The Biology of cag in the Helicobacter pylori-Human Interaction
2005; Elsevier BV; Volume: 128; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2005.03.053
ISSN1528-0012
Autores Tópico(s)Galectins and Cancer Biology
ResumoIt has been more than 15 years since Cover et al1Cover T.L. Dooley C.P. Blaser M.J. Characterization and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity.Infect Immun. 1990; 58: 603-610Crossref Google Scholar reported a strong association between serologic responses to what we now call the CagA protein and peptic ulcer disease. Independent confirmation and association with enhanced gastric inflammation2Crabtree J.E. Taylor J.D. Wyatt J.I. Heatley R.V. Shallcross T.M. Tompkins D.S. Rathbone B.J. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology.Lancet. 1991; 338: 332-335Google Scholar led to cloning of the gene, cagA; encoding the protein3Tummuru M.K.R. Cover T.L. Blaser M.J. Cloning and expression of a high molecular weight major antigen of Helicobacter pylorievidence of linkage to cytotoxin production.Infect Immun. 1993; 61: 1799-1809Crossref Google Scholar, 4Covacci A. Censini S. Bugnoli M. et al.Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer.Proc Natl Acad Sci U S A. 1993; 90: 5791-5795Google Scholar; identifying the role of the adjacent type 4 secretion system (TFSS) homolog in the enhanced inflammation5Tummuru M.K.R. Sharma S.A. Blaser M.J. Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells.Mol Microbiol. 1995; 18: 867-876Google Scholar; and recognizing that cagA is a marker for a 35–40-kilobase chromosomal region, the cag island, present in some but not all Helicobacter pylori strains.6Censini S. Lange C. Xiang Z.Y. Crabtree J.E. Ghiara P. Borodovsky M. Rappuoli R. Covacci A. Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors.Proc Natl Acad Sci U S A. 1996; 93: 14648-14653Google Scholar, 7Akopyanz N.S. Clifton S.W. Kersulyte D. et al.Analyses of the cag pathogenicity island of Helicobacter pylori.Mol Microbiol. 1998; 28: 37-53Google Scholar Although H pylori isolates are highly diverse, the presence or absence of the cag island represents a fundamental biologic and clinical dichotomy.8Blaser M.J. Atherton J. Helicobacter pylori persistence biology and disease.Clin Investig. 2004; 113: 321-333Google Scholar From multiple epidemiologic studies, it now is clear that persons with serologic evidence of carrying cag+ strains are at enhanced risk of developing both peptic ulcer disease and noncardia gastric adenocarcinoma.9Blaser M.J. Pérez-Pérez 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 associated with an increased risk of developing adenocarcinoma of the stomach.Cancer Res. 1995; 55: 2111-2115Google Scholar, 10Parsonnet J. Friedman G.D. Orentreich N. Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection.Gut. 1997; 40: 297-301Google Scholar, 11Nomura A.M.Y. Lee J. Stemmerman G. Nomura R.Y. Perez-Perez G.I. Blaser M.J. Helicobacter pylori cagA seropositivity and gastric carcinoma risk in a Japanese American population.J Infect Dis. 2002; 186: 1138-1144Google Scholar, 12Nomura A.M.Y. Perez-Perez G.I. Lee J. Stemmerman G. Blaser M.J. Relationship between H. pylori cagA status and risk of peptic ulcer disease.Am J Epidemiol. 2002; 155: 1054-1059Google Scholar In serologic studies of specimens from the same patient 21 years apart, α-CagA antibody titers were highly correlated,13Perez-Perez G.I. Salomaa A. Kosunen T.U. Daverman B. Rautelin H. Aromaa A. Knekt P. Blaser M.J. Evidence that cagA+Helicobacter pylori strains are disappearing more rapidly than cagA− strains.Gut. 2002; 50: 295-298Google Scholar indicating the stability of the H pylori/cagA/human interaction during at least 2 decades of life. Despite these strong relationships, the mechanisms underlying the phenomena were not well understood. Our knowledge advanced substantially 5 years ago when several groups independently reported that the putative TFSS encoded on the cag island was in fact functional, and injected the CagA protein into human gastric epithelial cells.14Odenbreit S. Püls J. Sedlmaier B. Gerland E. Fischer W. Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.Science. 2000; 287: 1497-1500Google Scholar, 15Stein M. Rappuoli R. Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation.Proc Natl Acad Sci U S A. 2000; 97: 1263-1268Google Scholar, 16Asahi M. Azuma T. Ito S. Ito Y. Suto H. Nagai Y. Tsubokawa M. Tohyama Y. Maeda S. Omata M. Suzuki T. Sasakawa C. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells.J Exp Med. 2000; 191: 593-602Google Scholar, 17Segal E.D. Cha J. Lo J. Falkow S. Tompkins L.S. Altered states involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori.Proc Natl Acad Sci U S A. 1999; 96: 14559-14564Google Scholar Most, but not all, CagA proteins contain 1 or more tyrosine phosphorylation motifs (TPM),14Odenbreit S. Püls J. Sedlmaier B. Gerland E. Fischer W. Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.Science. 2000; 287: 1497-1500Google Scholar, 18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar, 19Azuma T. Yamazaki S. Yamakawa A. Ohtani M. Muramatsu A. Suto H. Ito Y. Dojo M. Yamazaki Y. Kuriyama M. Keida Y. Higashi H. Hatakeyama M. Association between diversity in the Src homology 2 domain-containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer.J Infect Dis. 2004; 189: 820-827Google Scholar, 20Argent R.H. Kidd M. Owen R.J. Thomas R.J. Limb M.C. Atherton J.C. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori.Gastroenterology. 2004; 127: 514-523Abstract Full Text Full Text PDF Scopus (177) Google Scholar which, when injected into host epithelial cells, are phosphorylated by Src-like kinases.14Odenbreit S. Püls J. Sedlmaier B. Gerland E. Fischer W. Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion.Science. 2000; 287: 1497-1500Google Scholar, 15Stein M. Rappuoli R. Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation.Proc Natl Acad Sci U S A. 2000; 97: 1263-1268Google Scholar, 16Asahi M. Azuma T. Ito S. Ito Y. Suto H. Nagai Y. Tsubokawa M. Tohyama Y. Maeda S. Omata M. Suzuki T. Sasakawa C. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells.J Exp Med. 2000; 191: 593-602Google Scholar, 17Segal E.D. Cha J. Lo J. Falkow S. Tompkins L.S. Altered states involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori.Proc Natl Acad Sci U S A. 1999; 96: 14559-14564Google Scholar Therefore, there has been strong selection for H pylori strains that produce and introduce a bacterial protein that is interpreted by the host as self. H pylori are sending a strong and consistent signal to their hosts, but what is the message? Phospho-CagA then interacts with SHP-2, and other host molecules involved in a variety of signal transduction pathways, which affects host cell gene expression affecting cytokine release, cell cycle, cell structure, and even interactions with neighboring cells.21Fisher W. PPülsls J. Buhrdorf R. Gebert B. Odenbreit S. Haas R. Systematic mutagenesis of the Helicobacter pylori ca gpathogenicity island essential genes for CagA translocation in host cells and induction of interleukin-8.Mol Microbiol. 2001; 42: 1337-1348Google Scholar, 22Higashi H. Tsutsumi R. Muto S. Sugiyama T. Azuma T. Asaka M. Hatakeyama M. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.Science. 2001; 295: 683-686Google Scholar, 23Backert S. Moese S. Selbach M. Brinkmann V. Meyer T.F. Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells.Mol Microbiol. 2001; 42: 631-644Google Scholar, 24Tsutsumi R. Higashi H. Higuchi M. Okada M. Hatakeyama M. Attentuation of Helicobacter pylori CagA x SHP-2 signaling by interaction between CagA and C-terminal Src kinase.J Biol Chem. 2003; 278: 3664-3670Google Scholar, 25Amieva 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: 1430-1434Google Scholar, 26Naumann M. Wessler S. Bartsch C. Wieland B. Covacci A. Haas R. Meyer T.F. Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island.J Biol Chem. 1999; 274: 31655-31662Google Scholar Importantly, the CagA proteins vary in the number of TPM present and in their structure, which may help explain virulence differences among H pylori strains in human populations.18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar, 19Azuma T. Yamazaki S. Yamakawa A. Ohtani M. Muramatsu A. Suto H. Ito Y. Dojo M. Yamazaki Y. Kuriyama M. Keida Y. Higashi H. Hatakeyama M. Association between diversity in the Src homology 2 domain-containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer.J Infect Dis. 2004; 189: 820-827Google Scholar, 20Argent R.H. Kidd M. Owen R.J. Thomas R.J. Limb M.C. Atherton J.C. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori.Gastroenterology. 2004; 127: 514-523Abstract Full Text Full Text PDF Scopus (177) Google Scholar The typical CagA TPM is encoded by the 3′ region of cagA, which contains multiple repetitive DNA sequences.3Tummuru M.K.R. Cover T.L. Blaser M.J. Cloning and expression of a high molecular weight major antigen of Helicobacter pylorievidence of linkage to cytotoxin production.Infect Immun. 1993; 61: 1799-1809Crossref Google Scholar, 4Covacci A. Censini S. Bugnoli M. et al.Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer.Proc Natl Acad Sci U S A. 1993; 90: 5791-5795Google Scholar, 18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar, 27Yamaoka Y. Kodama T. Kashima K. Graham D.Y. Sepulveda A.R. Variants of the 3′ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases.J Clin Microbiol. 1998; 36: 2258-2263Crossref Google Scholar, 28Azuma T. Yamakawa A. Yamazaki S. Fukuta K. Ohtani M. Ito Y. Dojo M. Yamazaki Y. Kuriyama M. Correlation between variation of the 3′ region of the cagA gene in Helicobacter pylori and disease outcome in Japan.J Infect Dis. 2002; 186: 1621-1630Google Scholar Recombination events involving the repetitive DNA creates variants differing in the number of TPM, with consequently differing effects on host cells.18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar Individuals colonized by cag+ strains, in fact, contain populations of clonal variants that have fully intact and functional cag islands, or have a diversity of deletions.18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar, 29Peters T.M. Owen R.J. Slater E. et al.Genetic diversity in the Helicobacter pylori cag pathogenicity island and effect on expression of anti-CagA serum antibody in UK patients with dyspepsia.J Clin Pathol. 2001; 54: 219-223Google Scholar, 30Occhialini A. Marais A. Urdaci M. et al.Composition and gene expression of the cag pathogenicity island in Helicobacter pylori strains isolated from gastric carcinoma and gastrities patients in Coast Rica.Infec Immun. 2001; 69: 1902-1908Google Scholar, 31Tomasini M.L. Zanussi S. Sozzi M. et al.Heterogeneity of cag genotypes in Helicobacter pylori isolates from human biopsy specimans.J Clin Microbiol. 2003; 41: 976-980Google Scholar Each of these different genotypes has consequent variation in host cell interaction and function. Past work has provided a strong molecular basis for the enhanced significance of the cag+ genotype, but appreciation of the geographic and genetic variation of the cag island27Yamaoka Y. Kodama T. Kashima K. Graham D.Y. Sepulveda A.R. Variants of the 3′ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases.J Clin Microbiol. 1998; 36: 2258-2263Crossref Google Scholar, 28Azuma T. Yamakawa A. Yamazaki S. Fukuta K. Ohtani M. Ito Y. Dojo M. Yamazaki Y. Kuriyama M. Correlation between variation of the 3′ region of the cagA gene in Helicobacter pylori and disease outcome in Japan.J Infect Dis. 2002; 186: 1621-1630Google Scholar, 29Peters T.M. Owen R.J. Slater E. et al.Genetic diversity in the Helicobacter pylori cag pathogenicity island and effect on expression of anti-CagA serum antibody in UK patients with dyspepsia.J Clin Pathol. 2001; 54: 219-223Google Scholar, 30Occhialini A. Marais A. Urdaci M. et al.Composition and gene expression of the cag pathogenicity island in Helicobacter pylori strains isolated from gastric carcinoma and gastrities patients in Coast Rica.Infec Immun. 2001; 69: 1902-1908Google Scholar, 31Tomasini M.L. Zanussi S. Sozzi M. et al.Heterogeneity of cag genotypes in Helicobacter pylori isolates from human biopsy specimans.J Clin Microbiol. 2003; 41: 976-980Google Scholar has exceeded our knowledge of the biologic and pathophysiologic implications.32Crabtree J.E. Farmery S.M. Lindley I.J.D. Figura N. Peichl P. Tompkins D.S. CagA cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines.J Clin Pathol. 1994; 47: 945-950Google Scholar, 33Peek R.M. Miller G.G. Tham K.T. Perez-Perez G.I. Zhao X. Atherton J.C. Blaser M.J. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains.Lab Investig. 1995; 71: 760-770Google Scholar, 34Sharma S.A. Tummuru M.K. Blaser M.J. Kerr L.D. Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor nuclear factor-kappa B in gastric epithelial cells.J Immunol. 1998; 160: 2401-2407Google Scholar, 35Keates S. Hitti Y.S. Upton M. Kelly C.P. Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells.Gastroenterology. 1997; 113: 1099-1109Abstract Full Text Full Text PDF Scopus (375) Google Scholar Progress in this field has been hampered by the observation that experimental challenge of mice with cag+ H pylori rapidly leads to inactivation of cag functions, usually because of genetic deletions.36Sozzi M. Crosatti M. Kim S.K. et al.Heterogeneity of Helicobacter pylori cag genotypes in experimentally infected mice.FEMS Microbiol Lett. 2001; 203: 109-114Google Scholar, 37Crabtree J.E. Ferrero R.L. Kuster J.G. The mouse colonizing Helicobacter pylori strain SS1 may lack a functional cag pathogenicity island.Helicobacter. 2002; 7: 139-140Google Scholar None of the other Helicobacter species has been reported to contain cagA, and its deletion in mice suggests that the injection of CagA into host tissues is a human (or primate)-specific adaptation. However, previous studies have shown that Mongolian gerbils can be more easily infected with H pylori and show pathologic features after challenge that are more similar to findings in humans than are seen in mice.38Peek R.M. Wirth H.-P. Moss S.F. Yang M. Abdalla A.M. Tham K.T. Zhang T. Tang L.H. Modlin I.M. Blaser M.J. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils.Gastroenterology. 2000; 118: 48-59Google Scholar, 39Takashima M. Furuta T. Hanai H. Sugimura H. Kaneko E. Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils.Gut. 2001; 48: 765-773Google Scholar, 40Ikeno T. Ota H. Sugiyama A. Ishida K. Katsuyama T. Genta R.M. Kawasaki S. Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils.Am J Pathol. 1999; 154: 951-960Google Scholar Thus, Rieder et al41Rieder G. Merchant J.L. Haas R. Helicobacter pylori cag-Type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils.Gastroenterology. 2005; 218: 1229-1242Abstract Full Text Full Text PDF Scopus (151) Google Scholar used the gerbil model of H pylori challenge to extend our knowledge of cag function, and they made several important observations that fit new pieces into the jigsaw puzzle of H pylori-human interactions. They confirmed that a wild-type H pylori strain (with a fully functional cag island) and its isogenic Δ cagA and Δ cagY (which is required for TFSS function) mutants could colonize the gerbil stomach and showed that these strains all could persist for up to 32 weeks, which was when their study ended. As in humans, having a functional cag island is not necessary for extended colonization. Although many of the characteristics of the experimentally challenged gerbils were similar for the 3 strains, an important difference emerged related to the location of colonization. Rieder et al41Rieder G. Merchant J.L. Haas R. Helicobacter pylori cag-Type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils.Gastroenterology. 2005; 218: 1229-1242Abstract Full Text Full Text PDF Scopus (151) Google Scholar found that, for the wild-type strain, the numbers of H pylori cells in the antrum and corpus were essentially the same and, in the mutants, the antral colonization was approximately 1–1.5 logs (10–30-fold) higher than the corpus colonization. In essence, functional cag activity was required for full colonization of the gastric corpus. The difference in corpus colonization in the gerbils challenged with mutants was accompanied by marked decreases in corpus inflammation, cytokine production, and the prechallenge gastric acidity and gastrin levels were maintained, compared with the gerbils challenged by the wild-type cag+ strain. These studies indicate that the presence of an intact cag island permitted high-level colonization of the gastric corpus with subsequent effects on inflammation and acidity. The results were clear and consistent, but can they be generalized to H pylori interactions with humans? H pylori is naturally acquired in human populations early in life.42Oliveira A.M. Queiroz D.M. Rocha G.A. et al.Seroprevalence of Helicobacter pylori infection of children of low socioeconomic level in Belo Horizonte, Brazil.Am J Gastroenterol. 1994; 89: 2201-2204Google Scholar, 43Perez-Perez G.I. Sack R.B. Reid R. Santosham M. Croll J. Blaser M.J. Transient and persistent Helicobacter pylori colonization in Native American children.J Clin Microbiol. 2003; 41: 2401-2407Google Scholar Although little is known about early events in children, accidental and experimental infections has provided some information, albeit in adults.44Harford W.V. Barnett C. Lee E. Perez-Perez G. Blaser M.J. Peterson W.L. Acute gastritis with hypochlorhydria report of 35 cases with long-term follow-up.Gut. 2000; 47: 467-472Google Scholar There often is intense corpus gastrititis, hypochlorhydria, and hypergastrinemia, events quite parallel to those Rieder et al41Rieder G. Merchant J.L. Haas R. Helicobacter pylori cag-Type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils.Gastroenterology. 2005; 218: 1229-1242Abstract Full Text Full Text PDF Scopus (151) Google Scholar observed in the gerbil at 32 weeks. One limitation of this study is that use of the single time point does not permit assessment of temporal trends; other studies have shown hypergastrinemia in gerbil models beginning 16 weeks after challenge.38Peek R.M. Wirth H.-P. Moss S.F. Yang M. Abdalla A.M. Tham K.T. Zhang T. Tang L.H. Modlin I.M. Blaser M.J. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils.Gastroenterology. 2000; 118: 48-59Google Scholar In humans, after the intense early inflammation, hypochlorhydria, and hypergastrinemia, there is a return to baseline and the establishment of a long-term equilibrium,43Perez-Perez G.I. Sack R.B. Reid R. Santosham M. Croll J. Blaser M.J. Transient and persistent Helicobacter pylori colonization in Native American children.J Clin Microbiol. 2003; 41: 2401-2407Google Scholar not markedly different from preacquisition. Over time, with the gradual development of atrophic gastritis,45Kuipers E.J. Uyterlinde A.M. Peña A.S. et al.Long-term sequelae of Helicobacter pylori gastritis.Lancet. 1995; 345: 1525-1528Scopus (724) Google Scholar acidity begins to fall and gastrin rises.46Sipponen P. Harkonen M. Alanko A. Suovaniemi O. Diagnosis of atrophic gastritis from a serum sample.Clin Lab. 2002; 48: 505-515Google Scholar It is not clear whether the studies by Rieder et al41Rieder G. Merchant J.L. Haas R. Helicobacter pylori cag-Type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils.Gastroenterology. 2005; 218: 1229-1242Abstract Full Text Full Text PDF Scopus (151) Google Scholar in the gerbil better reflect the early events after human acquisition of H pylori or the long-term equilibrium with more modulated effects on inflammation and gastric secretory physiology. In any event, the demonstration of differences between the cag+ strain, and its cag mutants is significant. That the cagY mutant, which inactivates the TFSS and thus CagA injection, and the cagA mutant, which leaves the TFSS intact but precludes CagA injection, behaved similarly indicates that at least in this model, the major function of the TFSS that affects host responses is the delivery of CagA. Nevertheless, the TFSS can potentially inject other H pylori constituents into host cells, and has been reported to be required for injection of peptidoglycans.47Viala J. Chaput C. Boneca I.G. Cardona A. Girardin S.E. Moran A.P. Athman R. Memet S. Huerre M.R. Coyle A.J. DiStefano P.S. Sansonetti P.J. Labigne A. Bertin J. Philpott D.J. Ferrero R.L. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island.Nat Immunol. 2004; 5: 1166-1174Google Scholar If the presence of the cag island enables H pylori strains to more successfully colonize the gastric corpus of humans than cag− strains, this difference would provide one explanation for the enhanced ability of cag+ strains to lead to atrophic gastritis48Kuipers E.J. Pérez-Pérez G.I. Meuwissen S.G.M. Blaser M.J. Helicobacter pylori and atrophic gastritis importance of the cagA status.J Nat Can Instit. 1995; 87: 1777-1780Google Scholar, 49Webb P. Crabtree J.E. Forman D. Eurogast Study GroupGastric cancer, cytotoxin-associated geneA-positive Helicobacter pylori, and serum pepsinogens.Gastroenterology. 1999; 116: 269-276Google Scholar and to noncardia gastric adenocarcinoma.9Blaser M.J. Pérez-Pérez 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 associated with an increased risk of developing adenocarcinoma of the stomach.Cancer Res. 1995; 55: 2111-2115Google Scholar, 10Parsonnet J. Friedman G.D. Orentreich N. Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection.Gut. 1997; 40: 297-301Google Scholar, 11Nomura A.M.Y. Lee J. Stemmerman G. Nomura R.Y. Perez-Perez G.I. Blaser M.J. Helicobacter pylori cagA seropositivity and gastric carcinoma risk in a Japanese American population.J Infect Dis. 2002; 186: 1138-1144Google Scholar Perhaps the enhanced inflammation induced by cag+ strains is sufficient to induce adenocarcinoma, whether or not the malignant cells in fact migrate to the injury site from the bone marrow.50Houghton J. Stoicov C. Nomura S. Rogers A. Carlson J. Li H. Cai X. Fox J. Goldenring J. Wang T. Gastric cancer originating from bone marrow-derived cells.Science. 2004; 306: 1568-1571Google Scholar One hypothesis supported by these studies8Blaser M.J. Atherton J. Helicobacter pylori persistence biology and disease.Clin Investig. 2004; 113: 321-333Google Scholar is that one of the roles of the cag island is to help H pylori regulate gastric acidity, perhaps through differential effects on the various secretory epithelia. Evidence that cag function is acid-regulated has been emerging.51Karita M. Tummuru M.K.R. Wirth H.-P. Blaser M.J. Effect of growth phase and acid shock on Helicobacter pylori cagA expression.Infect Immun. 1996; 64: 4501-4507Crossref Google Scholar, 52Karita M. Blaser M.J. Acid tolerance response in Helicobacter pylori and differences between cagA+ and cagA− strains.J Infect Dis. 1998; 178: 213-219Google Scholar Why cag-positivity also is a risk factor of both gastric and duodenal peptic ulcers12Nomura A.M.Y. Perez-Perez G.I. Lee J. Stemmerman G. Blaser M.J. Relationship between H. pylori cagA status and risk of peptic ulcer disease.Am J Epidemiol. 2002; 155: 1054-1059Google Scholar remains an unanswered question. Because the long-term effect of cag+ strains is to lower gastric acidity by progressively inducing atrophic changes, the association with peptic ulceration, although real, appears paradoxical. Although peptic ulceration often is considered as a hypersecretory state, in many affected patients, gastric acid secretion is within the normal range; factors beyond acid secretion must be necessary for the ulcer diathesis. Perhaps one answer to this paradox comes from our growing understanding of the complexity of the H pylori interactions with humans. Clearly, differences in host genotype related to proinflammatory and anti-inflammatory cytokines are important to clinical outcome (multiple studies reviewed in Peek and Blaser53Peek R.M. Blaser M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nature Rev Cancer. 2002; 2: 28-37Google Scholar). In addition, H pylori+ persons may carry from 1 to several distinct H pylori strains.54Ghose C. Perez-Perez G.I. van Doorn L.J. Dominguez-Bello M.G. Blaser M.J. High frequency of gastric colonization with multiple Helicobacter pylori strains in Venezuelan subjects.J Clin Microbiol. 2005; (in press).Google Scholar These strains may undergo deletions or expansions of critical genetic elements, as in the cagA 3′ region,18Aras R.A. Lee Y. Kim S.-K. Israel D. Peek R.M. Blaser M.J. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype.J Infect Dis. 2003; 188: 486-496Google Scholar and being naturally competent, anything lost may be regained from a co-colonizing strain. Finally, the multiple strains themselves may recombine, producing novel genotypes.55Kersulyte D. Chalkauskas H. Berg D.E. Emergence of recombinant strains of Helicobacter pylori during human infection.Mol Microbiol. 1999; 31: 31-43Google Scholar Thus, there is no single H pylori isolate in any patient, but rather 1 or more interrelated quasispecies clouds, akin to human immunodeficiency virus, living in dynamic equilibrium with their changing host.8Blaser M.J. Atherton J. Helicobacter pylori persistence biology and disease.Clin Investig. 2004; 113: 321-333Google Scholar, 56Blaser M.J. Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host response.Proc Nat Acad Sci U S A. 1999; 96: 8359-8364Google Scholar Each cloud has its own characteristics, oscillating around a mean, and moving dynamically in response to selective changes in the local and global host environment.56Blaser M.J. Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host response.Proc Nat Acad Sci U S A. 1999; 96: 8359-8364Google Scholar Studies, such as those conducted by Rieder et al,41Rieder G. Merchant J.L. Haas R. Helicobacter pylori cag-Type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils.Gastroenterology. 2005; 218: 1229-1242Abstract Full Text Full Text PDF Scopus (151) Google Scholar help us understand the major H pylori genotypes and their pathophysiologic phenotypes. From such work, with eventual translational application, will come the ability for clinicians to individualize their approaches to H pylori+ persons. Helicobacter pylori cag-Type IV Secretion System Facilitates Corpus Colonization to Induce Precancerous Conditions in Mongolian GerbilsGastroenterologyVol. 128Issue 5PreviewBackground & Aims: Epidemiological studies suggest that atrophic corpus-dominant gastritis is an increased risk factor for gastric carcinogenesis. The role of the Helicobacter pylori type IV secretion system (T4SS) for pathogenesis in the Mongolian gerbil model was explored. Methods: Mongolian gerbils were infected for 32 weeks either with H pylori type I strain B128 or with isogenic mutant strain B128Δ cytotoxin-associated gene (cagY) or B128ΔcagA, defective in T4SS or in the production of its effector protein CagA, respectively. Full-Text PDF
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