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Volume 54, Issue 3

Cytolethal distending toxin: creating a gap in the cell cycle Free

Abstract

Cytolethal distending toxin (CDT) is a novel bacterial toxin that is produced by a variety of pathogenic bacteria. The mechanism of cytotoxicity of CDT is unique in that it enters into eukaryotic cells and breaks double-stranded DNA. This initiates the cell's own DNA damage-response mechanisms, resulting in the arrest of the cell cycle at the G/M boundary. Affected cells enlarge until they finally undergo programmed cell death. This review encompasses recent work on CDT and focuses on the molecular mechanisms used by this toxin to block cell-cycle progression, the benefit to the bacterium of possession of this toxin and the clinical relevance of intoxication.

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2005-03-01
2024-04-19
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References

  1. Ahmed H. J., Svensson L. A., Cope L. D., Latimer J. L., Hansen E. J., Ahlman K., Bayat-Turk J., Klamer D., Lagergård T. 2001; Prevalence of cdtABC genes encoding cytolethal distending toxin among Haemophilus ducreyi and Actinobacillus actinomycetemcomitans strains. J Med Microbiol 50:860–864
     [Google Scholar]
  2. Akifusa S., Poole S., Lewthwaite J., Henderson B., Nair S. P. 2001; Recombinant Actinobacillus actinomycetemcomitans cytolethal distending toxin proteins are required to interact to inhibit human cell cycle progression and to stimulate human leukocyte cytokine synthesis. Infect Immun 69:5925–5930 [CrossRef]
     [Google Scholar]
  3. Albert M. J., Faruque S. M., Faruque A. S. G., Bettelheim K. A., Neogi P. K. B., Bhuiyan N. A., Kaper J. B. 1996; Controlled study of cytolethal distending toxin-producing Escherichia coli infections in Bangladeshi children. J Clin Microbiol 34:717–719
     [Google Scholar]
  4. Aragon V., Chao K., Dreyfus L. A. 1997; Effect of cytolethal distending toxin on F-actin assembly and cell division in Chinese hamster ovary cells. Infect Immun 65:3774–3780
     [Google Scholar]
  5. Belibasakis G., Johansson A., Wang Y., Claesson R., Chen C., Asikainen S., Kalfas S. 2002; Inhibited proliferation of human periodontal ligament cells and gingival fibroblasts by Actinobacillus actinomycetemcomitans : involvement of the cytolethal distending toxin. Eur J Oral Sci 110:366–373 [CrossRef]
     [Google Scholar]
  6. Collazos J., Diaz F., Mayo J., Martinez E. 1999; Infectious endocarditis, vasculitis, and glomerulonephritis. Clin Infect Dis 28:1342–1343
     [Google Scholar]
  7. Comayras C., Tasca C., Pérès S. Y., Ducommun B., Oswald E., De Rycke J. 1997; Escherichia coli cytolethal distending toxin blocks the HeLa cell cycle at the G2/M transition by preventing cdc2 protein kinase dephosphorylation and activation. Infect Immun 65:5088–5095
     [Google Scholar]
  8. Cope L. D., Lumbley S., Latimer J. L. 8 other authors; 1997; A diffusible cytotoxin of Haemophilus ducreyi . Proc Natl Acad Sci U S A 94:4056–4061 [CrossRef]
     [Google Scholar]
  9. Cortes-Bratti X., Chaves-Olarte E., Lagergård T., Thelestam M. 1999; The cytolethal distending toxin from the chancroid bacterium Haemophilus ducreyi induces cell-cycle arrest in the G2 phase. J Clin Invest 103:107–115 [CrossRef]
     [Google Scholar]
  10. Cortes-Bratti X., Chaves-Olarte E., Lagergård T., Thelestam M. 2000; Cellular internalization of cytolethal distending toxin from Haemophilus ducreyi . Infect Immun 68:6903–6911 [CrossRef]
     [Google Scholar]
  11. Cortes-Bratti X., Karlsson C., Lagergård T., Thelestam M., Frisan T. 2001; The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways. J Biol Chem 276:5296–5302 [CrossRef]
     [Google Scholar]
  12. da Silva A. S., da Silva Leite D. 2002; Investigation of putative CDT gene in Escherichia coli isolates from pigs with diarrhea. Vet Microbiol 89:195–199 [CrossRef]
     [Google Scholar]
  13. Deng K., Hansen E. J. 2003; A CdtA-CdtC complex can block killing of HeLa cells by Haemophilus ducreyi cytolethal distending toxin. Infect Immun 71:6633–6640 [CrossRef]
     [Google Scholar]
  14. Deng K., Latimer J. L., Lewis D. A., Hansen E. J. 2001; Investigation of the interaction among the components of the cytolethal distending toxin of Haemophilus ducreyi . Biochem Biophys Res Commun 285:609–615 [CrossRef]
     [Google Scholar]
  15. Elwell C. A., Dreyfus L. A. 2000; DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest. Mol Microbiol 37:952–963 [CrossRef]
     [Google Scholar]
  16. Fabris A. S., DiRienzo J. M., Wïkstrom M., Mayer M. P. A. 2002; Detection of cytolethal distending toxin activity and cdt genes in Actinobacillus actinomycetemcomitans isolates from geographically diverse populations. Oral Microbiol Immunol 17:231–238 [CrossRef]
     [Google Scholar]
  17. Falnes P. Ø., Sandvig K. 2000; Penetration of protein toxins into cells. Curr Opin Cell Biol 12:407–413 [CrossRef]
     [Google Scholar]
  18. Fox J. G., Rogers A. B., Whary M. T., Ge Z., Taylor N. S., Xu S., Horwitz B. H., Erdman S. E. 2004; Gastroenteritis in NF-κB-deficient mice is produced with wild-type Camplyobacter jejuni but not with C.jejuni lacking cytolethal distending toxin despite persistent colonization with both strains. Infect Immun 72:1116–1125 [CrossRef]
     [Google Scholar]
  19. Frisan T., Cortes-Bratti X., Chaves-Olarte E., Stenerlöw B., Thelestam M. 2003; The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA. Cell Microbiol 5:695–707 [CrossRef]
     [Google Scholar]
  20. Frisk A., Lebens M., Johansson C., Ahmed H., Svensson L., Ahlman K., Lagergård T. 2001; The role of different protein components from the Haemophilus ducreyi cytolethal distending toxin in the generation of cell toxicity. Microb Pathog 30:313–324 [CrossRef]
     [Google Scholar]
  21. Gelfanova V., Hansen E. J., Spinola S. M. 1999; Cytolethal distending toxin of Haemophilus ducreyi induces apoptotic death of Jurkat T cells. Infect Immun 67:6394–6402
     [Google Scholar]
  22. Haghjoo E., Galán J. E. 2004; Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proc Natl Acad Sci U S A 101:4614–4619 [CrossRef]
     [Google Scholar]
  23. Hassane D. C., Lee R. B., Pickett C. L. 2003; Campylobacter jejuni cytolethal distending toxin promotes DNA repair responses in normal human cells. Infect Immun 71:541–545 [CrossRef]
     [Google Scholar]
  24. Hazes B., Read R. J. 1995; A mosquitocidal toxin with a ricin-like cell-binding domain. Nat Struct Biol 2:358–359 [CrossRef]
     [Google Scholar]
  25. Henderson B., Nair S. P., Ward J. M., Wilson M. 2003; Molecular pathogenicity of the oral opportunistic pathogen Actinobacillus actinomycetemcomitans . Annu Rev Microbiol 57:29–55 [CrossRef]
     [Google Scholar]
  26. Hickey T. E., McVeigh A. L., Scott D. A., Michielutti R. E., Bixby A., Carroll S. A., Bourgeois A. L., Guerry P. 2000; Campylobacter jejuni cytolethal distending toxin mediates release of interleukin-8 from intestinal epithelial cells. Infect Immun 68:6535–6541 [CrossRef]
     [Google Scholar]
  27. Hirabayashi J., Dutta S. K., Kasai K. 1998; Novel galactose-binding proteins in Annelida.Characterization of 29-kDa tandem repeat-type lectins from the earthworm Lumbricus terrestris . J Biol Chem 273:14450–14460 [CrossRef]
     [Google Scholar]
  28. Janka A., Bielaszewska M., Dobrindt U., Greune L., Schmidt M. A., Karch H. 2003; Cytolethal distending toxin gene cluster in enterohemorrhagic Escherichia coli O157 : H− and O157 : H7: characterization and evolutionary considerations. Infect Immun 71:3634–3638 [CrossRef]
     [Google Scholar]
  29. Johnson W. M., Lior H. 1988a; A new heat-labile cytolethal distending toxin (CLDT) produced by Escherichia coli isolates from clinical material. Microb Pathog 4:103–113 [CrossRef]
     [Google Scholar]
  30. Johnson W. M., Lior H. 1988b; A new heat-labile cytolethal distending toxin (CLDT) produced by Campylobacter spp. Microb Pathog 4:115–126 [CrossRef]
     [Google Scholar]
  31. Johnson J. R., Oswald E., O'Bryan T. T., Kuskowski M. A., Spanjaard L. 2003; Phylogenetic distribution of virulence-associated genes among Escherichia coli isolates associated with neonatal bacterial meningitis in the Netherlands. J Infect Dis 185:774–784
     [Google Scholar]
  32. Lally E. T., Kieba I. R., Demuth D. R., Rosenbloom J., Golub E. E., Taichman N. S., Gibson C. W. 1989; Identification and expression of the Actinobacillus actinomycetemcomitans leukotoxin gene. Biochem Biophys Res Commun 159:256–262 [CrossRef]
     [Google Scholar]
  33. Lara-Tejero M., Galán J. E. 2000; A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein. Science 290:354–357 [CrossRef]
     [Google Scholar]
  34. Lara-Tejero M., Galán J. E. 2001; CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity. Infect Immun 69:4358–4365 [CrossRef]
     [Google Scholar]
  35. Lara-Tejero M., Galán J. E. 2002; Cytolethal distending toxin: limited damage as a strategy to modulate cellular functions. Trends Microbiol 10:147–152 [CrossRef]
     [Google Scholar]
  36. Lax A. J., Thomas W. 2002; How bacteria could cause cancer: one step at a time. Trends Microbiol 10:293–299 [CrossRef]
     [Google Scholar]
  37. Lee R. B., Hassane D. C., Cottle D. L., Pickett C. L. 2003; Interactions of Campylobacter jejuni cytolethal distending toxin subunits CdtA and CdtC with HeLa cells. Infect Immun 71:4883–4890 [CrossRef]
     [Google Scholar]
  38. Lewis D. A., Stevens M. K., Latimer J. L., Ward C. K., Deng K., Blick R., Lumbley S. R., Ison C. A., Hansen E. J. 2001; Characterization of Haemophilus ducreyi cdtA , cdtB , and cdtC mutants in in vitro and in vivo systems. Infect Immun 69:5626–5634 [CrossRef]
     [Google Scholar]
  39. Li L., Sharipo A., Chaves-Olarte E., Masucci M. G., Levitsky V., Thelestam M., Frisan T. 2002; The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells. Cell Microbiol 4:87–99 [CrossRef]
     [Google Scholar]
  40. Mao X., DiRienzo J. M. 2002; Functional studies of the recombinant subunits of a cytolethal distending holotoxin. Cell Microbiol 4:245–255 [CrossRef]
     [Google Scholar]
  41. Marques L. R. M., Tavechio A. T., Abe C. M., Gomes T. A. T. 2003; Search for cytolethal distending toxin production among fecal Escherichia coli isolates from Brazilian children with diarrhea and without diarrhea. J Clin Microbiol 41:2206–2208 [CrossRef]
     [Google Scholar]
  42. Mayer M. P. A., Bueno L. C., Hansen E. J., DiRienzo J. M. 1999; Identification of a cytolethal distending toxin gene locus and features of a virulence-associated region in Actinobacillus actinomycetemcomitans . Infect Immun 67:1227–1237
     [Google Scholar]
  43. Nešić D., Hsu Y., Stebbins C. E. 2004; Assembly and function of a bacterial genotoxin. Nature 429:429–433 [CrossRef]
     [Google Scholar]
  44. Nishikubo S., Ohara M., Ueno Y., Ikura M., Kurihara H., Komatsuzawa H., Oswald E., Sugai M. 2003; An N-terminal segment of the active component of the bacterial genotoxin cytolethal distending toxin B (CDTB) directs CDTB into the nucleus. J Biol Chem 278:50671–50681 [CrossRef]
     [Google Scholar]
  45. Okuda J., Kurazono H., Takeda Y. 1995; Distribution of the cytolethal distending toxin A gene ( cdtA ) among species of Shigella and Vibrio , and cloning and sequencing of the cdt gene from Shigella dysenteriae . Microb Pathog 18:167–172 [CrossRef]
     [Google Scholar]
  46. Okuda J., Fukumoto M., Takeda Y., Nishibuchi M. 1997; Examination of diarrheagenicity of cytolethal distending toxin: suckling mouse response to the products of the cdtABC genes of Shigella dysenteriae . Infect Immun 65:428–433
     [Google Scholar]
  47. Parkhill J., Dougan G., James K. D. & 38 other authors; 2001; Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 413:848–852 [CrossRef]
     [Google Scholar]
  48. Pérès S. Y., Marchès O., Daigle F., Nougayrède J. P., Hérault F., Tasca C., De Rycke J., Oswald E. 1997; A new cytolethal distending toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase. Mol Microbiol 24:1095–1107 [CrossRef]
     [Google Scholar]
  49. Pickett C. L., Cottle D. L., Pesci E. C., Bikah G. 1994; Cloning, sequencing, and expression of the Escherichia coli cytolethal distending toxin genes. Infect Immun 62:1046–1051
     [Google Scholar]
  50. Purdy D., Buswell C. M., Hodgson A. E., McAlpine K., Henderson I., Leach S. A. 2000; Characterisation of cytolethal distending toxin (CDT) mutants of Campylobacter jejuni . J Med Microbiol 49:473–479
     [Google Scholar]
  51. Saiki K., Konishi K., Gomi T., Nishihara T., Yoshikawa M. 2001; Reconstitution and purification of cytolethal distending toxin of Actinobacillus actinomycetemcomitans . Microbiol Immunol 45:497–506 [CrossRef]
     [Google Scholar]
  52. Sato T., Koseki T., Yamato K., Saiki K., Konishi K., Yoshikawa M., Ishikawa I., Nishihara T. 2002; p53-independent expression of p21CIP1/WAF1 in plasmacytic cells during G2 cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin. Infect Immun 70:528–534 [CrossRef]
     [Google Scholar]
  53. Scott D. A., Kaper J. B. 1994; Cloning and sequencing of the genes encoding Escherichia coli cytolethal distending toxin. Infect Immun 62:244–251
     [Google Scholar]
  54. Sert V., Cans C., Tasca C., Bret-Bennis L., Oswald E., Ducommun B., De Rycke J. 1999; The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks. Oncogene 18:6296–6304 [CrossRef]
     [Google Scholar]
  55. Shenker B. J., McKay T., Datar S., Miller M., Chowhan R., Demuth D. 1999; Actinobacillus actinomycetemcomitans immunosuppressive protein is a member of the family of cytolethal distending toxins capable of causing a G2 arrest in human T cells. J Immunol 162:4773–4780
     [Google Scholar]
  56. Shenker B. J., Hoffmaster R. H., McKay T. L., Demuth D. R. 2000; Expression of the cytolethal distending toxin (Cdt) operon in Actinobacillus actinomycetemcomitans : evidence that the CdtB protein is responsible for G2 arrest of the cell cycle in human T cells. J Immunol 165:2612–2618 [CrossRef]
     [Google Scholar]
  57. Shenker B. J., Hoffmaster R. H., Zekavat A., Yamaguchi N., Lally E. T., Demuth D. R. 2001; Induction of apoptosis in human T cells by Actinobacillus actinomycetemcomitans cytolethal distending toxin is a consequence of G2 arrest of the cell cycle. J Immunol 167:435–441 [CrossRef]
     [Google Scholar]
  58. Slots J., Ting M. 1999; Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in human periodontal disease: occurrence and treatment. Periodontol 2000; 20:82–121 [CrossRef]
     [Google Scholar]
  59. Smits V. A. J., Medema R. H. 2001; Checking out the G2/M transition. Biochim Biophys Acta 15191–12 [CrossRef]
     [Google Scholar]
  60. Starccicc M., Johnson J. R., Stell A. L., van der Goot J., Hendriks H. G. C. J. M., van Vorstenbosch C., van Dijk L., Gaastra W. 2002; Haemolytic Escherichia coli isolated from dogs with diarrhea have characteristics of both uropathogenic and necrotoxigenic strains. Vet Microbiol 85:361–377 [CrossRef]
     [Google Scholar]
  61. Stevens M. K., Latimer J. L., Lumbley S. R., Ward C. K., Cope L. D., Lagergard T., Hansen E. J. 1999; Characterization of a Haemophilus ducreyi mutant deficient in expression of cytolethal distending toxin. Infect Immun 67:3900–3908
     [Google Scholar]
  62. Sugai M., Kawamoto T., Pérès S. Y., Ueno Y., Komatsuzawa H., Fujiwara T., Kurihara H., Suginaka H., Oswald E. 1998; The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin. Infect Immun 66:5008–5019
     [Google Scholar]
  63. Svensson L. A., Tarkowski A., Thelestam M., Lagergård T. 2001; The impact of Haemophilus ducreyi cytolethal distending toxin on cells involved in immune response. Microb Pathog 30:157–166 [CrossRef]
     [Google Scholar]
  64. Svensson L. A., Henning P., Lagergård T. 2002; The cytolethal distending toxin of Haemophilus ducreyi inhibits endothelial cell proliferation. Infect Immun 70:2665–2669 [CrossRef]
     [Google Scholar]
  65. Tan K. S., Song K.-P., Ong G. 2002; Cytolethal distending toxin of Actinobacillus actinomycetemcomitans .Occurrence and association with periodontal disease. J Periodontal Res 37:268–272 [CrossRef]
     [Google Scholar]
  66. Tóth I., Hérault F., Beutin L., Oswald E. 2003; Production of cytolethal distending toxins by pathogenic Escherichia coli strains isolated from human and animal sources: establishment of the existence of a new cdt variant (type IV). J Clin Microbiol 41:4285–4291 [CrossRef]
     [Google Scholar]
  67. Whitehouse C. A., Balbo P. B., Pesci E. C., Cottle D. L., Mirabito P. M., Pickett C. L. 1998; Campylobacter jejuni cytolethal distending toxin causes a G2-phase cell cycle block. Infect Immun 66:1934–1940
     [Google Scholar]
  68. Wising C., Svensson L. A., Ahmed H. J., Sundaeus V., Ahlman K., Jonsson I.-M., Mölne L., Lagergård T. 2002; Toxicity and immunogenicity of purified Haemophilus ducreyi cytolethal distending toxin in a rabbit model. Microb Pathog 33:49–62 [CrossRef]
     [Google Scholar]
  69. Xu T., Lundqvist A., Ahmed H. J., Eriksson K., Yang Y., Lagergård T. 2004; Interactions of Haemophilus ducreyi and purified cytolethal distending toxin with human monocyte-derived dendritic cells, macrophages and CD4+ T cells. Microbes Infect 6:1171–1181 [CrossRef]
     [Google Scholar]
  70. Yamano R., Ohara M., Nishikubo S. & 10 other authors; 2003; Prevalence of cytolethal distending toxin production in periodontopathogenic bacteria. J Clin Microbiol 41:1391–1398 [CrossRef]
     [Google Scholar]
  71. Young V. B., Knox K. A., Schauer D. B. 2000; Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus . Infect Immun 68:184–191 [CrossRef]
     [Google Scholar]
  72. Young R. S., Fortney K. R., Gelfanova V. & 7 other authors; 2001; Expression of cytolethal distending toxin and hemolysin is not required for pustule formation by Haemophilus ducreyi in human volunteers. Infect Immun 69:1938–1942 [CrossRef]
     [Google Scholar]
  73. Young V. B., Knox K. A., Pratt J. S., Cortez J. S., Mansfield L. S., Rogers A. B., Fox J. G., Schauer D. B. 2004; In vitro and in vivo characterization of Helicobacter hepaticus cytolethal distending toxin mutants. Infect Immun 72:2521–2527 [CrossRef]
     [Google Scholar]
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Cytolethal distending toxin: creating a gap in the cell cycle
J. Med. Microbiol. 54, 207 (2005); https://doi.org/10.1099/jmm.0.45694-0
/content/journal/jmm/10.1099/jmm.0.45694-0
/content/journal/jmm/10.1099/jmm.0.45694-0
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