With the momentous discovery in the 1980's that a bacterium, Helicobacter pylori, can cause peptic ulcer disease and gastric cancer, antibiotic therapies and prophylactic measures have been successful, only in part, in reducing the global burden of these diseases. To date, ~700,000 deaths worldwide are still attributable annually to gastric cancer alone. Here, we review H. pylori's contribution to the epidemiology and histopathology of both gastric cancer and peptic ulcer disease. Furthermore, we examine the host-pathogen relationship and H. pylori biology in context of these diseases, focusing on strain differences, virulence factors (CagA and VacA), immune activation and the challenges posed by resistance to existing therapies. We consider also the important role of host-genetic variants, for example, in inflammatory response genes, in determining infection outcome and the role of H. pylori in other pathologies—some accepted, for example, MALT lymphoma, and others more controversial, for example, idiopathic thrombocytic purpura. More recently, intriguing suggestions that H. pylori has protective effects in GERD and autoimmune diseases, such as asthma, have gained momentum. Therefore, we consider the basis for these suggestions and discuss the potential impact for future therapeutic rationales. 1. Introduction After a long history of discoveries on the pathology and bacterial colonization of the gastric mucosa starting in the beginning of the last century [1], the gastroenterologist Barry Marshall and the pathologist Robin Warren, in the 1980’s, fulfilled Koch’s postulates for the association between gastritis and the human gastric pathogen Helicobacter pylori [1–3]. This decisive demonstration substantially changed our views of the microbiology and pathology of the human stomach and resulted in Marshall and Warren receiving the 2005 Nobel Prize in Physiology and Medicine. Marshall and Warren’s discovery founded the concept that infection with H. pylori , and not (if at all, very indirectly) stress, can lead to a variety of upper gastrointestinal disorders (Figure 1) such as gastric inflammation (gastritis), peptic ulcer disease (10%–20%), distal gastric adenocarcinoma (1%-2%), and gastric mucosal-associated lymphoid tissue (MALT) lymphoma (<1%) [4–7]. These insights not only dramatically improved the management and therapy of gastric diseases but also provided an invaluable key for deeper insights into the pathogenesis of chronic infections. Moreover, during the past 20 years of research, the initially tentative association between persistent H.
References
[1]
M. Kidd and I. M. Modlin, “A century of Helicobacter pylori: paradigms lost-paradigms regained,” Digestion, vol. 59, no. 1, pp. 1–15, 1998.
[2]
J. R. Warren, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,” Lancet, vol. 1, no. 8336, pp. 1273–1275, 1983.
[3]
B. J. Marshall, J. A. Armstrong, D. B. McGechie, and R. J. Glancy, “Attempt to fulfil Koch's postulates for pyloric campylobacter,” Medical Journal of Australia, vol. 142, no. 8, pp. 436–439, 1985.
[4]
A. Nomura, G. N. Stemmermann, P. H. Chyou, I. Kato, G. I. Perez-Perez, and M. J. Blaser, “Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii,” New England Journal of Medicine, vol. 325, no. 16, pp. 1132–1136, 1991.
[5]
J. G. Kusters, A. H. M. van Vliet, and E. J. Kuipers, “Pathogenesis of Helicobacter pylori infection,” Clinical Microbiology Reviews, vol. 19, no. 3, pp. 449–490, 2006.
[6]
J. Parsonnet, G. D. Friedman, and D. P. Vandersteen, “Helicobacter pylori infection and the risk of gastric carcinoma,” New England Journal of Medicine, vol. 325, no. 16, pp. 1127–1131, 1991.
[7]
J. Parsonnet, S. Hansen, and L. Rodriguez, “Helicobacter pylori infection and gastric lymphoma,” New England Journal of Medicine, vol. 330, no. 18, pp. 1267–1271, 1994.
[8]
L. E. Hansson, L. Engstrand, and O. Nyren, “Helicobacter pylori infection: independent risk indicator of gastric adenocarcinoma,” Gastroenterology, vol. 105, no. 4, pp. 1098–1103, 1993.
[9]
P. J. Hu, H. M. Mitchell, Y. Y. Li, M. H. Zhou, and S. L. Hazell, “Association of Helicobacter pylori with gastric cancer and observations on the detection of this bacterium in gastric cancer cases,” American Journal of Gastroenterology, vol. 89, no. 10, pp. 1806–1810, 1994.
[10]
N. Uemura, S. Okamoto, and S. Yamamoto, “Helicobacter pylori infection and the development of gastric cancer,” New England Journal of Medicine, vol. 345, no. 11, pp. 784–789, 2001.
[11]
World Health Organisation, “Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June 1994,” IARC Monographs on the Evaluation of Carcinogenic Risks to Humans / World Health Organization, International Agency for Research on Cancer, vol. 61, pp. 1–241, 1994.
[12]
B. Linz, F. Balloux, and Y. Moodley, “An African origin for the intimate association between humans and Helicobacter pylori,” Nature, vol. 445, no. 7130, pp. 915–918, 2007.
[13]
D. Falush, T. Wirth, and B. Linz, “Traces of human migrations in Helicobacter pylori populations,” Science, vol. 299, no. 5612, pp. 1582–1585, 2003.
[14]
Y. Moodley, B. Linz, Y. Yamaoka, et al., “The peopling of the pacific from a bacterial perspective,” Science, vol. 323, no. 5913, pp. 527–530, 2009.
[15]
J. V. Solnick and D. B. Schauer, “Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases,” Clinical Microbiology Reviews, vol. 14, no. 1, pp. 59–97, 2001.
[16]
T. L. Cover and M. J. Blaser, “Helicobacter pylori in health and disease,” Gastroenterology, vol. 136, no. 6, pp. 1863–1873, 2009.
[17]
M. A. Al-Moagel, D. G. Evans, and M. E. Abdulghani, “Prevalence of Helicobacter (formerly Campylobacter) pylori infection in Saudia Arabia, and comparison of those with and without upper gastrointestinal symptoms,” American Journal of Gastroenterology, vol. 85, no. 8, pp. 944–948, 1990.
[18]
D. Y. Graham, M. F. Go, and D. J. Evans, “Review article: urease, gastric ammonium/ammonia, and Helicobacter pylori—the past, the present, and recommendations for future research,” Alimentary Pharmacology and Therapeutics, vol. 6, no. 6, pp. 659–669, 1992.
[19]
H. M. Malaty, “Epidemiology of Helicobacter pylori infection, best practice and research,” Clinical Gastroenterology, vol. 21, no. 2, pp. 205–214, 2007.
[20]
K. D. Crew and A. I. Neugut, “Epidemiology of gastric cancer,” World Journal of Gastroenterology, vol. 12, no. 3, pp. 354–362, 2006.
[21]
R. A. Feldman, A. J. P. Eccersley, and J. M. Hardie, “Epidemiology of Helicobacter pylori: acquisition, transmission, population prevalence and disease-to-infection ratio,” British Medical Bulletin, vol. 54, no. 1, pp. 39–53, 1998.
[22]
H. Malaty, H. M. T. El-Zimaity, R. M. Genta, R. A. Cole, and D. Y. Graham, “High-dose proton pump inhibitor plus amoxycillin for the treatment or retreatment of Helicobacter pylori infection,” Alimentary Pharmacology and Therapeutics, vol. 10, no. 6, pp. 1001–1004, 1996.
[23]
R. M. Peek and M. J. Blaser, “Helicobacter pylori and gastrointestinal tract adenocarcinomas,” Nature Reviews Cancer, vol. 2, no. 1, pp. 28–37, 2002.
[24]
M. Kurosawa, S. Kikuchi, Y. Inaba, T. Ishibashi, and F. Kobayashi, “Helicobacter pylori infection among Japanese children,” Journal of Gastroenterology and Hepatology, vol. 15, no. 12, pp. 1382–1385, 2000.
[25]
Y. Yamaoka, D. H. Kwon, and D. Y. Graham, “A M(r) 34000 proinflammatory outer membrane protein (OipA) of Helicobacter pylori,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7533–7538, 2000.
[26]
K. J. Goodman, P. Correa, H. J. Tenganá Aux, et al., “Helicobacter pylori infection in the Colombian Andes: a population-based study of transmission pathways,” American Journal of Epidemiology, vol. 144, no. 3, pp. 290–299, 1996.
[27]
R. J. Hopkins, P. A. Vial, and C. Ferreccio, “Seroprevalence of Helicobacter pylori in chile: vegetables may serve as one route of transmission,” Journal of Infectious Diseases, vol. 168, no. 1, pp. 222–226, 1993.
[28]
P. D. Klein, R. Gilman, and R. Leon-Barua, “Water source as risk factor for Helicobacter pylori infection in Peruvian children,” Lancet, vol. 337, no. 8756, pp. 1503–1506, 1991.
[29]
M. P. Dore, A. R. Sepulveda, and H. El-Zimaity, “Isolation of helicobacter pylori from sheep-implications for transmission to humans,” American Journal of Gastroenterology, vol. 96, no. 5, pp. 1396–1401, 2001.
[30]
J. G. Fox, “Non-human reservoirs of Helicobacter pylori,” Alimentary Pharmacology and Therapeutics, Supplement, vol. 9, no. 2, pp. 93–103, 1995.
[31]
T. Kwok, S. Backert, H. Schwarz, J. Berger, and T. F. Meyer, “Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism,” Infection and Immunity, vol. 70, no. 4, pp. 2108–2120, 2002.
[32]
J. D. Oh, S. M. Karam, and J. I. Gordon, “Intracellular Helicobacter pylori in gastric epithelial progenitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 14, pp. 5186–5191, 2005.
[33]
A. ？zbek, E. ？zbek, H. Dursun, Y. Kalkan, and T. Demirci, “Can Helicobacter pylori invade human gastric mucosa?: an in vivo study using electron microscopy, immunohistochemical methods, and real-time polymerase chain reaction,” Journal of Clinical Gastroenterology, vol. 44, no. 6, pp. 416–422, 2010.
[34]
A. M. Petersen, J. Blom, L. P. Andersen, and K. A. Krogfelt, “Role of strain type, AGS cells and fetal calf serum in Helicobacter pylori adhesion and invasion assays,” FEMS Immunology and Medical Microbiology, vol. 29, no. 1, pp. 59–67, 2000.
[35]
M. R. Terebiznik, C. L. Vazquez, and K. Torbicki, “Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells,” Infection and Immunity, vol. 74, no. 12, pp. 6599–6614, 2006.
[36]
H. M. S. Algood and T. L. Cover, “Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses,” Clinical Microbiology Reviews, vol. 19, no. 4, pp. 597–613, 2006.
[37]
N. J. Talley, J. E. Ormand, C. A. Frie, and A. R. Zinsmeister, “Stability of pH gradients in vivo across the stomach in Helicobacter pylori gastritis, dyspepsia, and health,” American Journal of Gastroenterology, vol. 87, no. 5, pp. 590–594, 1992.
[38]
J. V. Solnick, C. Josenhans, S. Suerbaum, L. S. Tompkins, and A. Labigne, “Construction and characterization of an isogenic urease-negative mutant of Helicobacter mustelae,” Infection and Immunity, vol. 63, no. 9, pp. 3718–3721, 1995.
[39]
G. Geis, H. Leying, S. Suerbaum, U. Mai, and W. Opferkuch, “Ultrastructure and chemical analysis of Campylobacter pylori flagella,” Journal of Clinical Microbiology, vol. 27, no. 3, pp. 436–441, 1989.
[40]
L. K. Sycuro, Z. Pincus, K. D. Gutierrez, et al., “Peptidoglycan crosslinking relaxation promotes Helicobacter pylori's helical shape and stomach colonization,” Cell, vol. 141, no. 5, pp. 822–833, 2010.
[41]
R. Haas, T. F. Meyer, and J. P. M. Van Putten, “Aflagellated mutants of Helicobacter pylori generated by genetic transformation of naturalloy competent strains using transposon shuttle mutagenesis,” Molecular Microbiology, vol. 8, no. 4, pp. 753–760, 1993.
[42]
S. Suerbaum, “The complex flagella of gastric Helicobacter species,” Trends in Microbiology, vol. 3, no. 5, pp. 168–170, 1995.
[43]
K. A. Eaton, S. Suerbaum, C. Josenhans, and S. Krakowka, “Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes,” Infection and Immunity, vol. 64, no. 7, pp. 2445–2448, 1996.
[44]
D. J. McGee, M. L. Langford, E. L. Watson, J. E. Carter, Y. T. Chen, and K. M. Ottemann, “Colonization and inflammation deficiencies in Mongolian gerbils infected by Helicobacter pylori chemotaxis mutants,” Infection and Immunity, vol. 73, no. 3, pp. 1820–1827, 2005.
[45]
S. R. Schreiber, M. Konradt, C. Groll, et al., “The spatial orientation of Helicobacter pylori in the gastric mucus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 5024–5029, 2004.
[46]
M. A. Croxen, G. Sisson, R. Melano, and P. S. Hoffman, “The Helicobacter pylori chemotaxis receptor tlpB (HP0103) is required for pH taxis and for colonization of the gastric mucosa,” Journal of Bacteriology, vol. 188, no. 7, pp. 2656–2665, 2006.
[47]
V. Necchi, M. E. Candusso, and F. Tava, “Intracellular, intercellular, and stromal invasion of gastric mucosa, preneoplastic lesions, and cancer by Helicobacter pylori,” Gastroenterology, vol. 132, no. 3, pp. 1009–1023, 2007.
[48]
L. A. Noach, T. M. Rolf, and G. N. J. Tytgat, “Electron microscopic study of association between Helicobacter pylori and gastric and duodenal mucosa,” Journal of Clinical Pathology, vol. 47, no. 8, pp. 699–704, 1994.
[49]
A. Dossumbekova, C. Prinz, J. Mages, et al., “Helicobacter pylori HopH (OipA) and bacterial pathogenicity: genetic and functional genomic analysis of hopH gene polymorphisms,” Journal of Infectious Diseases, vol. 194, no. 10, pp. 1346–1355, 2006.
[50]
D. Ilver, A. Arnqvist, J. ？gren, et al., “Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging,” Science, vol. 279, no. 5349, pp. 373–377, 1998.
[51]
J. Mahdavi, B. Sondén, M. Hurtig, et al., “Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation,” Science, vol. 297, no. 5581, pp. 573–578, 2002.
[52]
B. Peck, M. Ortkamp, K. D. Diehl, E. Hundt, and B. Knapp, “Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori,” Nucleic Acids Research, vol. 27, no. 16, pp. 3325–3333, 1999.
[53]
M. Aspholm-Hurtig, G. Dailide, M. Lahmann, et al., “Functional adaptation of BabA the H. pylori ABO blood group antigen binding adhesin,” Science, vol. 305, no. 5683, pp. 519–522, 2004.
[54]
A. B？ckstr？m, C. Lundberg, D. Kersulyte, D. E. Berg, T. Borén, and A. Arnqvist, “Metastability of Helicobacter pylori bab adhesin genes and dynamics in Lewis b antigen binding,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 48, pp. 16923–16928, 2004.
[55]
J. V. Solnick, L. M. Hansen, N. R. Salama, J. K. Boonjakuakul, and M. Syvanen, “Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 2106–2111, 2004.
[56]
C. Petersson, M. Forsberg, M. Aspholm, et al., “Helicobacter pylori SabA adhesin evokes a strong inflammatory response in human neutrophils which is down-regulated by the neutrophil-activating protein,” Medical Microbiology and Immunology, vol. 195, no. 4, pp. 195–206, 2006.
[57]
S. Tan, L. S. Tompkins, and M. R. Amieva, “Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche,” PLoS Pathogens, vol. 5, no. 5, Article ID e1000407, 2009.
[58]
R. Battan, M. C. Raviglione, A. Palagiano, et al., “Helicobacter pylori infection in patients with acquired immune deficiency syndrome,” American Journal of Gastroenterology, vol. 85, no. 12, pp. 1576–1579, 1990.
[59]
K. B. Bamford, X. Fan, S. E. Crowe, et al., “Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype,” Gastroenterology, vol. 114, no. 3, pp. 482–492, 1998.
[60]
A. Muotiala, I. M. Helander, L. Pyhala, T. U. Kosunen, and A. P. Moran, “Low biological activity of Helicobacter pylori lipopolysaccharide,” Infection and Immunity, vol. 60, no. 4, pp. 1714–1716, 1992.
[61]
P. M. Lepper, M. Triantafilou, C. Schumann, E. M. Schneider, and K. Triantafilou, “Lipopolysaccharides from Helicobacter pylori can act as antagonists for Toll-like receptor 4,” Cellular Microbiology, vol. 7, no. 4, pp. 519–528, 2005.
[62]
A. P. Moran, B. Lindner, and E. J. Walsh, “Structural characterization of the lipid A component of Helicobacter pylori rough- and smooth-form lipopolysaccharides,” Journal of Bacteriology, vol. 179, no. 20, pp. 6453–6463, 1997.
[63]
G. O. Aspinall and M. A. Monteiro, “Lipopolysaccharides of Helicobacter pylori strains P466 and MO19: structures of the O antigen and core oligosaccharide regions,” Biochemistry, vol. 35, no. 7, pp. 2498–2504, 1996.
[64]
B. J. Appelmelk, I. Simoons-Smit, R. Negrini, et al., “Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity,” Infection and Immunity, vol. 64, no. 6, pp. 2031–2040, 1996.
[65]
C. Wunder, Y. Churin, and F. Winau, “Cholesterol glucosylation promotes immune evasion by Helicobacter pylori,” Nature Medicine, vol. 12, no. 9, pp. 1030–1038, 2006.
[66]
M. Ringnér, K. H. Valkonen, and T. Wadstr？m, “Binding of vitronectin and plasminogen to Helicobacter pylori,” FEMS Immunology and Medical Microbiology, vol. 9, no. 1, pp. 29–34, 1994.
[67]
E. Andersen-Nissen, K. D. Smith, K. L. Strobe, et al., “Evasion of Toll-like receptor 5 by flagellated bacteria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 26, pp. 9247–9252, 2005.
[68]
A. T. Gewirtz, Y. Yu, U. S. Krishna, D. A. Israel, S. L. Lyons, and R. M. Peek, “Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity,” Journal of Infectious Diseases, vol. 189, no. 10, pp. 1914–1920, 2004.
[69]
S. K. Lee, A. Stack, E. Katzowitsch, S. I. Aizawa, S. Suerbaum, and C. Josenhans, “Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5,” Microbes and Infection, vol. 5, no. 15, pp. 1345–1356, 2003.
[70]
B. Gebert, W. Fischer, E. Weiss, R. Hoffmann, and R. Haas, “Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation,” Science, vol. 301, no. 5636, pp. 1099–1102, 2003.
[71]
V. J. Torres, S. E. VanCompernolle, M. S. Sundrud, D. Unutmaz, and T. L. Cover, “Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets,” Journal of Immunology, vol. 179, no. 8, pp. 5433–5440, 2007.
[72]
R. J. Menaker, P. J. M. Ceponis, and N. L. Jones, “Helicobacter pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway,” Infection and Immunity, vol. 72, no. 5, pp. 2889–2898, 2004.
[73]
P. Y. Zheng and N. L. Jones, “Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein,” Cellular Microbiology, vol. 5, no. 1, pp. 25–40, 2003.
[74]
C. Schmees, C. Prinz, T. Treptau, et al., “Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase,” Gastroenterology, vol. 132, no. 5, pp. 1820–1833, 2007.
[75]
J. Zabaleta, D. J. McGee, A. H. Zea, et al., “Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta),” Journal of Immunology, vol. 173, no. 1, pp. 586–593, 2004.
[76]
A. P. Gobert, D. J. McGee, M. Akhtar, et al., “Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13844–13849, 2001.
[77]
J. Yuan, P. Li, J. Tao, et al., “H. pylori escape host immunoreaction through inhibiting ILK expression by VacA,” Cellular and Molecular Immunology, vol. 6, no. 3, pp. 191–197, 2009.
[78]
N. Akopyanz, N. O. Bukanov, T. U. Westblom, S. Kresovich, and D. E. Berg, “DNA diversity among clinical isolates of helicobacter pylori detected by PCR-based RAPD fingerprinting,” Nucleic Acids Research, vol. 20, no. 19, pp. 5137–5142, 1992.
[79]
I. Kansau, J. Raymond, and E. Bingen, “Genotyping of Helicobacter pylori isolates by sequencing of PCR products and comparison with the RAPD technique,” Research in Microbiology, vol. 147, no. 8, pp. 661–669, 1996.
[80]
S. Miehlke, R. M. Genta, D. Y. Graham, and M. F. Go, “Molecular relationships of Helicobacter pylori strains in a family with gastroduodenal disease,” American Journal of Gastroenterology, vol. 94, no. 2, pp. 364–368, 1999.
[81]
B. Bj？rkholm, M. Sj？lund, P. G. Falk, O. G. Berg, L. Engstrand, and D. I. Andersson, “Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 25, pp. 14607–14612, 2001.
[82]
S. Suerbaum and C. Josenhans, “Helicobacter pylori evolution and phenotypic diversification in a changing host,” Nature Reviews Microbiology, vol. 5, no. 6, pp. 441–452, 2007.
[83]
J. F. Tomb, O. White, A. R. Kerlavage, et al., “The complete genome sequence of the gastric pathogen Helicobacter pylori,” Nature, vol. 388, no. 6642, pp. 539–547, 1997.
[84]
B. D. Robertson and T. F. Meyer, “Genetic variation in pathogenic bacteria,” Trends in Genetics, vol. 8, no. 12, pp. 422–427, 1992.
[85]
L. Salaün, B. Linz, S. Suerbaum, and N. J. Saunders, “The diversity within an expanded and redefined repertoire of phase-variable genes in Helicobacter pylori,” Microbiology, vol. 150, no. 4, pp. 817–830, 2004.
[86]
N. J. Saunders, J. F. Peden, D. W. Hood, and E. R. Moxon, “Simple sequence repeats in the Helicobacter pylori genome,” Molecular Microbiology, vol. 27, no. 6, pp. 1091–1098, 1998.
[87]
M. Pérez-Losada, E. B. Browne, A. Madsen, T. Wirth, R. P. Viscidi, and K. A. Crandall, “Population genetics of microbial pathogens estimated from multilocus sequence typing (MLST) data,” Infection, Genetics and Evolution, vol. 6, no. 2, pp. 97–112, 2006.
[88]
M. S. Dorer, J. Fero, and N. R. Salama, “DNA damage triggers genetic exchange in Helicobacter pylori,” PLoS Pathogens, vol. 6, no. 7, Article ID e1001026, pp. 1–10, 2010.
[89]
D. N. Baldwin, B. Shepherd, and P. Kraemer, “Identification of Helicobacter pylori genes that contribute to stomach colonization,” Infection and Immunity, vol. 75, no. 2, pp. 1005–1016, 2007.
[90]
D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, “Global cancer statistics, 2002,” CA: A Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74–108, 2002.
[91]
World Health Organization, “Disease and injury country estimates,” 2009.
[92]
P. Bertuccio, L. Chatenoud, and F. Levi, “Recent patterns in gastric cancer: a global overview,” International Journal of Cancer, vol. 125, no. 3, pp. 666–673, 2009.
[93]
P. Lauren, “The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification,” Acta Pathologica et Microbiologica Scandinavica, vol. 64, pp. 31–49, 1965.
[94]
D. B. Polk and R. M. Peek, “Helicobacter pylori: gastric cancer and beyond,” Nature Reviews Cancer, vol. 10, no. 6, pp. 403–414, 2010.
[95]
P. Correa, “Diet modification and gastric cancer prevention,” Journal of the National Cancer Institute. Monographs, vol. 12, no. 12, pp. 75–78, 1992.
[96]
J. L. Telford, A. Covacci, R. Rappuoli, and P. Chiara, “Immunobiology of Helicobacter pylori infection,” Current Opinion in Immunology, vol. 9, no. 4, pp. 498–503, 1997.
[97]
J. H. Kurata and B. M. Haile, “Epidemiology of peptic ulcer disease,” Clinics in Gastroenterology, vol. 13, no. 2, pp. 289–307, 1984.
[98]
S. J. van Zanten, M. F. Dixon, and A. Lee, “The gastric transitional zones: neglected links between gastroduodenal pathology and Helicobacter ecology,” Gastroenterology, vol. 116, no. 5, pp. 1217–1229, 1999.
[99]
L. A. García Rodríguez and L. Barreales Tolosa, “Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population,” Gastroenterology, vol. 132, no. 2, pp. 498–506, 2007.
[100]
S. Take, M. Mizuno, K. Ishiki, et al., “The effect of eradicating Helicobacter pylori on the development of gastric cancer in patients with peptic ulcer disease,” American Journal of Gastroenterology, vol. 100, no. 5, pp. 1037–1042, 2005.
[101]
C. Holcombe, “Helicobacter pylori: the African enigma,” Gut, vol. 33, no. 4, pp. 429–431, 1992.
[102]
R. Ally, H. M. Mitchell, and I. Segal, “Differences in the immune response to H. pylori infection in Sowetan subjects may relate to concurrent parasitic infections,” South African Medical Journal, vol. 90, p. 642, 2000.
[103]
J. G. Fox, P. Beck, C. A. Dangler, et al., “Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy,” Nature Medicine, vol. 6, no. 5, pp. 536–542, 2000.
[104]
R. D. Leunk, P. T. Johnson, B. C. David, W. G. Kraft, and D. R. Morgan, “Cytotoxic activity in broth-culture filtrates of Campylobacter pylori,” Journal of Medical Microbiology, vol. 26, no. 2, pp. 93–99, 1988.
[105]
M. Gerhard, N. Lehn, N. Neumayer, et al., “Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 22, pp. 12778–12783, 1999.
[106]
L. J. Van Doorn, C. Figueiredo, R. Sanna, et al., “Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori,” Gastroenterology, vol. 115, no. 1, pp. 58–66, 1998.
[107]
R. A. Alm, L. S. L. Ling, D. T. Moir, et al., “Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori,” Nature, vol. 397, no. 6715, pp. 176–180, 1999.
[108]
J. C. Atherton, “H. pylori virulence factors,” British Medical Bulletin, vol. 54, no. 1, pp. 105–120, 1998.
[109]
M. Rohde, J. Püls, R. Buhrdorf, W. Fischer, and R. Haas, “A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system,” Molecular Microbiology, vol. 49, no. 1, pp. 219–234, 2003.
[110]
J. Tanaka, T. Suzuki, H. Mimuro, and C. Sasakawa, “Structural definition on the surface of Helicobacter pylori type IV secretion apparatus,” Cellular Microbiology, vol. 5, no. 6, pp. 395–404, 2003.
[111]
T. Kubori, Y. Matsushima, and D. Nakamura, “Supramolecular structure of the salmonella typhimurium type III protein secretion system,” Science, vol. 280, no. 5363, pp. 602–605, 1998.
[112]
S. Odenbreit, J. Püls, B. Sedlmaier, E. Gerland, W. Fischer, and R. Haas, “Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion,” Science, vol. 287, no. 5457, pp. 1497–1500, 2000.
[113]
B. Bauer, S. Moese, S. Bartfeld, T. F. Meyer, and M. Selbach, “Analysis of cell type-specific responses mediated by the type IV secretion system of Helicobacter pylori,” Infection and Immunity, vol. 73, no. 8, pp. 4643–4652, 2005.
[114]
A. Olofsson, A. Vallstr？m, K. Petzold, et al., “Biochemical and functional characterization of Helicobacter pylori vesicles,” Molecular Microbiology, vol. 77, no. 6, pp. 1539–1555, 2010.
[115]
T. Kwok, D. Zabler, S. Urman, et al., “Helicobacter exploits integrin for type IV secretion and kinase activation,” Nature, vol. 449, no. 7164, pp. 862–866, 2007.
[116]
L. F. Jiménez-Soto, S. Kutter, and X. Sewald, “Helicobacter pylori type IV secretion apparatus exploits β1 integrin in a novel RGD-independent manner,” PLoS Pathogens, vol. 5, no. 12, Article ID e1000684, 2009.
[117]
A. Saha, S. Backert, C. E. Hammond, M. Gooz, and A. J. Smolka, “Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase α subunit,” Gastroenterology, vol. 139, no. 1, pp. 239–248, 2010.
[118]
C. Weydig, A. Starzinski-Powitz, G. Carra, J. L？wer, and S. Wessler, “CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity,” Experimental Cell Research, vol. 313, no. 16, pp. 3459–3471, 2007.
[119]
A. M. Y. Nomura, J. Lee, G. N. Stemmermann, R. Y. Nomura, G. I. Perez-Perez, and M. J. Blaser, “Helicobacter pylori CagA seropositivity and gastric carcinoma risk in a Japanese American population,” Journal of Infectious Diseases, vol. 186, no. 8, pp. 1138–1144, 2002.
[120]
M. J. Blaser, G. I. Perez-Perez, H. Kleanthous, et al., “Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach,” Cancer Research, vol. 55, no. 10, pp. 2111–2115, 1995.
[121]
A. H. Wu, J. E. Crabtree, L. Bernstein et al., “Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus,” International Journal of Cancer, vol. 103, no. 6, pp. 815–821, 2003.
[122]
N. Ohnishi, H. Yuasa, S. Tanaka, et al., “Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 3, pp. 1003–1008, 2008.
[123]
H. Mimuro, T. Suzuki, S. Nagai, et al., “Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach,” Cell Host and Microbe, vol. 2, no. 4, pp. 250–263, 2007.
[124]
B. Bauer, S. Bartfeld, and T. F. Meyer, “H. pylori selectively blocks EGFR endocytosis via the non-receptor kinase c-Abl and CagA,” Cellular Microbiology, vol. 11, no. 1, pp. 156–169, 2009.
[125]
S. Brandt, T. Kwok, R. Hartig, W. K？nig, and S. Backert, “NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 26, pp. 9300–9305, 2005.
[126]
D. M. Bronte-Tinkew, M. Terebiznik, and A. Franco, “Helicobacter pylori cytotoxin-associated gene a activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo,” Cancer Research, vol. 69, no. 2, pp. 632–639, 2009.
[127]
N. Murata-Kamiya, K. Kikuchi, T. Hayashi, H. Higashi, and M. Hatakeyama, “Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein,” Cell Host and Microbe, vol. 7, no. 5, pp. 399–411, 2010.
[128]
M. Stein, R. Rappuoli, and A. Covacci, “Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 3, pp. 1263–1268, 2000.
[129]
M. Asahi, T. Azuma, and S. Ito, “Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells,” Journal of Experimental Medicine, vol. 191, no. 4, pp. 593–602, 2000.
[130]
M. Selbach, S. Moese, C. R. Hauck, T. F. Meyer, and S. Backert, “Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo,” Journal of Biological Chemistry, vol. 277, no. 9, pp. 6775–6778, 2002.
[131]
M. Poppe, S. M. Feller, G. R？mer, and S. Wessler, “Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility,” Oncogene, vol. 26, no. 24, pp. 3462–3472, 2007.
[132]
M. Selbach, S. Moese, R. Hurwitz, C. R. Hauck, T. F. Meyer, and S. Backert, “The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation,” EMBO Journal, vol. 22, no. 3, pp. 515–528, 2003.
[133]
I. Tammer, S. Brandt, R. Hartig, W. K？nig, and S. Backert, “Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering,” Gastroenterology, vol. 132, no. 4, pp. 1309–1319, 2007.
[134]
M. Hatakeyama, “SagA of CagA in Helicobacter pylori pathogenesis,” Current Opinion in Microbiology, vol. 11, no. 1, pp. 30–37, 2008.
[135]
M. Stein, F. Bagnoli, R. Halenbeck, R. Rappuoli, W. J. Fantl, and A. Covacci, “c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs,” Molecular Microbiology, vol. 43, no. 4, pp. 971–980, 2002.
[136]
K. R. Jones, Y. M. Joo, S. Jang, et al., “Polymorphism in the cagA EPIYA motif impacts development of gastric cancer,” Journal of Clinical Microbiology, vol. 47, no. 4, pp. 959–968, 2009.
[137]
H. Higashi, R. Tsutsumi, S. Muto, et al., “SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein,” Science, vol. 295, no. 5555, pp. 683–686, 2002.
[138]
E. D. Segal, J. Cha, J. Lo, S. Falkow, and L. S. Tompkins, “Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 25, pp. 14559–14564, 1999.
[139]
M. Naito, T. Yamazaki, R. Tsutsumi, et al., “Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA,” Gastroenterology, vol. 130, no. 4, pp. 1181–1190, 2006.
[140]
S. Backert, N. Tegtmeyer, and M. Selbach, “The versatility of helicobacter pylori Cag A effector protein functions: the master key hypothesis,” Helicobacter, vol. 15, no. 3, pp. 163–176, 2010.
[141]
M. R. Amieva, R. Vogetmann, A. Covacci, L. S. Tompkins, W. J. Nelson, and S. Falkow, “Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA,” Science, vol. 300, no. 5624, pp. 1430–1434, 2003.
[142]
I. Saadat, H. Higashi, and C. Obuse, “Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity,” Nature, vol. 447, no. 7142, pp. 330–333, 2007.
[143]
S. Ren, H. Higashi, H. Lu, T. Azuma, and M. Hatakeyama, “Structural basis and functional consequence of Helicobacter pylori cagA multimerization in cells,” Journal of Biological Chemistry, vol. 281, no. 43, pp. 32344–32352, 2006.
[144]
D. Nesi？, M. C. Miller, Z. T. Quinkert, M. Stein, B. T. Chait, and C. E. Stebbins, “Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates,” Nature Structural and Molecular Biology, vol. 17, no. 1, pp. 130–132, 2010.
[145]
D. Wu and W. Pan, “GSK3: a multifaceted kinase in Wnt signaling,” Trends in Biochemical Sciences, vol. 35, no. 3, pp. 161–168, 2010.
[146]
A. T. Franco, D. A. Israel, M. K. Washington, et al., “Activation of β-catenin by carcinogenic Helicobacter pylori,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10646–10651, 2005.
[147]
N. Murata-Kamiya, Y. Kurashima, Y. Teishikata, et al., “Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells,” Oncogene, vol. 26, no. 32, pp. 4617–4626, 2007.
[148]
M. Suzuki, H. Mimuro, T. Suzuki, M. Park, T. Yamamoto, and C. Sasakawa, “Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion,” Journal of Experimental Medicine, vol. 202, no. 9, pp. 1235–1247, 2005.
[149]
O. Sokolova, P. M. Bozko, and M. Naumann, “Helicobacter pylori suppresses glycogen synthase kinase 3β to promote β-catenin activity,” Journal of Biological Chemistry, vol. 283, no. 43, pp. 29367–29374, 2008.
[150]
V. Ricci, C. Ciacci, R. Zarrilli, et al., “Effect of Helicobacter pylori on gastric epithelial cell migration and proliferation in vitro: role of VacA and CagA,” Infection and Immunity, vol. 64, no. 7, pp. 2829–2833, 1996.
[151]
S. A. Sharma, M. K. R. Tummuru, M. J. Blaser, and L. D. Kerr, “Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor nuclear factor-kappa B in gastric epithelial cells,” Journal of Immunology, vol. 160, no. 5, pp. 2401–2407, 1998.
[152]
A. Bhattacharyya, S. Pathak, S. Datta, S. Chattopadhyay, J. Basu, and M. Kundu, “Mitogen-activated protein kinases and nuclear factor-κB regulate Helicobacter pylori-mediated interleukin-8 release from macrophages,” Biochemical Journal, vol. 368, no. 1, pp. 121–129, 2002.
[153]
M. Naumann, S. Wessler, C. Bartsch, et al., “Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island,” Journal of Biological Chemistry, vol. 274, no. 44, pp. 31655–31662, 1999.
[154]
C. C. Allison, T. A. Kufer, E. Kremmer, M. Kaparakis, and R. L. Ferrero, “Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism,” Journal of Immunology, vol. 183, no. 12, pp. 8099–8109, 2009.
[155]
J. Viala, C. Chaput, I. G. Boneca, et al., “Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island,” Nature Immunology, vol. 5, no. 11, pp. 1166–1174, 2004.
[156]
M. L. Hutton, M. Kaparakis-Liaskos, L. Turner, A. Cardona, T. Kwok, and R. L. Ferrero, “Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-κB-dependent responses and peptidoglycan delivery in epithelial cells,” Infection and Immunity, vol. 78, no. 11, pp. 4523–4531, 2010.
[157]
M. Kaparakis, L. Turnbull, L. Carneiro, et al., “Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells,” Cellular Microbiology, vol. 12, no. 3, pp. 372–385, 2010.
[158]
S.-Y. Kim, Y.-C. Lee, H. K. Kim, and M. J. Blaser, “Helicobacter pylori CagA transfection of gastric epithelial cells induces interleukin-8,” Cellular Microbiology, vol. 8, no. 1, pp. 97–106, 2006.
[159]
V. Necchi, P. Sommi, V. Ricci, and E. Solcia, “In vivo accumulation of Helicobacter pylori products, NOD1, ubiquitinated proteins and proteasome in a novel cytoplasmic structure,” PloS One, vol. 5, no. 3, article e9716, 2010.
[160]
A. T. Franco, D. B. Friedman, T. A. Nagy, et al., “Delineation of a carcinogenic Helicobacter pylori proteome,” Molecular and Cellular Proteomics, vol. 8, no. 8, pp. 1947–1958, 2009.
[161]
A. Wada, E. Yamasaki, and T. Hirayama, “Helicobacter pylori vacuolating cytotoxin, VacA, is responsible for gastric ulceration,” Journal of Biochemistry, vol. 136, no. 6, pp. 741–746, 2004.
[162]
M. Molinari, C. Galli, N. Norais, et al., “Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers,” Journal of Biological Chemistry, vol. 272, no. 40, pp. 25339–25344, 1997.
[163]
E. Papini, M. De Bernard, E. Milia, et al., “Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 21, pp. 9720–9724, 1994.
[164]
Y. Li, A. Wandinger-Ness, J. R. Goldenring, and T. L. Cover, “Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin,” Molecular Biology of the Cell, vol. 15, no. 4, pp. 1946–1959, 2004.
[165]
T. L. Cover and S. R. Blanke, “Helicobacter pylori VacA, a paradigm for toxin multifunctionality,” Nature Reviews Microbiology, vol. 3, no. 4, pp. 320–332, 2005.
[166]
J. C. Atherton, P. Cao, R. M. Peek, M. K. R. Tummuru, M. J. Blaser, and T. L. Cover, “Mosaicism in vacuolating cytotoxin alleles of helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration,” Journal of Biological Chemistry, vol. 270, no. 30, pp. 17771–17777, 1995.
[167]
C. Figueiredo, J. C. Machado, P. Pharoah, et al., “Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma,” Journal of the National Cancer Institute, vol. 94, no. 22, pp. 1680–1687, 2002.
[168]
L. J. Van Doorn, C. Figueiredo, F. Megraud, et al., “Geographic distribution of vacA allelic types of Helicobacter pylori,” Gastroenterology, vol. 116, no. 4, pp. 823–830, 1999.
[169]
J. L. Telford, P. Ghiara, M. Dell'Orco, et al., “Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease,” Journal of Experimental Medicine, vol. 179, no. 5, pp. 1653–1658, 1994.
[170]
K. Ogura, S. Maeda, M. Nakao, et al., “Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil,” Journal of Experimental Medicine, vol. 192, no. 11, pp. 1601–1609, 2000.
[171]
T. L. Cover and M. J. Blaser, “Purification and characterization of the vacuolating toxin from Helicobacter pylori,” Journal of Biological Chemistry, vol. 267, no. 15, pp. 10570–10575, 1992.
[172]
W. Fischer, R. Buhrdorf, E. Gerland, and R. Haas, “Outer membrane targeting of passenger proteins by the vacuolating cytotoxin autotransporter of Helicobacter pylori,” Infection and Immunity, vol. 69, no. 11, pp. 6769–6775, 2001.
[173]
D. Ilver, S. Barone, D. Mercati, P. Lupetti, and J. L. Telford, “Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism,” Cellular Microbiology, vol. 6, no. 2, pp. 167–174, 2004.
[174]
P. Lupetti, J. E. Heuser, and R. Manetti, “Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin,” Journal of Cell Biology, vol. 133, no. 4, pp. 801–807, 1996.
[175]
M. S. McClain, H. Iwamoto, P. Cao, et al., “Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin,” Journal of Biological Chemistry, vol. 278, no. 14, pp. 12101–12108, 2003.
[176]
A. D. Vinion-Dubiel, M. S. McClain, D. M. Czajkowsky, et al., “A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation,” Journal of Biological Chemistry, vol. 274, no. 53, pp. 37736–37742, 1999.
[177]
D. Ye, D. C. Willhite, and S. R. Blanke, “Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin,” Journal of Biological Chemistry, vol. 274, no. 14, pp. 9277–9282, 1999.
[178]
J. A. Garner and T. L. Cover, “Binding and internalization of the Helicobacter pylori vacuolating cytotoxin by epithelial cells,” Infection and Immunity, vol. 64, no. 10, pp. 4197–4203, 1996.
[179]
K. Yahiro, T. Niidome, M. Kimura, et al., “Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyrosine phosphatase β,” Journal of Biological Chemistry, vol. 274, no. 51, pp. 36693–36699, 1999.
[180]
E. E. Hennig, M. M. Godlewski, E. Butruk, and J. Ostrowski, “Helicobacter pylori VacA cytotoxin interacts with fibronectin and alters HeLa cell adhesion and cytoskeletal organization in vitro,” FEMS Immunology and Medical Microbiology, vol. 44, no. 2, pp. 143–150, 2005.
[181]
K. Seto, Y. Hayashi-Kuwabara, T. Yoneta, H. Suda, and H. Tamaki, “Vacuolation induced by cytotoxin from Helicobacter pylori is mediated by the EGF receptor in HeLa cells,” FEBS Letters, vol. 431, no. 3, pp. 347–350, 1998.
[182]
X. Sewald, B. Gebert-Vogl, S. Prassl, et al., “Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin,” Cell Host and Microbe, vol. 3, no. 1, pp. 20–29, 2008.
[183]
M. Molinari, C. Galli, M. De Bernard, et al., “The acid activation of Helicobacter pylori toxin VacA: structural and membrane binding studies,” Biochemical and Biophysical Research Communications, vol. 248, no. 2, pp. 334–340, 1998.
[184]
V. R. Gupta, H. K. Patel, S. S. Kostolansky, R. A. Ballivian, J. Eichberg, and S. R. Blanke, “Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA,” PLoS Pathogens, vol. 4, no. 5, Article ID e1000073, 2008.
[185]
T. L. Cover, U. S. Krishna, D. A. Israel, and R. M. Peek, “Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin,” Cancer Research, vol. 63, no. 5, pp. 951–957, 2003.
[186]
D. C. Willhite and S. R. Blanke, “Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity,” Cellular Microbiology, vol. 6, no. 2, pp. 143–154, 2004.
[187]
A. Galmiche, J. Rassow, A. Doye, et al., “The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release,” EMBO Journal, vol. 19, no. 23, pp. 6361–6370, 2000.
[188]
D. C. Willhite, T. L. Cover, and S. R. Blanke, “Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation,” Journal of Biological Chemistry, vol. 278, no. 48, pp. 48204–48209, 2003.
[189]
A. Oldani, M. Cormont, and V. Hofman, “Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells,” PLoS Pathogens, vol. 5, no. 10, article e1000603, 2009.
[190]
R. H. Argent, R. J. Thomas, D. P. Letley, M. G. Rittig, K. R. Hardie, and J. C. Atherton, “Functional association between the Helicobacter pylori virulence factors VacA and CagA,” Journal of Medical Microbiology, vol. 57, no. 2, pp. 145–150, 2008.
[191]
N. Tegtmeyer, D. Zabler, D. Schmidt, R. Hartig, S. Brandt, and S. Backert, “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,” Cellular Microbiology, vol. 11, no. 3, pp. 488–505, 2009.
[192]
H. Lu, P.-I. Hsu, D. Y. Graham, and Y. Yamaoka, “Duodenal ulcer promoting gene of Helicobacter pylori,” Gastroenterology, vol. 128, no. 4, pp. 833–848, 2005.
[193]
N. R. Hussein, R. H. Argent, C. K. Marx, S. R. Patel, K. Robinson, and J. C. Atherton, “Helicobacter pylori dupA is polymorphic, and its active form induces proinflammatory cytokine secretion by mononuclear cells,” Journal of Infectious Diseases, vol. 202, no. 2, pp. 261–269, 2010.
[194]
Y. Yamaoka, T. Kodama, O. Gutierrez, J. G. Kim, K. Kashima, and D. Y. Graham, “Relationship between Helicobacter priori iceA, cagA, and vacA status and clinical outcome: studies in four different countries,” Journal of Clinical Microbiology, vol. 37, no. 7, pp. 2274–2279, 1999.
[195]
C. Figueiredo, W. G. V. Quint, and R. Sanna, “Genetic organization and heterogeneity of the iceA locus of Helicobacter pylori,” Gene, vol. 246, no. 1-2, pp. 59–68, 2000.
[196]
Q. Xu, R. D. Morgan, R. J. Roberts, et al., “Functional analysis of iceA1, a CATG-recognizing restriction endonuclease gene in Helicobacter pylori,” Nucleic Acids Research, vol. 30, no. 17, pp. 3839–3847, 2002.
[197]
R. M. Peek, S. A. Thompson, J. P. Donahue, et al., “Adherence to gastric epithelial cells induces expression of a Helicobacter pylori gene, iceA, that is associated with clinical outcome,” Proceedings of the Association of American Physicians, vol. 110, no. 6, pp. 531–544, 1998.
[198]
Y. Yamaoka, S. Kikuchi, H. M. T. ElZimaity, O. Gutierrez, M. S. Osato, and D. Y. Graham, “Importance of Helicobacter pylori OipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production,” Gastroenterology, vol. 123, no. 2, pp. 414–424, 2002.
[199]
F. H. Tabassam, D. Y. Graham, and Y. Yamaoka, “OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization,” Cellular Microbiology, vol. 10, no. 4, pp. 1008–1020, 2008.
[200]
J. Calam, “Helicobacter pylori modulation of gastric acid,” Yale Journal of Biology and Medicine, vol. 72, no. 2-3, pp. 195–202, 1999.
[201]
E. M. El-Omar, M. Carrington, and W. H. Chow, “The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer.,” Nature, vol. 412, no. 6842, p. 99, 2001.
[202]
E. M. El-Omar, C. S. Rabkin, M. D. Gammon, et al., “Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms,” Gastroenterology, vol. 124, no. 5, pp. 1193–1201, 2003.
[203]
T. Furuta, N. Shirai, F. Xiao, et al., “Polymorphism of interleukin-1β affects the eradication rates of Helicobacter pylori by triple therapy,” Clinical Gastroenterology and Hepatology, vol. 2, no. 1, pp. 22–30, 2004.
[204]
I. R. Hwang, P. I. Hsu, and L. E. Peterson, “Interleukin-6 genetic polymorphisms are not related to Helicobacter pylori-associated gastroduodenal diseases,” Helicobacter, vol. 8, no. 2, pp. 142–148, 2003.
[205]
J. C. Machado, C. Figueiredo, P. Canedo, et al., “A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma,” Gastroenterology, vol. 125, no. 2, pp. 364–371, 2003.
[206]
R. Rad, C. Prinz, B. Neu, et al., “Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa,” Journal of Infectious Diseases, vol. 188, no. 2, pp. 272–281, 2003.
[207]
C. F. Zambon, D. Basso, F. Navaglia, et al., “Helicobacter pylori virulence genes and host IL-1RN and IL-1β genes interplay in favouring the development of peptic ulcer and intestinal metaplasia,” Cytokine, vol. 18, no. 5, pp. 242–251, 2002.
[208]
T. Suzuki, E. Grand, and C. Bowman, “TNF-α and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms,” American Journal of Physiology Gastrointestinal and Liver Physiology, vol. 281, no. 6, pp. G1405–G1412, 2001.
[209]
E. J. Yoo, S. Y. Park, and N. Y. Cho, “Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer,” Virchows Archiv, vol. 456, no. 6, pp. 647–652, 2010.
[210]
I. Ohyama, N. Ohmiya, Y. Niwa, et al., “The association between tumour necrosis factor-α gene polymorphism and the susceptibility to rugal hyperplastic gastritis and gastric carcinoma,” European Journal of Gastroenterology and Hepatology, vol. 16, no. 7, pp. 693–700, 2004.
[211]
S. S. Yea, Y. I. Yang, W. H. Jang, Y. J. Lee, H. S. Bae, and K. H. Paik, “Association between TNF-α promoter polymorphism and Helicobacter pylori cagA subtype infection,” Journal of Clinical Pathology, vol. 54, no. 9, pp. 703–706, 2001.
[212]
N. Hamajima, N. Katsuda, K. Matsuo, et al., “High anti-Helicobacter pylori antibody seropositivity associated with the combination of IL-8-251TT and IL-10-819TT genotypes,” Helicobacter, vol. 8, no. 2, pp. 105–110, 2003.
[213]
S. Hellmig, J. Hampe, U. R. F？lsch, and S. Schreiber, “Role of IL-10 promoter haplotypes in Helicobacter pylori associated gastric inflammation,” Gut, vol. 54, no. 6, p. 888, 2005.
[214]
C. F. Zambon, D. Basso, F. Navaglia, et al., “Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome,” Cytokine, vol. 29, no. 4, pp. 141–152, 2005.
[215]
R. Rad, A. Dossumbekova, and B. Neu, “Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection,” Gut, vol. 53, no. 8, pp. 1082–1089, 2004.
[216]
M. T. H. Ng, R. Van't Hof, and J. C. Crockett, “Increase in NF-κB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease,” Infection and Immunity, vol. 78, no. 3, pp. 1345–1352, 2010.
[217]
P. Hofner, Z. Gyulai, Z. F. Kiss, et al., “Genetic polymorphisms of NOD1 and IL-8, but not polymorphisms of TLR4 genes, are associated with Helicobacter pylori-induced duodenal ulcer and gastritis,” Helicobacter, vol. 12, no. 2, pp. 124–131, 2007.
[218]
M. Macarthur, G. L. Hold, and E. M. El-Omar, “Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy,” American Journal of Physiology Gastrointestinal and Liver Physiology, vol. 286, no. 4, pp. G515–G520, 2004.
[219]
S. Eidt, M. Stolte, and R. Fischer, “Helicobacter pylori gastritis and primary gastric non-Hodgkin's lymphomas,” Journal of Clinical Pathology, vol. 47, no. 5, pp. 436–439, 1994.
[220]
J. Parsonnet and P. G. Isaacson, “Bacterial infection and MALT lymphoma,” New England Journal of Medicine, vol. 350, no. 3, pp. 213–215, 2004.
[221]
A. De Mascarel, A. Ruskone-Fourmestraux, A. Lavergne-Slove, F. Megraud, P. Dubus, and J. P. Merlio, “Clinical, histological and molecular follow-up of 60 patients with gastric marginal zone lymphoma of mucosa-associated lymphoid tissue,” Virchows Archiv, vol. 446, no. 3, pp. 219–224, 2005.
[222]
W. Fischbach, M. E. Goebeler-Kolve, B. Dragosics, A. Greiner, and M. Stolte, “Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series,” Gut, vol. 53, no. 1, pp. 34–37, 2004.
[223]
S. Nakamura, T. Matsumoto, H. Suekane, et al., “Long-term clinical outcome of Helicobacter pylori eradication for gastric mucosa-associated lymphoid tissue lymphoma with a reference to second-line treatment,” Cancer, vol. 104, no. 3, pp. 532–540, 2005.
[224]
T. Wündisch, C. Thiede, A. Morgner, et al., “Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication,” Journal of Clinical Oncology, vol. 23, no. 31, pp. 8018–8024, 2005.
[225]
M. Raderer, B. Streubel, S. Woehrer, et al., “High relapse rate in patients with MALT lymphoma warrants lifelong follow-up,” Clinical Cancer Research, vol. 11, no. 9, pp. 3349–3352, 2005.
[226]
H. Liu, H. Ye, and A. RuskoneFourmestraux, “T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication,” Gastroenterology, vol. 122, no. 5, pp. 1286–1294, 2002.
[227]
H. Inagaki, T. Nakamura, C. Li, et al., “Gastric MALT lymphomas are divided into three groups based on responsiveness to Helicobacter pylori eradication and detection of API2-MALT1 fusion,” American Journal of Surgical Pathology, vol. 28, no. 12, pp. 1560–1567, 2004.
[228]
P. Malfertheiner, F. Megraud, C. O'Morain, et al., “Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report,” Gut, vol. 56, no. 6, pp. 772–781, 2007.
[229]
B. F. M. Werdmuller and R. J. L. F. Loffeld, “Helicobacter pylori infection has no role in the pathogenesis of reflux esophagitis,” Digestive Diseases and Sciences, vol. 42, no. 1, pp. 103–105, 1997.
[230]
C. A. Fallone, A. N. Barkun, M. U. G？ttke, et al., “Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases,” American Journal of Gastroenterology, vol. 95, no. 3, pp. 659–669, 2000.
[231]
R. Befrits, S. Sj？stedt, B. ？dman, H. S？rng？rd, and G. Lindberg, “Curing Helicobacter pylori infection in patients with duodenal ulcer does not provoke gastroesophageal reflux disease,” Helicobacter, vol. 5, no. 4, pp. 202–205, 2000.
[232]
E. M. El-Omar, K. Oien, A. El-Nujumi, et al., “Helicobacter pylori infection and chronic gastric acid hyposecretion,” Gastroenterology, vol. 113, no. 1, pp. 15–24, 1997.
[233]
N. Vakil, B. Hahn, and D. McSorley, “Recurrent symptoms and gastro-oesophageal reflux disease in patients with duodenal ulcer treated for Helicobacter pylori infection,” Alimentary Pharmacology and Therapeutics, vol. 14, no. 1, pp. 45–51, 2000.
[234]
A. Gasbarrini, F. Franceschi, R. Tartaglione, R. Landolfi, P. Pola, and G. Gasbarrini, “Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori,” Lancet, vol. 352, no. 9131, p. 878, 1998.
[235]
G. Emilia, M. Luppi, P. Zucchini, et al., “Helicobacter pylori infection and chronic immune thrombocytopenic purpura: long-term results of bacterium eradication and association with bacterium virulence profiles,” Blood, vol. 110, no. 12, pp. 3833–3841, 2007.
[236]
A. Asahi, M. Kuwana, H. Suzuki, T. Hibi, Y. Kawakami, and Y. Ikeda, “Effects of a Helicobacter pylori eradication regimen on anti-platelet autoantibody response in infected and uninfected patients with idiopathic thrombocytopenic purpura,” Haematologica, vol. 91, no. 10, pp. 1436–1437, 2006.
[237]
M. Kodama, Y. Kitadai, M. Ito, et al., “Immune response to CagA protein is associated with improved platelet count after Helicobacter pylori eradication in patients with idiopathic thrombocytopenic purpura,” Helicobacter, vol. 12, no. 1, pp. 36–42, 2007.
[238]
C. Hershko, M. Ianculovich, and M. Souroujon, “A hematologist's view of unexplained iron deficiency anemia in males: impact of Helicobacter pylori eradication,” Blood Cells, Molecules and Diseases, vol. 38, no. 1, pp. 45–53, 2007.
[239]
Y. Chen and M. J. Blaser, “Inverse associations of Helicobacter pylori with asthma and allergy,” Archives of Internal Medicine, vol. 167, no. 8, pp. 821–827, 2007.
[240]
O. Herbarth, M. Bauer, G. J. Fritz, et al., “Helicobacter pylori colonisation and eczema,” Journal of Epidemiology and Community Health, vol. 61, no. 7, pp. 638–640, 2007.
[241]
F. Cremonini and A. Gasbarrini, “Atopy, Helicobacter pylori and the hygiene hypothesis,” European Journal of Gastroenterology and Hepatology, vol. 15, no. 6, pp. 635–636, 2003.
[242]
M. Kist, “Helicobacter pylori: primary antimicrobial resistance and first-line treatment strategies,” Eurosurveillance, vol. 12, no. 7, pp. E1–2, 2007.
[243]
N. Wueppenhorst, H. P. Stueger, M. Kist, and E. Glocker, “Identification and molecular characterization of triple- and quadruple-resistant Helicobacter pylori clinical isolates in Germany,” Journal of Antimicrobial Chemotherapy, vol. 63, no. 4, pp. 648–653, 2009.
[244]
P. F. Saldinger, N. Porta, P. Launois, et al., “Immunization of BALB/c mice with Helicobacter urease B induces a T helper 2 response absent in Helicobacter infection,” Gastroenterology, vol. 115, no. 4, pp. 891–897, 1998.
[245]
T. Aebischer, D. Bumann, H. J. Epple, et al., “Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines,” Gut, vol. 57, no. 8, pp. 1065–1072, 2008.
[246]
Y. Du, A. Agnew, X.-P. Ye, P. A. Robinson, D. Forman, and J. E. Crabtree, “Helicobacter pylori and Schistosoma japonicum co-infection in a Chinese population: helminth infection alters humoral responses to H. pylori and serum pepsinogen I/II ratio,” Microbes and Infection, vol. 8, no. 1, pp. 52–60, 2006.
[247]
M. F. Elshal, I. H. Elsayed, and I. M. El Kady, “Role of concurrent S. mansoni infection in H. pylori-associated gastritis: a flow cytometric DNA-analysis and oxyradicals correlations,” Clinica Chimica Acta, vol. 346, no. 2, pp. 191–198, 2004.
[248]
G. L. Lorca, T. Wadstr？m, G. Font de Valdez, and ？ Ljungh, “Lactobacillus acidophilus autolysins inhibit Helicobacter pylori in vitro,” Current Microbiology, vol. 42, no. 1, pp. 39–44, 2001.
[249]
P. D. Midolo, J. R. Lambert, R. Hull, F. Luo, and M. L. Grayson, “In vitro inhibition of Helicobacter pylori NCTC 11637 by organic acids and lactic acid bacteria,” Journal of Applied Bacteriology, vol. 79, no. 4, pp. 475–479, 1995.
[250]
I. Sakamoto, M. Igarashi, K. Kimura, A. Takagi, T. Miwa, and Y. Koga, “Suppressive effect of Lactobacillus gasseri OLL 2716 (LG21) on Helicobacter pylori infection in humans,” Journal of Antimicrobial Chemotherapy, vol. 47, no. 5, pp. 709–710, 2001.
[251]
J. Zou, J. Dong, and X. Yu, “Meta-analysis: lactobacillus containing quadruple therapy versus standard triple first-line therapy for Helicobacter pylori eradication,” Helicobacter, vol. 14, no. 5, pp. 97–107, 2009.
