeding, N.J., Gonzalez-Rivera, C., McDonald, N.A., Gould, K.L., Cover, T.L., Ohi, M.D. Structural organization of membrane-inserted hexamers formed by Helicobacter pylori VacA toxin. Mol. Microbiol. 2016, 102, 22-36.
59. Papini, E., de Bernard, M., Milia, E., Bugnoli, M., Zerial, M., Rappuoli, R., Montecucco, C. Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments. Proc. Natl. Acad. Sci. USA 1994, 91, 9720-9724.
60. Molinari, M., Galli, C., Norais, N., Telford, J.L., Rappuoli, R., Luzio, J.P., Montecucco, C. Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. J. Biol. Chem. 1997, 272, 25339-25344.
61. Morbiato, L., Tombola, F., Campello, S., Del Giudice, G., Rappuoli, R., Zoratti, M., Papini, E. Vacuolation induced by VacA toxin of Helicobacter pylori requires the intracellular accumulation of membrane permeant bases, Cl(-) and water. FEBS Lett. 2001, 508, 479-483.
62. 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, 1481-1490.
63. Satin, B., Norais, N., Telford, J., Rappuoli, R., Murgia, M., Montecucco, C., Papini, E. 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, 25022-25028.
64. Molinari, M., Salio, M., Galli, C., Norais, N., Rappuoli, R., Lanzavecchia, A., Montecucco, C. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J. Exp. Med. 1998, 187, 135-140.
65. Tan, S., Noto, J.M., Romero-Gallo, J., Peek, R.M., Jr., Amieva, M.R. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog. 2011, 7, e1002050.
66. Kimura, M., Goto, S., Wada, A., Yahiro, K., Niidome, T., Hatakeyama, T., Aoyagi, H., Hirayama, T., Kondo, T. Vacuolating cytotoxin purified from Helicobacter pylori causes mitochondrial damage in human gastric cells. Microb. Pathog. 1999, 26, 45-52.
67. Yamasaki, E., Wada, A., Kumatori, A., Nakagawa, I., Funao, J., Nakayama, M., Hisatsune, J., Kimura, M., Moss, J., Hirayama, T. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J. Biol. Chem. 2006, 281, 11250-11259.
68. Jain, P., Luo, Z.Q., Blanke, S.R. Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc. Natl. Acad. Sci. USA 2011, 108, 16032-16037.
69. Kuck, D., Kolmerer, B., Iking-Konert, C., Krammer, P.H., Stremmel, W., Rudi, J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect. Immun. 2001, 69, 5080-5087.
70. Cover, T.L., Krishna, U.S., Israel, D.A., Peek, R.M., Jr. Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res. 2003, 63, 951-957.
71. Oldani, A., Cormont, M., Hofman, V., Chiozzi, V., Oregioni, O., Canonici, A., Sciullo, A., Sommi, P., Fabbri, A., Ricci, V., et al. Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog. 2009, 5, e1000603.
72. Radin, J.N., Gonzalez-Rivera, C., Ivie, S.E., McClain, M.S., Cover, T.L. Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect. Immun. 2011, 79, 2535-2543.
73. Matsumoto, A., Isomoto, H., Nakayama, M., Hisatsune, J., Nishi, Y., Nakashima, Y., Matsushima, K., Kurazono, H., Nakao, K., Hirayama, T., et al. Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-XL, leading to apoptosis in gastric epithelial cells. Dig. Dis. Sci. 2011, 56, 999-1006.
74. Ito, Y., Azuma, T., Ito, S., Suto, H., Miyaji, H., Yamazaki, Y., Kohli, Y., Kuriyama, M. Full-length sequence analysis of the vacA gene from cytotoxic and noncytotoxic Helicobacter pylori. J. Infect. Dis. 1998, 178, 1391-1398.
75. Atherton, J.C., Cao, P., Peek, R.M., Jr., Tummuru, M.K., Blaser, M.J., Cover, T.L. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J. Biol. Chem. 1995, 270, 17771-17777.
76. Letley, D.P., Atherton, J.C. Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J. Bacteriol. 2000, 182, 3278-3280.
77. McClain, M.S., Cao, P., Iwamoto, H., Vinion-Dubiel, A.D., Szabo, G., Shao, Z., Cover, T.L. 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. 2001, 183, 6499-6508.
78. Letley, D.P., Rhead, J.L., Twells, R.J., Dove, B., Atherton, J.C. Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J. Biol. Chem. 2003, 278, 26734-26741.
79. Gangwer, K.A., Shaffer, C.L., Suerbaum, S., Lacy, D.B., Cover, T.L., Bordenstein, S.R. Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J. Bacteriol. 2010, 192, 6126-6135.
80. Forsyth, M.H., Atherton, J.C., Blaser, M.J., Cover, T.L. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect. Immun. 1998, 66, 3088-3094.
81. Rhead, J.L., Letley, D.P., Mohammadi, M., Hussein, N., Mohagheghi, M.A., Eshagh Hosseini, M., Atherton, J.C. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 2007, 133, 926-936.
82. Ogiwara, H., Sugimoto, M., Ohno, T., Vilaichone, R.K., Mahachai, V., Graham, D.Y., Yamaoka, Y. Role of deletion located between the intermediate and middle regions of the Helicobacter pylori vacA gene in cases of gastroduodenal diseases. J. Clin. Microbiol. 2009, 47, 3493-3500.
83. Gonzalez-Rivera, C., Algood, H.M., Radin, J.N., McClain, M.S., Cover, T.L. The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay. Infect. Immun. 2012, 80, 2578-2588.
84. Pagliaccia, C., de Bernard, M., Lupetti, P., Ji, X., Burroni, D., Cover, T.L., Papini, E., Rappuoli, R., Telford, J.L., Reyrat, J.M. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc. Natl. Acad. Sci. USA 1998, 95, 10212-10217.
85. Ji, X., Fernandez, T., Burroni, D., Pagliaccia, C., Atherton, J.C., Reyrat, J.M., Rappuoli, R., Telford, J.L. Cell specificity of helicobacter pylori cytotoxin is determined by a short region in the polymorphic midregion. Infect. Immun. 2000, 68, 3754-3757.
86. Wang, W.-C., Wang, H.-J., Kuo, C.-H. Two distinctive cell binding patterns by vacuolating toxin fused with glutathione S-transferase: One high-affinity m1-specific binding and the other lower-affinity binding for variant m forms. Biochemistry 2001, 40, 11887-11896.
87. Skibinski, D.A., Genisset, C., Barone, S., Telford, J.L. The cell-specific phenotype of the polymorphic vacA midregion is independent of the appearance of the cell surface receptor protein tyrosine phosphatase beta. Infect. Immun. 2006, 74, 49-55.
88. Tombola, F., Pagliaccia, C., Campello, S., Telford, J.L., Montecucco, C., Papini, E., Zoratti, M. How the loop and middle regions influence the properties of Helicobacter pylori VacA channels. Biophys. J. 2001, 81, 3204-3215.
89. Yahiro, K., Satoh, M., Nakano, M., Hisatsune, J., Isomoto, H., Sap, J., Suzuki, H., Nomura, F., Noda, M., Moss, 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, 31104-31115.
90. Tsugawa, H., Suzuki, H., Saya, H., Hatakeyama, M., Hirayama, T., Hirata, K., Nagano, O., Matsuzaki, J., Hibi, T. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 2012, 12, 764-777.
91. Atherton, J.C., Sharp, P.M., Cover, T.L., Gonzalez-Valencia, G., Peek, R.M., Jr., Thompson, S.A., Hawkey, C.J., Blaser, M.J. Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori comprise two geographically widespread types, m1 and m2, and have evolved through limited recombination. Curr. Microbiol. 1999, 39, 211-218.
92. Pan, Z.J., Berg, D.E., van der Hulst, R.W., Su, W.W., Raudonikiene, A., Xiao, S.D., Dankert, J., Tytgat, G.N., van der Ende, A. Prevalence of vacuolating cytotoxin production and distribution of distinct vacA alleles in Helicobacter pylori from China. J. Infect. Dis. 1998, 178, 220-226.
93. Chung, C., Olivares, A., Torres, E., Yilmaz, O., Cohen, H., Perez-Perez, G. Diversity of VacA intermediate region among Helicobacter pylori strains from several regions of the world. J. Clin. Microbiol. 2010, 48, 690-696.
94. Letley, D.P., Lastovica, A., Louw, J.A., Hawkey, C.J., Atherton, J.C. Allelic diversity of the Helicobacter pylori vacuolating cytotoxin gene in South Africa: Rarity of the vacA s1a genotype and natural occurrence of an s2/m1 allele. J. Clin. Microbiol. 1999, 37, 1203-1205.
95. Bridge, D.R., Merrell, D.S. Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease. Gut Microbes 2013, 4, 101-117.
96. Ferreira, R.M., Machado, J.C., Figueiredo, C. Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. Best Pract. Res. Clin. Gastroenterol. 2014, 28, 1003-1015.
97. Thi Huyen Trang, T., Thanh Binh, T., Yamaoka, Y. Relationship between vacA Types and Development of Gastroduodenal Diseases. Toxins (Basel) 2016, 8, 182.
98. Figueiredo, C., Machado, J.C., Pharoah, P., Seruca, R., Sousa, S., Carvalho, R., Capelinha, A.F., Quint, W., Caldas, C., van Doorn, L.J., et al. Helicobacter pylori and interleukin 1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma. J. Natl. Cancer Inst. 2002, 94, 1680-1687.
99. Basso, D., Zambon, C.F., Letley, D.P., Stranges, A., Marchet, A., Rhead, J.L., Schiavon, S., Guariso, G., Ceroti, M., Nitti, D., et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008, 135, 91-99.
100. Miehlke, S., Kirsch, C., Agha-Amiri, K., Gunther, T., Lehn, N., Malfertheiner, P., Stolte, M., Ehninger, G., Bayerdorffer, E. The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany. Int. J. Cancer 2000, 87, 322-327.
101. Nogueira, C., Figueiredo, C., Carneiro, F., Gomes, A.T., Barreira, R., Figueira, P., Salgado, C., Belo, L., Peixoto, A., Bravo, J.C., et al. Helicobacter pylori genotypes may determine gastric histopathology. Am. J. Pathol. 2001, 158, 647-654.
102. Ashour, A.A., Magalhaes, P.P., Mendes, E.N., Collares, G.B., de Gusmao, V.R., Queiroz, D.M., Nogueira, A.M., Rocha, G.A., de Oliveira, C.A. Distribution of vacA genotypes in Helicobacter pylori strains isolated from Brazilian adult patients with gastritis, duodenal ulcer or gastric carcinoma. FEMS Immunol. Med. Microbiol. 2002, 33, 173-178.
103. Gonzalez, C.A., Figueiredo, C., Lic, C.B., Ferreira, R.M., Pardo, M.L., Ruiz Liso, J.M., Alonso, P., Sala, N., Capella, G., Sanz-Anquela, J.M. Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: A long-term follow-up in a high-risk area in Spain. Am. J. Gastroenterol. 2011, 106, 867-874.
104. Matos, J.I., de Sousa, H.A., Marcos-Pinto, R., Dinis-Ribeiro, M. Helicobacter pylori CagA and VacA genotypes and gastric phenotype: A meta-analysis. Eur. J. Gastroenterol. Hepatol. 2013, 25, 1431-1441.
105. Ferreira, R.M., Machado, J.C., Letley, D., Atherton, J.C., Pardo, M.L., Gonzalez, C.A., Carneiro, F., Figueiredo, C. A novel method for genotyping the Helicobacter pylori vacA intermediate region directly in gastric biopsy specimens. J. Clin. Microbiol. 2012, 50, 3983-3989.
106. Memon, A.A., Hussein, N.R., Miendje Deyi, V.Y., Burette, A., Atherton, J.C. Vacuolating cytotoxin genotypes are strong markers of gastric cancer and duodenal ulcer-associated Helicobacter pylori strains: A matched case-control study. J. Clin. Microbiol. 2014, 52, 2984-2989.
107. Winter, J.A., Letley, D.P., Cook, K.W., Rhead, J.L., Zaitoun, A.A., Ingram, R.J., Amilon, K.R., Croxall, N.J., Kaye, P.V., Robinson, K., et al. A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. J. Infect. Dis. 2014, 210, 954-963.
108. Atherton, J.C., Peek, R.M., Jr., Tham, K.T., Cover, T.L., Blaser, M.J. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 1997, 112, 92-99.
109. Van Doorn, L.J., Figueiredo, C., Sanna, R., Plaisier, A., Schneeberger, P., de Boer, W., Quint, W. Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori. Gastroenterology 1998, 115, 58-66.
110. Van Doorn, L.J., Figueiredo, C., Megraud, F., Pena, S., Midolo, P., Queiroz, D.M., Carneiro, F., Vanderborght, B., Pegado, M.D., Sanna, R., et al. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 1999, 116, 823-830.
111. Fischer, W. Assembly and molecular mode of action of the Helicobacter pylori Cag type IV secretion apparatus. FEBS J. 2011, 278, 1203-1212.
112. Terradot, L., Waksman, G. Architecture of the Helicobacter pylori Cag-type IV secretion system. FEBS J. 2011, 278, 1213-1222.
113. Frick-Cheng, A.E., Pyburn, T.M., Voss, B.J., McDonald, W.H., Ohi, M.D., Cover, T.L. Molecular and Structural Analysis of the Helicobacter pylori cag Type IV Secretion System Core Complex. MBio 2016, 7, e02001-15.
114. Hatakeyama, M. Helicobacter pylori CagA and gastric cancer: A paradigm for hit-and-run carcinogenesis. Cell Host Microbe 2014, 15, 306-316.
115. Tegtmeyer, N., Neddermann, M., Asche, C.I., Backert, S. Subversion of host kinases: A key network in cellular signaling hijacked by Helicobacter pylori CagA. Mol. Microbiol. 2017, 105, 358-372.
116. Odenbreit, S., Swoboda, K., Barwig, I., Ruhl, S., Boren, T., Koletzko, S., Haas, R. Outer membrane protein expression profile in Helicobacter pylori clinical isolates. Infect. Immun. 2009, 77, 3782-3790.
117. Cover, T.L. Helicobacter pylori Diversity and Gastric Cancer Risk. MBio 2016, 7, e01869-15.
118. Blaser, M.J., Perez-Perez, G.I., Kleanthous, H., Cover, T.L., Peek, R.M., Chyou, P.H., Stemmermann, G.N., Nomura, A. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995, 55, 2111-2115.
119. Plummer, M., van Doorn, L.J., Franceschi, S., Kleter, B., Canzian, F., Vivas, J., Lopez, G., Colin, D., Munoz, N., Kato, I. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J. Natl. Cancer Inst. 2007, 99, 1328-1334.
120. Gerhard, M., Lehn, N., Neumayer, N., Boren, T., Rad, R., Schepp, W., Miehlke, S., Classen, M., Prinz, C. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc. Natl. Acad. Sci. USA 1999, 96, 12778-12783.
121. Prinz, C., Schoniger, M., Rad, R., Becker, I., Keiditsch, E., Wagenpfeil, S., Classen, M., Rosch, T., Schepp, W., Gerhard, M. Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation. Cancer Res. 2001, 61, 1903-1909.
122. Yu, J., Leung, W.K., Go, M.Y., Chan, M.C., To, K.F., Ng, E.K., Chan, F.K., Ling, T.K., Chung, S.C., Sung, J.J. Relationship between Helicobacter pylori babA2 status with gastric epithelial cell turnover and premalignant gastric lesions. Gut 2002, 51, 480-484.
123. Yamaoka, Y., Ojo, O., Fujimoto, S., Odenbreit, S., Haas, R., Gutierrez, O., El-Zimaity, H.M., Reddy, R., Arnqvist, A., Graham, D.Y. Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut 2006, 55, 775-781.
124. Jung, S.W., Sugimoto, M., Graham, D.Y., Yamaoka, Y. homB status of Helicobacter pylori as a novel marker to distinguish gastric cancer from duodenal ulcer. J. Clin. Microbiol. 2009, 47, 3241-3245.
125. Talebi Bezmin Abadi, A., Rafiei, A., Ajami, A., Hosseini, V., Taghvaei, T., Jones, K.R., Merrell, D.S. Helicobacter pylori homB, but not cagA, is associated with gastric cancer in Iran. J. Clin. Microbiol. 2011, 49, 3191-3197.
126. Yakoob, J., Abbas, Z., Khan, R., Salim, S.A., Awan, S., Abrar, A., Jafri, W. Helicobacter pylori outer membrane protein Q allele distribution is associated with distinct pathologies in Pakistan. Infect. Genet. Evol. 2015.
127. Cao, P., Cover, T.L. Two different families of hopQ alleles in Helicobacter pylori. J. Clin. Microbiol. 2002, 40, 4504-4511.
128. Dossumbekova, A., Prinz, C., Mages, J., Lang, R., Kusters, J.G., van Vliet, A.H.M., Reindl, W., Backert, S., Saur, D., Schmid, R.M., et al. Helicobacter pylori HopH (OipA) and bacterial pathogenicity: Genetic and functional genomic analysis of hopH gene polymorphisms. J. Infect. Dis. 2006, 194, 1346-1355.
129. Hennig, E.E., Allen, J.M., Cover, T.L. Multiple chromosomal loci for the babA gene in Helicobacter pylori. Infect. Immun. 2006, 74, 3046-3051.
130. Oleastro, M., Cordeiro, R., Ferrand, J., Nunes, B., Lehours, P., Carvalho-Oliveira, I., Mendes, A.I., Penque, D., Monteiro, L., Megraud, F., et al. Evaluation of the clinical significance of homB, a novel candidate marker of Helicobacter pylori strains associated with peptic ulcer disease. J. Infect. Dis. 2008, 198, 1379-1387.
131. Oleastro, M., Cordeiro, R., Yamaoka, Y., Queiroz, D., Megraud, F., Monteiro, L., Menard, A. Disease association with two Helicobacter pylori duplicate outer membrane protein genes, homB and homA. Gut Pathog. 2009, 1, 12.
132. Asahi, M., Tanaka, Y., Izumi, T., Ito, Y., Naiki, H., Kersulyte, D., Tsujikawa, K., Saito, M., Sada, K., Yanagi, S., et al. Helicobacter pylori CagA containing ITAM-like sequences localized to lipid rafts negatively regulates VacA-induced signaling in vivo. Helicobacter 2003, 8, 1-14.
133. Argent, R.H., Thomas, R.J., Letley, D.P., Rittig, M.G., Hardie, K.R., Atherton, J.C. Functional association between the Helicobacter pylori virulence factors VacA and CagA. J. Med. Microbiol. 2008, 57, 145-150.
134. Yokoyama, K., Higashi, H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, H., Azuma, T., Wada, A., Hirayama, T., Aburatani, H., et al. 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. USA 2005, 102, 9661-9666.
135. Tegtmeyer, N., Zabler, D., Schmidt, D., Hartig, R., Brandt, S., Backert, S. 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. 2009, 11, 488-505.
136. Akada, J.K., Aoki, H., Torigoe, Y., Kitagawa, T., Kurazono, H., Hoshida, H., Nishikawa, J., Terai, S., Matsuzaki, M., Hirayama, T., et al. Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells. Dis. Models Mech. 2010, 3, 605-617.
137. Ito, Y., Azuma, T., Ito, S., Miyaji, H., Hirai, M., Yamazaki, Y., Sato, F., Kato, T., Kohli, Y., Kuriyama, M. Analysis and typing of the vacA gene from cagA-positive strains of Helicobacter pylori isolated in Japan. J. Clin. Microbiol. 1997, 35, 1710-1714.
138. Jang, S., Jones, K.R., Olsen, C.H., Joo, Y.M., Yoo, Y.J., Chung, I.S., Cha, J.H., Merrell, D.S. Epidemiological link between gastric disease and polymorphisms in VacA and CagA. J. Clin. Microbiol. 2010, 48, 559-567.
139. De Martel, C., Forman, D., Plummer, M. Gastric cancer: Epidemiology and risk factors. Gastroenterol. Clin. N. Am. 2013, 42, 219-240.
140. Eaton, K.A., Cover, T.L., Tummuru, M.K., Blaser, M.J., Krakowka, S. Role of vacuolating cytotoxin in gastritis due to Helicobacter pylori in gnotobiotic piglets. Infect. Immun. 1997, 65, 3462-3464.
141. Ogura, K., Maeda, S., Nakao, M., Watanabe, T., Tada, M., Kyutoku, T., Yoshida, H., Shiratori, Y., Omata, M. Virulence factors of Helicobacter pylori responsible for gastric diseases in mongolian gerbil. J. Exp. Med. 2000, 192, 1601-1610.
142. Salama, N.R., 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, 730-736.
143. Wirth, H.P., Beins, M.H., Yang, M., Tham, K.T., Blaser, M.J. Experimental infection of Mongolian gerbils with wild-type and mutant Helicobacter pylori strains. Infect. Immun. 1998, 66, 4856-4866.
144. Oertli, M., Noben, M., Engler, D.B., Semper, R.P., Reuter, S., Maxeiner, J., Gerhard, M., Taube, C., Muller, A. Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc. Natl. Acad. Sci. USA 2013, 110, 3047-3052.
145. McClain, M.S., Shaffer, C.L., Israel, D.A., Peek, R.M., Jr., Cover, T.L. Genome sequence analysis of Helicobacter pylori strains associated with gastric ulceration and gastric cancer. BMC Genom. 2009, 10, 3.
146. Loh, J.T., Gaddy, J.A., Algood, H.M., Gaudieri, S., Mallal, S., Cover, T.L. Helicobacter pylori adaptation in vivo in response to a high-salt diet. Infect. Immun. 2015, 83, 4871-4883.
147. Beckett, A.C., Piazuelo, M.B., Noto, J.M., Peek, R.M., Jr., Washington, M.K., Algood, H.M., Cover, T.L. Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration. Infect. Immun. 2016, 84, 3338-3349.
148. Ilver, D., Barone, S., Mercati, D., Lupetti, P., Telford, J.L. Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism. Cell. Microbiol. 2004, 6, 167-174.
149. Wang, F., Xia, P., Wu, F., Wang, D., Wang, W., Ward, T., Liu, Y., Aikhionbare, F., Guo, Z., Powell, M., et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J. Biol. Chem. 2008, 283, 26714-26725.
150. Kobayashi, H., Kamiya, S., Suzuki, T., Kohda, K., Muramatsu, S., Kurumada, T., Ohta, U., Miyazawa, M., Kimura, N., Mutoh, N., et al. The effect of Helicobacter pylori on gastric acid secretion by isolated parietal cells from a guinea pig. Association with production of vacuolating toxin by H. pylori. Scand. J. Gastroenterol. 1996, 31, 428-433.
151. Gebert, B., Fischer, W., Weiss, E., Hoffman, R., Haas, R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 2003, 301, 1099-1102.
152. Sundrud, M.S., Torres, V.J., Unutmaz, D., Cover, T.L. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc. Natl. Acad. Sci. USA 2004, 101, 7727-7732.
153. Boncristiano, M., Paccani, S.R., Barone, S., Ulivieri, C., Patrussi, L., Ilver, D., Amedei, A., D’Elios, M.M., Telford, J.L., Baldari, C.T. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J. Exp. Med. 2003, 198, 1887-1897.
154. Torres, V.J., VanCompernolle, S.E., Sundrud, M.S., Unutmaz, D., Cover, T.L. Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets. J. Immunol. 2007, 179, 5433-5440.
155. Gaddy, J.A., Radin, J.N., Loh, J.T., Zhang, F., Washington, M.K., Peek, R.M., Jr., Algood, H.M., Cover, T.L. High Dietary Salt Intake Exacerbates Helicobacter pylori-Induced Gastric Carcinogenesis. Infect. Immun. 2013, 81, 2258-2267.
156. Noto, J.M., Romero-Gallo, J., Piazuelo, M.B., Peek, R.M. The Mongolian Gerbil: A Robust Model of Helicobacter pylori-Induced Gastric Inflammation and Cancer. Methods Mol. Biol. 2016, 1422, 263-280.
157. Ghiara, P., Marchetti, M., Blaser, M.J., Tummuru, M.K., Cover, T.L., Segal, E.D., Tompkins, L.S., Rappuoli, R. Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease. Infect. Immun. 1995, 63, 4154-4160.
158. Supajatura, V., Ushio, H., Wada, A., Yahiro, K., Okumura, K., Ogawa, H., Hirayama, T., Ra, C. Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J. Immunol. 2002, 168, 2603-2607.
159. Fujikawa, A., Shirasaka, D., Yamamoto, S., Ota, H., Yahiro, K., Fukada, M., Shintani, T., Wada, A., Aoyama, N., Hirayama, T., 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, 375-381.
160. Algood, H.M., Torres, V.J., Unutmaz, D., Cover, T.L. Resistance of primary murine CD4+ T cells to Helicobacter pylori vacuolating cytotoxin. Infect. Immun. 2007, 75, 334-341.
161. Javaheri, A., Kruse, T., Moonens, K., Mejias-Luque, R., Debraekeleer, A., Asche, C.I., Tegtmeyer, N., Kalali, B., Bach, N.C., Sieber, S.A., et al. Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat. Microbiol. 2016, 2, 16189.
162. Koniger, V., Holsten, L., Harrison, U., Busch, B., Loell, E., Zhao, Q., Bonsor, D.A., Roth, A., Kengmo-Tchoupa, A., Smith, S.I., et al. Helicobacter pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat. Microbiol. 2016, 2, 16188.
163. Papini, E., Satin, B., Norais, N., de Bernard, M., Telford, J.L., Rappuoli, R., Montecucco, C. Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J. Clin. Investig. 1998, 102, 813-820.
164. Amieva, M.R., Vogelmann, R., Covacci, A., Tompkins, L.S., Nelson, W.J., Falkow, S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 2003, 300, 1430-1434.
165. Radin, J.N., Gonzalez-Rivera, C., Frick-Cheng, A.E., Sheng, J., Gaddy, J.A., Rubin, D.H., Algood, H.M., McClain, M.S., Cover, T.L. Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect. Immun. 2014, 82, 423-432.
166. Yahiro, K., Akazawa, Y., Nakano, M., Suzuki, H., Hisatune, J., Isomoto, H., Sap, J., Noda, M., Moss, J., Hirayama, T. Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway. Cell Death Discov. 2015, 1, 15035.
167. Aasen, T., Mesnil, M., Naus, C.C., Lampe, P.D., Laird, D.W. Gap junctions and cancer: Communicating for 50 years. Nat. Rev. Cancer 2016, 16, 775-788.
168. Sigal, M., Rothenberg, M.E., Logan, C.Y., Lee, J.Y., Honaker, R.W., Cooper, R.L., Passarelli, B., Camorlinga, M., Bouley, D.M., Alvarez, G., et al. Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands. Gastroenterology 2015, 148, 1392-1404.
169. Sigal, M., Logan, C.Y., Kapalczynska, M., Mollenkopf, H.J., Berger, H., Wiedenmann, B., Nusse, R., Amieva, M.R., Meyer, T.F. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature 2017, 548, 451-455.
170. Engler, D.B., Reuter, S., van Wijck, Y., Urban, S., Kyburz, A., Maxeiner, J., Martin, H., Yogev, N., Waisman, A., Gerhard, M., 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, 11810-11815.
171. Kyburz, A., Urban, S., Altobelli, A., Floess, S., Huehn, J., Cover, T.L., Muller, A. Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. Clin. Exp. Allergy 2017, 47, 1331-1341.
172. Montecucco, C., de Bernard, M. Immunosuppressive and proinflammatory activities of the VacA toxin of Helicobacter pylori. J. Exp. Med. 2003, 198, 1767-1771.
173. Elinav, E., Nowarski, R., Thaiss, C.A., Hu, B., Jin, C., Flavell, R.A. Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 2013, 13, 759-771.