Chapter 31 : The Pathogenicity Island

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This chapter focuses on the functions that are encoded by a 40-kb chromosomal region with the features of a pathogenicity island (PAI). The PAI was originally named cytotoxin-associated gene () since it was thought to be associated with expression of the vacuolating toxin (VacA). The module also forms the core of the left and right ends of an insertion sequence common in , the IS605 element. One of the most exciting research areas in microbial pathogenesis over the past decade has been the exploration of type III secretion systems. The type IV secretion system can translocate virulence proteins into the host cells. The resulting protrusions on the cell surface (pedestals) somehow resemble the cup-like structures induced by , although they are clearly different structures. Recent observations characterized the involvement of the PAI in phagocytosis of . Mononuclear phagocytes were shown to engulf within approximately 4 minutes, but the internalized bacteria were not killed if type I strains were used for the infection. Instead, induced homotypic phagosome fusions leading to the formation of large vacuoles. The function of the (PAI) in -associated disease has been the subject of controversy ever since its discovery in 1993. Clinical studies with different outcomes have been performed to test whether the presence of the PAI is connected with peptic ulcer disease or gastric cancer. Future approaches have to consider that the presence of the gene alone is not equal to virulence.

Citation: Stein M, Rappouli R, Covacci A. 2001. The Pathogenicity Island, p 345-353. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch31
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Figure 1

Genetic organization of the pathogenicity island. The open reading frames within the 40-kb PAI are depicted as arrows with the gene designations (single letters) below and names of homologs above. The whole genome gene designations are given as a three-digit number. Below, three alternative arrangements of the PAI in three additional strains are shown, is an insertion sequence; tnpA, transposon A; tnpB, transposon B.

Citation: Stein M, Rappouli R, Covacci A. 2001. The Pathogenicity Island, p 345-353. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch31
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Figure 2

Activation of CagA and intracellular actin condensation. Translocation is mediated by the TFSS (a); activation is dependent by a membrane-associated host kinase (b, c) that phosphorylate CagA at multiple sites; small GTP-binding proteins may be involved in recruitment of the N-WASP and Arp 2/3 complex for cortical actin polymerization (d).

Citation: Stein M, Rappouli R, Covacci A. 2001. The Pathogenicity Island, p 345-353. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch31
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Figure 3

Cellular responses to CagA activation. Isolated cells forming the structure of an epithelium are represented during contacts with type I strains of (defined as positive for expression, translocation, and activation of CagA). Two predominant classes of signals are indicated: signals for inflammation and signals for autocrine stimulation and cell cycle control.

Citation: Stein M, Rappouli R, Covacci A. 2001. The Pathogenicity Island, p 345-353. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch31
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Figure 4

Mutations affecting CagA activation, (a) Mutations in CagA expression and structure, (b) mutations in the component of the type IV secretion system, and (c) mutations for absence of phosphorylated CagA or for absence or unresponsiveness of intracellular targets.

Citation: Stein M, Rappouli R, Covacci A. 2001. The Pathogenicity Island, p 345-353. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch31
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1. Akopyanz, N.,, S. W. Clifton,, D. Kersulyte,, J. E. Crabtree,, B. E. Youree,, C. A. Reece,, N. O. Bukanov,, E. S. Drazek,, B. A. Roe,, and D. E. Berg. 1998. Analyses of the cag pathogenicity island of Helicobacter pylori. Mol. Microbiol. 28: 37 53.
2. Allen, L. A.,, L. S. Schlesinger,, and B. Rang. 2000. Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J. Exp. Med. 191: 115 128.
3. Andersson, S. G.,, A. Zomorodipour,, J. O. Andersson,, T. Sich-eritz-Ponten,, U. C. Alsmark,, R. M. Podowski,, A. K. Naslund,, A. S. Eriksson,, H. H. Winkler,, and C. G. Kurland. 1998. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396: 133 140.
4. Asahi, M.,, T. Awuma,, S. Ito,, Y. Ito,, H. Suto,, Y. Nagai,, M. Tsubokawa,, Y. Tohyama,, S. Maeda,, M. Omata,, T. Suzuki,, and C. Sasakawa. 2000. Helicobacter pylori CagA protein can be tyrosine phosphoylated in the gastric epithelial cells. J. Exp. Med. 191: 593 602.
5. Backert, S.,, E. Ziska,, V. Brinkmann,, U. Zimmy-Arndt,, A. Fau-connier,, P. R. Jungblut,, M. Naumann,, and T. F. Meyer. 2000. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell. Microbiol. 2: 155 164.
6. Baker, B.,, P. Zambryski,, B. Staskawicz,, and S. P. Dinesh-Kumar. 1997. Signaling in plant-microbe interactions. Science 276: 726 733.
7. Blaser, M. J. 1998. Helicobacter pylori and gastric diseases. Br. Med. J. 316: 1507 1510.
8. Blum, G.,, M. Ott,, A. Lischewski,, A. Ritter,, H. Imrich,, H. Tschape,, and J. Hacker. 1994. Excision of large DNA regions termed pathogenicity islands from tRNA-specific loci in the chromosome of an Escherichia coli wild-type pathogen. Infect. Immun. 62: 606 614.
9. Censini, S.,, C. Lange,, Z. Xiang,, J. E. Crabtree,, P. Ghiara,, M. Borodovsky,, R. Rappuoli,, and A. Covacci. 1996. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA 93: 14648 14653.
10. Christie, P. 1997. Agrobacterium tumefaciens T-complex transport apparatus: a paradigm for a new family of multifunctional transporters in eubacteria. J. Bacteriol. 179: 3085 3094.
11. Christie, P. J. 1997. The cag pathogenicity island: mechanistic insights. Trends Microbiol. 5: 264 265.
12. Covacci, A.,, S. Censini,, M. Bugnoli,, R. Petracca,, D. Burroni,, G. Macchia,, A. Massone,, E. Papini,, Z. Xiang,, N. Figura,, and R. Rappuoli. 1993. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc. Natl. Acad. Sci. USA 90: 5791 5795.
13. Covacci, A.,, S. Falkow,, D. E. Berg,, and R. Rappuoli. 1997. Did the inheritance of a pathogenicity island modify the virulence of Helicobacter pylori? Trends Microbiol. 5: 205 208.
14. Covacci, A.,, and R. Rappuoli. 1993. Pertussis toxin export requires accessory genes located downstream from the pertussis toxin operon. Mol. Microbiol. 8: 429 434.
15. Covacci, A.,, and R. Rappuoli. 1998. Helicobacter pylori: molecular evolution of a bacterial quasi-species. Curr. Opin. Microbiol. 1: 96 102.
16. Covacci, A.,, and R. Rappuoli. 2000. Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J. Exp. Med. 191: 587 592.
17. Crabtree, J. E.,, D. Kersulyte,, S. D. Li,, I. J. Lindley,, and D. E. Berg. 1999. Modulation of Helicobacter pylori induced in-terleukin-8 synthesis in gastric epithelial cells mediated by cag PAI encoded VirD4 homologue. J. Clin. Pathol. 52: 653 657.
18. Crabtree, J. E.,, Z. Xiang,, I. J. Lindley,, D. S. Tompkins,, R. Rappuoli,, and A. Covacci. 1995. Induction of interleukin-8 secretion from gastric epithelial cells by a cagA negative isogenic mutant of Helicobacter pylori. J. Clin. Pathol. 48: 967 969.
19. Egile, C.,, T. P. Loisel,, V. Laurent,, R. Li,, D. Pantaloni,, P. J. Sansonetti,, and M. F. Carlier. 1999. Activation of the CDC42 effector N-WASP by the Shigella flexneri lcsA protein promotes actin nucleation by Arp2/3 complex and bacterial actin-based motility. J. Cell. Biol. 146: 1319 1332.
20. Falkow, S. 1998. Who speaks for the microbes? Emerg. Infect. Dis. 4: 495 497.
21. Foryst-Ludwig, A.,, and M. Naumann. 2000. PAK1 activates the NIK-IKK NF-kappaB pathway and proinflammatory cytokines in H. pylori infection. J. Biol. Chem. epub ahead of print.
22. Fullner, K. J.,, J. C. Lara,, and E. W. Nester. 1996. Pilus assembly by agrobacterium T-DNA transfer genes. Science 273: 1107 1109.
23. Glocker, E.,, C. Lange,, A. Covacci,, S. Bereswill,, M. Kist,, and H. L. Pahl. 1998. Proteins encoded by the cag pathogenicity island of Helicobacter pylori are required for NF-kappaB activation. Infect. Immun. 66: 2346 2348.
24. Groisman, E. A.,, and H. Ochman. 1996. Pathogenicity islands: bacterial evolution in quantum leaps. Cell 87: 791 794.
25. Hacker, J.,, G. Blum-Oehler,, I. Muhldorfer,, and H. Tschape. 1997. Pathogenicity islands of virulent bacteria: structure, function and impact on microbial evolution. Mol. Microbiol. 23: 1089 1097.
26. Hueck, C.J. 1998. Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol. Mol. Biol. Rev. 62: 379 433.
27. Jiang, Q.,, K. Hiratsuka,, and D. E. Taylor. 1996. Variability of gene order in different Helicobacter pylori strains contributes to genome diversity. Mol. Microbiol. 20: 833 842.
28. Kalman, D.,, O. D. Weiner,, D. L. Goosney,, J. W. Sedat,, B. B. Finlay,, A. Abe,, and J. M. Bishop. 1999. Enteropathogenic E. coli acts through WASP and Arp2/3 complex to form actin pedestals. Nat. Cell. Biol. 1: 389 391.
29. Kenny, B.,, R. DeVinney,, M. Stein,, D. J. Reinscheid,, E. A. Frey,, and B. B. Finlay. 1997. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell 91: 511 520.
30. Kersulyte, D.,, H. Chalkauskas,, and D. E. Berg. 1999. Emergence of recombinant strains of Helicobacter pylori during human infection. Mol. Microbiol. 31: 31 43.
31. Kubori, T.,, Y. Matsushima,, D. Nakamura,, J. Uralil,, M. Lara-Tejero,, A. Sukhan,, J. E. Galan,, and S. I. Aizawa. 1998. Supra-molecular structure of the Salmonella typhimurium type III protein secretion system. Science 280: 602 605.
32. Lai, E. M.,, and C. I. Kado. 1998. Processed VirB2 is the major subunit of the promiscuous pilus of Agrobacterium tumefaciens. J. Bacterial. 180: 2711 2717.
33. Lange, C.,, A. Covacci,, and R. Rappuoli. 1999. The CagT of cag, the pathogenicity island of Helicobacter pylori, is a lipoprotein that assembles into a core system and requires CagM for stabilization. Submitted for publication.
34. Lee, C.,, A. 1996. Pathogenicity islands and the evolution of bacterial pathogens. Infect. Agents Dis. 5: 1 7.
35. Lee, C. A. 1997. Type III secretion systems: machines to deliver bacterial proteins into eukaryotic cells? Trends Microbiol. 5: 148 156.
36. Loisel, T. P.,, R. Boujemaa,, D. Pantaloni,, and M. F. Carlier. 1999. Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Nature 401: 613 616.
37. Macnab, R. M. 1992. Genetics and biogenesis of bacterial flagella. Annu. Rev. Genet. 26: 131 158.
38. Meyer-Ter-Vehn, T.,, A. Covacci,, M. Kist,, and H. L. Pahl. 2000. Helicobacter pylori activates mitogen-activated protein kinase cascades and induces expression of the proto-oncogenes c-fos and c-jun. J. Biol. Chem. 275: 16064 16072.
39. Munzenmaier, A.,, C. Lange,, E. Glocker,, A. Covacci,, A. Moran,, S. Bereswill,, P. A. Baeuerle,, M. Kist,, and H. L. Pahl. 1997. A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-kappa B. J. Immunol. 159: 6140 6147.
40. Naumann, M.,, S. Wessler,, C. Bartsch,, W. Wieland,, A. Covacci,, R. Haas,, and T. F. Meyer. 1999. Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island. J. Biol. Chem. 274: 31655 31662.
41. O'Callaghan, D.,, C. Cazevieille,, A. Allardet-Servent,, M. L. Boschiroli,, G. Bourg,, V. Foulongne,, P. Frutos,, Y. Kulakov,, and M. Ramuz. 1999. A homologue of the Agrobacterium tumefaciens VirB and Bordetella pertussis Ptl type IV secretion systems is essential for intracellular survival of Brucella suis. Mol. Microbiol. 33: 1210 1220.
42. Odenbreit, S.,, J. Puis,, B. Sedlmaier,, E. Gerland,, W. Fischer,, and R. Haas. 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287: 1497 1500.
43. Parsonnet, J.,, G. D. Friedman,, N. Orentreich,, and H. Vogelman. 1997. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40: 297 301.
44. Peek, R. M.,, M. J. Blaser,, D. J. Mays,, M. H. Forsyth,, T. L. Cover,, S. Y. Song,, U. Krishna,, and J. A. Pietenol. 1999. Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res. 59: 6124 6131.
45. Ramarao, N.,, S. D. Gray-Owen,, S. Backert,, and T. F. Meyer. 2000. Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol. Microbiol. 37: 1389 1404.
46. Segal, E. D.,, J. Cha,, J. Lo,, S. Falkow,, and L. S. Tompkins. 1999. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc. Natl. Acad. Sci. USA 96: 14559 14564.
47. Segal, E. D.,, S. Falkow,, and L. S. Tompkins. 1996. Helicobacter pylori attachment to gastric cells induces cytoskeletal rearrangements and tyrosine phosphorylation of host cell proteins. Proc. Natl. Acad. Sci. USA 93: 1259 1264.
48. Segal, E. D.,, C. Lange,, A. Covacci,, L. S. Tompkins,, and S. Falkow. 1997. Induction of host signal transduction pathways by Helicobacter pylori. Proc. Natl. Acad. Sci. USA 94: 7595 7599.
49. Segal, G.,, J. J. Russo,, and H. A. Shuman. 1999. Relationships between a new type IV secretion system and the icm/dot virulence system of Legionella pneumophila. Mol. Microbiol. 34: 799 809.
50. Segal, G.,, and H. A. Shuman. 1998. How is the intracellular fate of the Legionella pneumophila phagosome determined? Trends Microbiol. 6: 253 255.
51. Stein, M.,, R. Rappuoli,, and A. Covacci. 2000. Tyrosine-phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc. Natl. Acad. Sci. USA 97: 1263 1268.
52. Tummuru, M. K.,, T. L. Cover,, and M. J. Blaser. 1993. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect. Immun. 61: 1799 1809.
53. Tummuru, M. K.,, T. L. Cover,, and M. J. Blaser. 1994. Mutation of the cytotoxin-associated cagA gene does not affect the vacuolating cytotoxin activity of Helicobacter pylori. Infect. Immun. 62: 2609 2613.
54. Tummuru, M.,, S. A. Sharma,, and M. J. Blaser. 1995. 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. 18: 867 876.
55. Vergunst, A. C.,, B. Schrammeijer,, A. Dulk-Ras,, C. M. T. de Vlaam,, T. J. G. Regensburg-Tuink,, and P. J. J. Hooykaas. 2000. VirB/D4-dependent protein translocation from agrobacterium into plant cells. Science 290: 979 982.
56. Weiss, A. A.,, F. D. Johnson,, and D. L. Burns. 1993. Molecular characterization of an operon required for pertussis toxin secretion. Proc. Natl. Acad. Sci. USA 90: 2970 2974.
57. Welch, M. D. 1999. The world according to arp: regulation of actin nucleation by the Arp2/3 complex. Trends Cell. Biol. 9: 423 427.
58. Winans, S. C.,, D. L. Burns,, and P. J. Christie. 1996. Adaptation of a conjugal transfer system for the export of pathogenic macromolecules. Trends Microbiol. 4: 64 68.
59. Xiang, Z.,, S. Censini,, P. F. Bayeli,, J. L. Telford,, N. Figura,, R. Rappuoli,, and A. Covacci. 1995. Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin. Infect. Immun. 63: 94 98.

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