1887

Abstract

Cytolethal distending toxin (CDT) is a heterotrimeric AB-type genotoxin produced by several clinically important Gram-negative mucocutaneous bacterial pathogens. Irrespective of the bacterial species of origin, CDT causes characteristic and irreversible cell cycle arrest and apoptosis in a broad range of cultured mammalian cell lineages. The active subunit CdtB has structural homology with the phosphodiesterase family of enzymes including mammalian DNase I, and alone is necessary and sufficient to account for cellular toxicity. Indeed, mammalian cells treated with CDT initiate a DNA damage response similar to that elicited by ionizing radiation-induced DNA double strand breaks resulting in cell cycle arrest and apoptosis. The mechanism of CDT-induced apoptosis remains incompletely understood, but appears to involve both p53-dependent and -independent pathways. While epithelial, endothelial and fibroblast cell lines respond to CDT by undergoing arrest of cell cycle progression resulting in nuclear and cytoplasmic distension that precedes apoptotic cell death, cells of haematopoietic origin display rapid apoptosis following a brief period of cell cycle arrest. In this review, the ecology of pathogens producing CDT, the molecular biology of bacterial CDT and the molecular mechanisms of CDT-induced cytotoxicity are critically appraised. Understanding the contribution of a broadly conserved bacterial genotoxin that blocks progression of the mammalian cell cycle, ultimately causing cell death, should assist with elucidating disease mechanisms for these important pathogens.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.049536-0
2011-07-01
2020-04-02
Loading full text...

Full text loading...

/deliver/fulltext/micro/157/7/1851.html?itemId=/content/journal/micro/10.1099/mic.0.049536-0&mimeType=html&fmt=ahah

References

  1. Abeck D., Freinkel A. L., Korting H. C., Szeimis R. M., Ballard R. C.. ( 1997;). Immunohistochemical investigations of genital ulcers caused by Haemophilus ducreyi . Int J STD AIDS8:585–588 [CrossRef][PubMed]
    [Google Scholar]
  2. Abuoun M., Manning G., Cawthraw S. A., Ridley A., Ahmed I. H., Wassenaar T. M., Newell D. G.. ( 2005;). Cytolethal distending toxin (CDT)-negative Campylobacter jejuni strains and anti-CDT neutralizing antibodies are induced during human infection but not during colonization in chickens. Infect Immun73:3053–3062 [CrossRef][PubMed]
    [Google Scholar]
  3. 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 Microbiol50:860–864[PubMed]
    [Google Scholar]
  4. 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 Immun69:5925–5930 [CrossRef][PubMed]
    [Google Scholar]
  5. Alaoui-El-Azher M., Mans J. J., Baker H. V., Chen C., Progulske-Fox A., Lamont R. J., Handfield M.. ( 2010;). Role of the ATM-checkpoint kinase 2 pathway in CDT-mediated apoptosis of gingival epithelial cells. PLoS ONE5:e11714 [CrossRef][PubMed]
    [Google Scholar]
  6. Alouf J. E.. ( 2006;). A 116-year story of bacterial protein toxins (1888–2004): from “diphtheritic poison” to molecular toxinology. The Comprehensive Sourcebook of Bacterial Protein Toxins3–21 Alouf J. E., Popoff M. R.. New York: Academic Press; [CrossRef]
    [Google Scholar]
  7. Ando E. S., De-Gennaro L. A., Faveri M., Feres M., DiRienzo J. M., Mayer M. P.. ( 2010;). Immune response to cytolethal distending toxin of Aggregatibacter actinomycetemcomitans in periodontitis patients. J Periodontal Res45:471–480[PubMed]
    [Google Scholar]
  8. Ansaruzzaman M., Albert M. J., Nahar S., Byun R., Katouli M., Kühn I., Möllby R.. ( 2000;). Clonal groups of enteropathogenic Escherichia coli isolated in case-control studies of diarrhoea in Bangladesh. J Med Microbiol49:177–185[PubMed]
    [Google Scholar]
  9. 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 Immun65:3774–3780[PubMed]
    [Google Scholar]
  10. Asakura M., Hinenoya A., Alam M. S., Shima K., Zahid S. H., Shi L., Sugimoto N., Ghosh A. N., Ramamurthy T. et al. ( 2007;a). An inducible lambdoid prophage encoding cytolethal distending toxin (Cdt-I) and a type III effector protein in enteropathogenic Escherichia coli . Proc Natl Acad Sci U S A104:14483–14488 [CrossRef][PubMed]
    [Google Scholar]
  11. Asakura M., Samosornsuk W., Taguchi M., Kobayashi K., Misawa N., Kusumoto M., Nishimura K., Matsuhisa A., Yamasaki S.. ( 2007;b). Comparative analysis of cytolethal distending toxin (cdt) genes among Campylobacter jejuni, C. coli and C. fetus strains. Microb Pathog42:174–183 [CrossRef][PubMed]
    [Google Scholar]
  12. Asakura M., Samosornsuk W., Hinenoya A., Misawa N., Nishimura K., Matsuhisa A., Yamasaki S.. ( 2008;). Development of a cytolethal distending toxin (cdt) gene-based species-specific multiplex PCR assay for the detection and identification of Campylobacter jejuni, Campylobacter coli and Campylobacter fetus . FEMS Immunol Med Microbiol52:260–266 [CrossRef][PubMed]
    [Google Scholar]
  13. Bakkenist C. J., Kastan M. B.. ( 2003;). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature421:499–506 [CrossRef][PubMed]
    [Google Scholar]
  14. Bang D. D., Nielsen E. M., Scheutz F., Pedersen K., Handberg K., Madsen M.. ( 2003;). PCR detection of seven virulence and toxin genes of Campylobacter jejuni and Campylobacter coli isolates from Danish pigs and cattle and cytolethal distending toxin production of the isolates. J Appl Microbiol94:1003–1014 [CrossRef][PubMed]
    [Google Scholar]
  15. Bartek J., Lukas J.. ( 2007;). DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol19:238–245 [CrossRef][PubMed]
    [Google Scholar]
  16. Belibasakis G. N., Mattsson A., Wang Y., Chen C., Johansson A.. ( 2004;). Cell cycle arrest of human gingival fibroblasts and periodontal ligament cells by Actinobacillus actinomycetemcomitans: involvement of the cytolethal distending toxin. APMIS112:674–685 [CrossRef][PubMed]
    [Google Scholar]
  17. Bielaszewska M., Fell M., Greune L., Prager R., Fruth A., Tschäpe H., Schmidt M. A., Karch H.. ( 2004;). Characterization of cytolethal distending toxin genes and expression in shiga toxin-producing Escherichia coli strains of non-O157 serogroups. Infect Immun72:1812–1816 [CrossRef][PubMed]
    [Google Scholar]
  18. Bielaszewska M., Sinha B., Kuczius T., Karch H.. ( 2005;). Cytolethal distending toxin from Shiga toxin-producing Escherichia coli O157 causes irreversible G2/M arrest, inhibition of proliferation, and death of human endothelial cells. Infect Immun73:552–562 [CrossRef][PubMed]
    [Google Scholar]
  19. Bielaszewska M., Stoewe F., Fruth A., Zhang W., Prager R., Brockmeyer J., Mellmann A., Karch H., Friedrich A. W.. ( 2009;). Shiga toxin, cytolethal distending toxin, and hemolysin repertoires in clinical Escherichia coli O91 isolates. J Clin Microbiol47:2061–2066[CrossRef]
    [Google Scholar]
  20. Blikslager A. T., Moeser A. J., Gookin J. L., Jones S. L., Odle J.. ( 2007;). Restoration of barrier function in injured intestinal mucosa. Physiol Rev87:545–564 [CrossRef][PubMed]
    [Google Scholar]
  21. Bloom S. E., Lemley A. T., Muscarella D. E.. ( 2006;). Potentiation of apoptosis by heat stress plus pesticide exposure in stress resistant human B-lymphoma cells and its attenuation through interaction with follicular dendritic cells: role for c-Jun N-terminal kinase signaling. Toxicol Sci89:214–223 [CrossRef][PubMed]
    [Google Scholar]
  22. Boesze-Battaglia K., Besack D., McKay T., Zekavat A., Otis L., Jordan-Sciutto K., Shenker B. J.. ( 2006;). Cholesterol-rich membrane microdomains mediate cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal-distending toxin. Cell Microbiol8:823–836 [CrossRef][PubMed]
    [Google Scholar]
  23. Boesze-Battaglia K., Brown A., Walker L., Besack D., Zekavat A., Wrenn S., Krummenacher C., Shenker B. J.. ( 2009;). Cytolethal distending toxin-induced cell cycle arrest of lymphocytes is dependent upon recognition and binding to cholesterol. J Biol Chem284:10650–10658 [CrossRef][PubMed]
    [Google Scholar]
  24. Boutin S. R., Shen Z., Roesch P. L., Stiefel S. M., Sanderson A. E., Multari H. M., Pridhoko E. A., Smith J. C., Taylor N. S. et al. ( 2010;). Helicobacter pullorum outbreak in C57BL/6NTac and C3H/HeNTac barrier-maintained mice. J Clin Microbiol48:1908–1910 [CrossRef][PubMed]
    [Google Scholar]
  25. Callén E., Jankovic M., Difilippantonio S., Daniel J. A., Chen H. T., Celeste A., Pellegrini M., McBride K., Wangsa D. et al. ( 2007;). ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell130:63–75 [CrossRef][PubMed]
    [Google Scholar]
  26. Cao L., Volgina A., Huang C. M., Korostoff J., DiRienzo J. M.. ( 2005;). Characterization of point mutations in the cdtA gene of the cytolethal distending toxin of Actinobacillus actinomycetemcomitans . Mol Microbiol58:1303–1321 [CrossRef][PubMed]
    [Google Scholar]
  27. Carette J. E., Guimaraes C. P., Varadarajan M., Park A. S., Wuethrich I., Godarova A., Kotecki M., Cochran B. H., Spooner E. et al. ( 2009;). Haploid genetic screens in human cells identify host factors used by pathogens. Science326:1231–1235 [CrossRef][PubMed]
    [Google Scholar]
  28. Ceelen L. M., Haesebrouck F., Favoreel H., Ducatelle R., Decostere A.. ( 2006;). The cytolethal distending toxin among Helicobacter pullorum strains from human and poultry origin. Vet Microbiol113:45–53 [CrossRef][PubMed]
    [Google Scholar]
  29. Cheng J., Haas M.. ( 1990;). Frequent mutations in the p53 tumor suppressor gene in human leukemia T-cell lines. Mol Cell Biol10:5502–5509[PubMed]
    [Google Scholar]
  30. Chien C. C., Taylor N. S., Ge Z., Schauer D. B., Young V. B., Fox J. G.. ( 2000;). Identification of cdtB homologues and cytolethal distending toxin activity in enterohepatic Helicobacter spp. J Med Microbiol49:525–534[PubMed]
    [Google Scholar]
  31. Ciccia A., Elledge S. J.. ( 2010;). The DNA damage response: making it safe to play with knives. Mol Cell40:179–204 [CrossRef][PubMed]
    [Google Scholar]
  32. Clark C. G., Johnson S. T., Easy R. H., Campbell J. L., Rodgers F. G.. ( 2002;). PCR for detection of cdt-III and the relative frequencies of cytolethal distending toxin variant-producing Escherichia coli isolates from humans and cattle. J Clin Microbiol40:2671–2674 [CrossRef][PubMed]
    [Google Scholar]
  33. 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 Immun65:5088–5095[PubMed]
    [Google Scholar]
  34. Cope L. D., Lumbley S., Latimer J. L., Klesney-Tait J., Stevens M. K., Johnson L. S., Purven M., Munson R. S. Jr, Lagergard T. et al. ( 1997;). A diffusible cytotoxin of Haemophilus ducreyi . Proc Natl Acad Sci U S A94:4056–4061 [CrossRef][PubMed]
    [Google Scholar]
  35. 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 Invest103:107–115 [CrossRef][PubMed]
    [Google Scholar]
  36. Cortes-Bratti X., Chaves-Olarte E., Lagergård T., Thelestam M.. ( 2000;). Cellular internalization of cytolethal distending toxin from Haemophilus ducreyi . Infect Immun68:6903–6911 [CrossRef][PubMed]
    [Google Scholar]
  37. Cortes-Bratti X., Frisan T., Thelestam M.. ( 2001;a). The cytolethal distending toxins induce DNA damage and cell cycle arrest. Toxicon39:1729–1736 [CrossRef][PubMed]
    [Google Scholar]
  38. Cortes-Bratti X., Karlsson C., Lagergård T., Thelestam M., Frisan T.. ( 2001;b). The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways. J Biol Chem276:5296–5302 [CrossRef][PubMed]
    [Google Scholar]
  39. Creagh E. M., Conroy H., Martin S. J.. ( 2003;). Caspase-activation pathways in apoptosis and immunity. Immunol Rev193:10–21 [CrossRef][PubMed]
    [Google Scholar]
  40. Dassanayake R. P., Griep M. A., Duhamel G. E.. ( 2005;a). The cytolethal distending toxin B sub-unit of Helicobacter hepaticus is a Ca2+- and Mg2+-dependent neutral nuclease. FEMS Microbiol Lett251:219–225 [CrossRef][PubMed]
    [Google Scholar]
  41. Dassanayake R. P., Zhou Y., Hinkley S., Stryker C. J., Plauche G., Borda J. T., Sestak K., Duhamel G. E.. ( 2005;b). Characterization of cytolethal distending toxin of Campylobacter species isolated from captive macaque monkeys. J Clin Microbiol43:641–649 [CrossRef][PubMed]
    [Google Scholar]
  42. Dasti J. I., Tareen A. M., Lugert R., Zautner A. E., Gross U.. ( 2010;). Campylobacter jejuni: a brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol300:205–211 [CrossRef][PubMed]
    [Google Scholar]
  43. Degnan P. H., Moran N. A.. ( 2008;). Diverse phage-encoded toxins in a protective insect endosymbiont. Appl Environ Microbiol74:6782–6791 [CrossRef][PubMed]
    [Google Scholar]
  44. Deng K., Hansen E. J.. ( 2003;). A CdtA–CdtC complex can block killing of HeLa cells by Haemophilus ducreyi cytolethal distending toxin. Infect Immun71:6633–6640 [CrossRef][PubMed]
    [Google Scholar]
  45. 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 Commun285:609–615 [CrossRef][PubMed]
    [Google Scholar]
  46. Derheimer F. A., Kastan M. B.. ( 2010;). Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett584:3675–3681 [CrossRef][PubMed]
    [Google Scholar]
  47. Dlakić M.. ( 2000;). Functionally unrelated signalling proteins contain a fold similar to Mg2+-dependent endonucleases. Trends Biochem Sci25:272–273 [CrossRef][PubMed]
    [Google Scholar]
  48. Doungudomdacha S., Volgina A., DiRienzo J. M.. ( 2007;). Evidence that the cytolethal distending toxin locus was once part of a genomic island in the periodontal pathogen Aggregatibacter (Actinobacillus) actinomycetemcomitans strain Y4. J Med Microbiol56:1519–1527 [CrossRef][PubMed]
    [Google Scholar]
  49. Dreyfus L. A.. ( 2003;). Cytolethal distending toxin. Bacterial Protein Toxins257–270 Burns D. L., Barbieri J. T., Iglewski B. H., Rappuoli R.. Washington, DC: American Society for Microbiology;
    [Google Scholar]
  50. Edmonds P., Patton C. M., Griffin P. M., Barrett T. J., Schmid G. P., Baker C. N., Lambert M. A., Brenner D. J.. ( 1987;). Campylobacter hyointestinalis associated with human gastrointestinal disease in the United States. J Clin Microbiol25:685–691[PubMed]
    [Google Scholar]
  51. Elwell C. A., Dreyfus L. A.. ( 2000;). DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest. Mol Microbiol37:952–963 [CrossRef][PubMed]
    [Google Scholar]
  52. Elwell C., Chao K., Patel K., Dreyfus L.. ( 2001;). Escherichia coli CdtB mediates cytolethal distending toxin cell cycle arrest. Infect Immun69:3418–3422 [CrossRef][PubMed]
    [Google Scholar]
  53. Ericsson A. C., Myles M., Davis W., Ma L., Lewis M., Maggio-Price L., Franklin C.. ( 2010;). Noninvasive detection of inflammation-associated colon cancer in a mouse model. Neoplasia12:1054–1065[PubMed][CrossRef]
    [Google Scholar]
  54. Eshraghi A., Maldonado-Arocho F. J., Gargi A., Cardwell M. M., Prouty M. G., Blanke S. R., Bradley K. A.. ( 2010;). Cytolethal distending toxin family members are differentially affected by alterations in host glycans and membrane cholesterol. J Biol Chem285:18199–18207 [CrossRef][PubMed]
    [Google Scholar]
  55. Fabris A. S., DiRienzo J. M., Wïkstrom M., Mayer M. P.. ( 2002;). Detection of cytolethal distending toxin activity and cdt genes in Actinobacillus actinomycetemcomitans isolates from geographically diverse populations. Oral Microbiol Immunol17:231–238 [CrossRef][PubMed]
    [Google Scholar]
  56. Fernandez K. R., Hansen L. M., Vandamme P., Beaman B. L., Solnick J. V.. ( 2002;). Captive rhesus monkeys (Macaca mulatta) are commonly infected with Helicobacter cinaedi . J Clin Microbiol40:1908–1912 [CrossRef][PubMed]
    [Google Scholar]
  57. Fouts D. E., Mongodin E. F., Mandrell R. E., Miller W. G., Rasko D. A., Ravel J., Brinkac L. M., DeBoy R. T., Parker C. T. et al. ( 2005;). Major structural differences and novel potential virulence mechanisms from the genomes of multiple Campylobacter species. PLoS Biol3:e15 [CrossRef][PubMed]
    [Google Scholar]
  58. Fox J. G.. ( 2007;). Helicobacter bilis: bacterial provocateur orchestrates host immune responses to commensal flora in a model of inflammatory bowel disease. Gut56:898–900 [CrossRef][PubMed]
    [Google Scholar]
  59. Fox J. G., Ackerman J. I., Taylor N., Claps M., Murphy J. C.. ( 1987;). Campylobacter jejuni infection in the ferret: an animal model of human campylobacteriosis. Am J Vet Res48:85–90[PubMed]
    [Google Scholar]
  60. Fox J. G., Drolet R., Higgins R., Messier S., Yan L., Coleman B. E., Paster B. J., Dewhirst F. E.. ( 1996;). Helicobacter canis isolated from a dog liver with multifocal necrotizing hepatitis. J Clin Microbiol34:2479–2482[PubMed]
    [Google Scholar]
  61. Fox J. G., Handt L., Sheppard B. J., Xu S., Dewhirst F. E., Motzel S., Klein H.. ( 2001;). Isolation of Helicobacter cinaedi from the colon, liver, and mesenteric lymph node of a rhesus monkey with chronic colitis and hepatitis. J Clin Microbiol39:1580–1585 [CrossRef][PubMed]
    [Google Scholar]
  62. Fox J. G., Rogers A. B., Whary M. T., Ge Z., Taylor N. S., Xu S., Horwitz B. H., Erdman S. E.. ( 2004;a). Gastroenteritis in NF-kappaB-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 Immun72:1116–1125 [CrossRef][PubMed]
    [Google Scholar]
  63. Fox J. G., Rogers A. B., Whary M. T., Taylor N. S., Xu S., Feng Y., Keys S.. ( 2004;b). Helicobacter bilis-associated hepatitis in outbred mice. Comp Med54:571–577[PubMed]
    [Google Scholar]
  64. Fox J. G., Ge Z., Whary M. T., Erdman S. E., Horwitz B. H.. ( 2011;). Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. Mucosal Immunol4:22–30 [CrossRef][PubMed]
    [Google Scholar]
  65. 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 Microbiol5:695–707 [CrossRef][PubMed]
    [Google Scholar]
  66. 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 Pathog30:313–324 [CrossRef][PubMed]
    [Google Scholar]
  67. Garrity G. M., Bell J. A., Lilburn T.. ( 2005;). The Epsilonproteobacteria . In Bergey's Manual of Systematic Bacteriology, vol. 2, Proteobacteria1145–1160 Brenner D. J., Krieg N. R., Staley J. T.. New York: Springer;
    [Google Scholar]
  68. Ge Z., Feng Y., Whary M. T., Nambiar P. R., Xu S., Ng V., Taylor N. S., Fox J. G.. ( 2005;). Cytolethal distending toxin is essential for Helicobacter hepaticus colonization in outbred Swiss Webster mice. Infect Immun73:3559–3567 [CrossRef][PubMed]
    [Google Scholar]
  69. Ge Z., Rogers A. B., Feng Y., Lee A., Xu S., Taylor N. S., Fox J. G.. ( 2007;). Bacterial cytolethal distending toxin promotes the development of dysplasia in a model of microbially induced hepatocarcinogenesis. Cell Microbiol9:2070–2080 [CrossRef][PubMed]
    [Google Scholar]
  70. Ge Z., Schauer D. B., Fox J. G.. ( 2008;). In vivo virulence properties of bacterial cytolethal-distending toxin. Cell Microbiol10:1599–1607 [CrossRef][PubMed]
    [Google Scholar]
  71. Gebhart C. J., Ward G. E., Chang K., Kurtz H. J.. ( 1983;). Campylobacter hyointestinalis (new species) isolated from swine with lesions of proliferative ileitis. Am J Vet Res44:361–367[PubMed]
    [Google Scholar]
  72. Gelfanova V., Hansen E. J., Spinola S. M.. ( 1999;). Cytolethal distending toxin of Haemophilus ducreyi induces apoptotic death of Jurkat T cells. Infect Immun67:6394–6402[PubMed]
    [Google Scholar]
  73. Giono L. E., Manfredi J. J.. ( 2006;). The p53 tumor suppressor participates in multiple cell cycle checkpoints. J Cell Physiol209:13–20 [CrossRef][PubMed]
    [Google Scholar]
  74. Gudkov A. V., Komarova E. A.. ( 2003;). The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer3:117–129 [CrossRef][PubMed]
    [Google Scholar]
  75. Guerra L., Teter K., Lilley B. N., Stenerlöw B., Holmes R. K., Ploegh H. L., Sandvig K., Thelestam M., Frisan T.. ( 2005;). Cellular internalization of cytolethal distending toxin: a new end to a known pathway. Cell Microbiol7:921–934 [CrossRef][PubMed]
    [Google Scholar]
  76. Guerra L., Carr H. S., Richter-Dahlfors A., Masucci M. G., Thelestam M., Frost J. A., Frisan T.. ( 2008;). A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage. PLoS ONE3:e2254 [CrossRef][PubMed]
    [Google Scholar]
  77. Guerra L., Nemec K. N., Massey S., Tatulian S. A., Thelestam M., Frisan T., Teter K.. ( 2009;). A novel mode of translocation for cytolethal distending toxin. Biochim Biophys Acta1793:489–495 [CrossRef][PubMed]
    [Google Scholar]
  78. Guerra L., Albihn A., Tronnersjö S., Yan Q., Guidi R., Stenerlöw B., Sterzenbach T., Josenhans C., Fox J. G. et al. ( 2010;). Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage. PLoS ONE5:e8924 [CrossRef][PubMed]
    [Google Scholar]
  79. 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 A101:4614–4619 [CrossRef][PubMed]
    [Google Scholar]
  80. Hänninen M. L., Kärenlampi R. I., Koort J. M., Mikkonen T., Björkroth K. J.. ( 2005;). Extension of the species Helicobacter bilis to include the reference strains of Helicobacter sp. flexispira taxa 2, 3 and 8 and Finnish canine and feline flexispira strains. Int J Syst Evol Microbiol55:891–898 [CrossRef][PubMed]
    [Google Scholar]
  81. Hassane D. C., Lee R. B., Pickett C. L.. ( 2003;). Campylobacter jejuni cytolethal distending toxin promotes DNA repair responses in normal human cells. Infect Immun71:541–545 [CrossRef][PubMed]
    [Google Scholar]
  82. Henderson B., Wilson M., Sharp L., Ward J. M.. ( 2002;). Actinobacillus actinomycetemcomitans . J Med Microbiol51:1013–1020[PubMed]
    [Google Scholar]
  83. 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 Immun68:6535–6541 [CrossRef][PubMed]
    [Google Scholar]
  84. Hickey T. E., Majam G., Guerry P.. ( 2005;). Intracellular survival of Campylobacter jejuni in human monocytic cells and induction of apoptotic death by cytholethal distending toxin. Infect Immun73:5194–5197 [CrossRef][PubMed]
    [Google Scholar]
  85. Hinenoya A., Naigita A., Ninomiya K., Asakura M., Shima K., Seto K., Tsukamoto T., Ramamurthy T., Faruque S. M., Yamasaki S.. ( 2009;). Prevalence and characteristics of cytolethal distending toxin-producing Escherichia coli from children with diarrhea in Japan. Microbiol Immunol53:206–215 [CrossRef][PubMed]
    [Google Scholar]
  86. Hoeijmakers J. H.. ( 2001;). DNA repair mechanisms. Maturitas38:17–22, discussion 22–23 [CrossRef][PubMed]
    [Google Scholar]
  87. Hontz J. S., Villar-Lecumberri M. T., Dreyfus L. A., Yoder M. D.. ( 2006a;). Crystallization of Escherichia coli CdtB, the biologically active subunit of cytolethal distending toxin. Acta Crystallogr Sect F Struct Biol Cryst Commun62:192–195 [CrossRef][PubMed]
    [Google Scholar]
  88. Hontz J. S., Villar-Lecumberri M. T., Potter B. M., Yoder M. D., Dreyfus L. A., Laity J. H.. ( 2006b;). Differences in crystal and solution structures of the cytolethal distending toxin B subunit: Relevance to nuclear translocation and functional activation. J Biol Chem281:25365–25372 [CrossRef][PubMed]
    [Google Scholar]
  89. Hu X., Stebbins C. E.. ( 2006;). Dynamics and assembly of the cytolethal distending toxin. Proteins65:843–855 [CrossRef][PubMed]
    [Google Scholar]
  90. Hu X., Nesic D., Stebbins C. E.. ( 2006;). Comparative structure–function analysis of cytolethal distending toxins. Proteins62:421–434 [CrossRef][PubMed]
    [Google Scholar]
  91. Hyma K. E., Lacher D. W., Nelson A. M., Bumbaugh A. C., Janda J. M., Strockbine N. A., Young V. B., Whittam T. S.. ( 2005;). Evolutionary genetics of a new pathogenic Escherichia species: Escherichia albertii and related Shigella boydii strains. J Bacteriol187:619–628 [CrossRef][PubMed]
    [Google Scholar]
  92. Inglis G. D., McAllister T. A., Busz H. W., Yanke L. J., Morck D. W., Olson M. E., Read R. R.. ( 2005;). Effects of subtherapeutic administration of antimicrobial agents to beef cattle on the prevalence of antimicrobial resistance in Campylobacter jejuni and Campylobacter hyointestinalis . Appl Environ Microbiol71:3872–3881 [CrossRef][PubMed]
    [Google Scholar]
  93. Jackson S. P., Bartek J.. ( 2009;). The DNA-damage response in human biology and disease. Nature461:1071–1078 [CrossRef][PubMed]
    [Google Scholar]
  94. 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 Immun71:3634–3638 [CrossRef][PubMed]
    [Google Scholar]
  95. Johnson W. M., Lior H.. ( 1987;). Production of Shiga toxin and a cytolethal distending toxin (CLDT) by serogroups of Shigella spp. FEMS Microbiol Lett48:235–238 [CrossRef]
    [Google Scholar]
  96. Johnson W. M., Lior H.. ( 1988a;). A new heat-labile cytolethal distending toxin (CLDT) produced by Campylobacter spp. Microb Pathog4:115–126 [CrossRef][PubMed]
    [Google Scholar]
  97. Johnson W. M., Lior H.. ( 1988b;). A new heat-labile cytolethal distending toxin (CLDT) produced by Escherichia coli isolates from clinical material. Microb Pathog4:103–113 [CrossRef][PubMed]
    [Google Scholar]
  98. Johnson J. R., Stell A. L.. ( 2000;). Extended virulence genotypes of Escherichia coli strains from patients with urosepsis in relation to phylogeny and host compromise. J Infect Dis181:261–272 [CrossRef][PubMed]
    [Google Scholar]
  99. Johnson T. J., Kariyawasam S., Wannemuehler Y., Mangiamele P., Johnson S. J., Doetkott C., Skyberg J. A., Lynne A. M., Johnson J. R., Nolan L. K.. ( 2007;). The genome sequence of avian pathogenic Escherichia coli strain O1 : K1 : H7 shares strong similarities with human extraintestinal pathogenic E. coli genomes. J Bacteriol189:3228–3236 [CrossRef][PubMed]
    [Google Scholar]
  100. Johnson T. J., DebRoy C., Belton S., Williams M. L., Lawrence M., Nolan L. K., Thorsness J. L.. ( 2010;). Pyrosequencing of the Vir plasmid of necrotoxigenic Escherichia coli . Vet Microbiol144:100–109 [CrossRef][PubMed]
    [Google Scholar]
  101. Kitagawa T., Hoshida H., Akada R.. ( 2007;). Genome-wide analysis of cellular response to bacterial genotoxin CdtB in yeast. Infect Immun75:1393–1402 [CrossRef][PubMed]
    [Google Scholar]
  102. Konkel M. E., Monteville M. R., Rivera-Amill V., Joens L. A.. ( 2001;). The pathogenesis of Campylobacter jejuni-mediated enteritis. Curr Issues Intest Microbiol2:55–71[PubMed]
    [Google Scholar]
  103. Kostia S., Veijalainen P., Hirvi U., Hänninen M. L.. ( 2003;). Cytolethal distending toxin B gene (cdtB) homologues in taxa 2, 3 and 8 and in six canine isolates of Helicobacter sp. flexispira . J Med Microbiol52:103–108 [CrossRef][PubMed]
    [Google Scholar]
  104. Lara-Tejero M., Galán J. E.. ( 2000;). A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein. Science290:354–357 [CrossRef][PubMed]
    [Google Scholar]
  105. Lara-Tejero M., Galán J. E.. ( 2001;). CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity. Infect Immun69:4358–4365 [CrossRef][PubMed]
    [Google Scholar]
  106. Lavin M. F.. ( 2008;). Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol9:759–769 [CrossRef][PubMed]
    [Google Scholar]
  107. Lavin M. F., Kozlov S.. ( 2007;). ATM activation and DNA damage response. Cell Cycle6:931–942 [CrossRef][PubMed]
    [Google Scholar]
  108. Leemann C., Gambillara E., Prod'hom G., Jaton K., Panizzon R., Bille J., Francioli P., Greub G., Laffitte E., Tarr P. E.. ( 2006;). First case of bacteremia and multifocal cellulitis due to Helicobacter canis in an immunocompetent patient. J Clin Microbiol44:4598–4600 [CrossRef][PubMed]
    [Google Scholar]
  109. 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 Immun69:5626–5634 [CrossRef][PubMed]
    [Google Scholar]
  110. 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 Microbiol4:87–99 [CrossRef][PubMed]
    [Google Scholar]
  111. Lindmark B., Rompikuntal P. K., Vaitkevicius K., Song T., Mizunoe Y., Uhlin B. E., Guerry P., Wai S. N.. ( 2009;). Outer membrane vesicle-mediated release of cytolethal distending toxin (CDT) from Campylobacter jejuni . BMC Microbiol9:220 [CrossRef][PubMed]
    [Google Scholar]
  112. Liyanage N. P., Manthey K. C., Dassanayake R. P., Kuszynski C. A., Oakley G. G., Duhamel G. E.. ( 2010;). Helicobacter hepaticus cytolethal distending toxin causes cell death in intestinal epithelial cells via mitochondrial apoptotic pathway. Helicobacter15:98–107 [CrossRef][PubMed]
    [Google Scholar]
  113. Lundqvist A., Fernandez-Rodrigues J., Ahlman K., Lagergård T.. ( 2010;). Detoxified Haemophilus ducreyi cytolethal distending toxin and induction of toxin specific antibodies in the genital tract. Vaccine28:5768–5773 [CrossRef][PubMed]
    [Google Scholar]
  114. Mao X., DiRienzo J. M.. ( 2002;). Functional studies of the recombinant subunits of a cytolethal distending holotoxin. Cell Microbiol4:245–255 [CrossRef][PubMed]
    [Google Scholar]
  115. Matangkasombut O., Wattanawaraporn R., Tsuruda K., Ohara M., Sugai M., Mongkolsuk S.. ( 2010;). Cytolethal distending toxin from Aggregatibacter actinomycetemcomitans induces DNA damage, S/G2 cell cycle arrest, and caspase-independent death in a Saccharomyces cerevisiae model. Infect Immun78:783–792 [CrossRef][PubMed]
    [Google Scholar]
  116. Matsuoka S., Ballif B. A., Smogorzewska A., McDonald E. R. III, Hurov K. E., Luo J., Bakalarski C. E., Zhao Z., Solimini N. et al. ( 2007;). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science316:1160–1166 [CrossRef][PubMed]
    [Google Scholar]
  117. Mbwana J., Ahmed H. J., Ahlman K., Sundaeus V., Dahlén G., Lyamuya E., Lagergård T.. ( 2003;). Specificity of antibodies directed against the cytolethal distending toxin of Haemophilus ducreyi in patients with chancroid. Microb Pathog35:133–137 [CrossRef][PubMed]
    [Google Scholar]
  118. McSweeney L. A., Dreyfus L. A.. ( 2004;). Nuclear localization of the Escherichia coli cytolethal distending toxin CdtB subunit. Cell Microbiol6:447–458 [CrossRef][PubMed]
    [Google Scholar]
  119. McSweeney L. A., Dreyfus L. A.. ( 2005;). Carbohydrate-binding specificity of the Escherichia coli cytolethal distending toxin CdtA-II and CdtC-II subunits. Infect Immun73:2051–2060 [CrossRef][PubMed]
    [Google Scholar]
  120. Melito P. L., Munro C., Chipman P. R., Woodward D. L., Booth T. F., Rodgers F. G.. ( 2001;). Helicobacter winghamensis sp. nov., a novel Helicobacter sp. isolated from patients with gastroenteritis. J Clin Microbiol39:2412–2417 [CrossRef][PubMed]
    [Google Scholar]
  121. Mise K., Akifusa S., Watarai S., Ansai T., Nishihara T., Takehara T.. ( 2005;). Involvement of ganglioside GM3 in G(2)/M cell cycle arrest of human monocytic cells induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin. Infect Immun73:4846–4852 [CrossRef][PubMed]
    [Google Scholar]
  122. Moolhuijzen P. M., Lew-Tabor A. E., Wlodek B. M., Agüero F. G., Comerci D. J., Ugalde R. A., Sanchez D. O., Appels R., Bellgard M.. ( 2009;). Genomic analysis of Campylobacter fetus subspecies: identification of candidate virulence determinants and diagnostic assay targets. BMC Microbiol9:86 [CrossRef][PubMed]
    [Google Scholar]
  123. Mooney A., Clyne M., Curran T., Doherty D., Kilmartin B., Bourke B.. ( 2001;). Campylobacter upsaliensis exerts a cytolethal distending toxin effect on HeLa cells and T lymphocytes. Microbiology147:735–743[PubMed]
    [Google Scholar]
  124. Murphy H., Cogan T., Humphrey T.. ( 2011;). Direction of neutrophil movements by Campylobacter-infected intestinal epithelium. Microbes Infect13:42–48 [CrossRef][PubMed]
    [Google Scholar]
  125. Nešić D., Hsu Y., Stebbins C. E.. ( 2004;). Assembly and function of a bacterial genotoxin. Nature429:429–433 [CrossRef][PubMed]
    [Google Scholar]
  126. 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 Chem278:50671–50681 [CrossRef][PubMed]
    [Google Scholar]
  127. Nishikubo S., Ohara M., Ikura M., Katayanagi K., Fujiwara T., Komatsuzawa H., Kurihara H., Sugai M.. ( 2006;). Single nucleotide polymorphism in the cytolethal distending toxin B gene confers heterogeneity in the cytotoxicity of Actinobacillus actinomycetemcomitans . Infect Immun74:7014–7020 [CrossRef][PubMed]
    [Google Scholar]
  128. Nougayrède J. P., Taieb F., De Rycke J., Oswald E.. ( 2005;). Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. Trends Microbiol13:103–110 [CrossRef][PubMed]
    [Google Scholar]
  129. O'Brien K. A., Muscarella D. E., Bloom S. E.. ( 2001;). Differential induction of apoptosis and MAP kinase signaling by mitochondrial toxicants in drug-sensitive compared to drug-resistant B-lineage lymphoid cell lines. Toxicol Appl Pharmacol174:245–256 [CrossRef][PubMed]
    [Google Scholar]
  130. Ohara M., Hayashi T., Kusunoki Y., Miyauchi M., Takata T., Sugai M.. ( 2004;). Caspase-2 and caspase-7 are involved in cytolethal distending toxin-induced apoptosis in Jurkat and MOLT-4 T-cell lines. Infect Immun72:871–879 [CrossRef][PubMed]
    [Google Scholar]
  131. Ohara M., Hayashi T., Kusunoki Y., Nakachi K., Fujiwara T., Komatsuzawa H., Sugai M.. ( 2008;). Cytolethal distending toxin induces caspase-dependent and -independent cell death in MOLT-4 cells. Infect Immun76:4783–4791 [CrossRef][PubMed]
    [Google Scholar]
  132. Ohara M., Miyauchi M., Tsuruda K., Takata T., Sugai M.. ( 2011;). Topical application of Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces cell cycle arrest in the rat gingival epithelium in vivo. J Periodontal Res46:389–395 [CrossRef][PubMed]
    [Google Scholar]
  133. Ohguchi M., Ishisaki A., Okahashi N., Koide M., Koseki T., Yamato K., Noguchi T., Nishihara T.. ( 1998;). Actinobacillus actinomycetemcomitans toxin induces both cell cycle arrest in the G2/M phase and apoptosis. Infect Immun66:5980–5987[PubMed]
    [Google Scholar]
  134. Ohya T., Tominaga K., Nakazawa M.. ( 1993;). Production of cytolethal distending toxin (CLDT) by Campylobacter fetus subsp. fetus isolated from calves. J Vet Med Sci55:507–509[PubMed][CrossRef]
    [Google Scholar]
  135. Okeke I. N., Lamikanra A., Steinrück H., Kaper J. B.. ( 2000;). Characterization of Escherichia coli strains from cases of childhood diarrhea in provincial southwestern Nigeria. J Clin Microbiol38:7–12[PubMed]
    [Google Scholar]
  136. 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 Immun65:428–433[PubMed]
    [Google Scholar]
  137. Orth D., Grif K., Dierich M. P., Würzner R.. ( 2006;). Cytolethal distending toxins in Shiga toxin-producing Escherichia coli: alleles, serotype distribution and biological effects. J Med Microbiol55:1487–1492 [CrossRef][PubMed]
    [Google Scholar]
  138. Oswald E., Sugai M., Labigne A., Wu H. C., Fiorentini C., Boquet P., O'Brien A. D.. ( 1994;). Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Proc Natl Acad Sci U S A91:3814–3818 [CrossRef][PubMed]
    [Google Scholar]
  139. Oswald E., Nougayrède J. P., Taieb F., Sugai M.. ( 2005;). Bacterial toxins that modulate host cell-cycle progression. Curr Opin Microbiol8:83–91 [CrossRef][PubMed]
    [Google Scholar]
  140. Ow Y. P., Green D. R., Hao Z., Mak T. W.. ( 2008;). Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol9:532–542 [CrossRef][PubMed]
    [Google Scholar]
  141. Pérès S. Y., Marchès O., Daigle F., Nougayrède J. P., Herault 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 Microbiol24:1095–1107 [CrossRef][PubMed]
    [Google Scholar]
  142. Pickett C. L., Lee R. B.. ( 2005;). The cytolethal distending toxins. Microbial Toxins: Molecular and Cellular Biology81–97 Proft T.. Norfolk, UK: Horizon Bioscience;
    [Google Scholar]
  143. Pickett C. L., Whitehouse C. A.. ( 1999;). The cytolethal distending toxin family. Trends Microbiol7:292–297 [CrossRef][PubMed]
    [Google Scholar]
  144. 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 Immun62:1046–1051[PubMed]
    [Google Scholar]
  145. Pickett C. L., Pesci E. C., Cottle D. L., Russell G., Erdem A. N., Zeytin H.. ( 1996;). Prevalence of cytolethal distending toxin production in Campylobacter jejuni and relatedness of Campylobacter sp. cdtB gene. Infect Immun64:2070–2078[PubMed]
    [Google Scholar]
  146. Pratt J. S., Sachen K. L., Wood H. D., Eaton K. A., Young V. B.. ( 2006;). Modulation of host immune responses by the cytolethal distending toxin of Helicobacter hepaticus . Infect Immun74:4496–4504 [CrossRef][PubMed]
    [Google Scholar]
  147. 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 Microbiol49:473–479[PubMed]
    [Google Scholar]
  148. Purvén M., Lagergård T.. ( 1992;). Haemophilus ducreyi, a cytotoxin-producing bacterium. Infect Immun60:1156–1162[PubMed]
    [Google Scholar]
  149. Purvén M., Frisk A., Lönnroth I., Lagergard T.. ( 1997;). Purification and identification of Haemophilus ducreyi cytotoxin by use of a neutralizing monoclonal antibody. Infect Immun65:3496–3499[PubMed]
    [Google Scholar]
  150. Rabin S. D., Flitton J. G., Demuth D. R.. ( 2009;). Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces apoptosis in nonproliferating macrophages by a phosphatase-independent mechanism. Infect Immun77:3161–3169 [CrossRef][PubMed]
    [Google Scholar]
  151. Roos W. P., Kaina B.. ( 2006;). DNA damage-induced cell death by apoptosis. Trends Mol Med12:440–450 [CrossRef][PubMed]
    [Google Scholar]
  152. Sahin O., Plummer P. J., Jordan D. M., Sulaj K., Pereira S., Robbe-Austerman S., Wang L., Yaeger M. J., Hoffman L. J., Zhang Q.. ( 2008;). Emergence of a tetracycline-resistant Campylobacter jejuni clone associated with outbreaks of ovine abortion in the United States. J Clin Microbiol46:1663–1671 [CrossRef][PubMed]
    [Google Scholar]
  153. Scott D. A., Kaper J. B.. ( 1994;). Cloning and sequencing of the genes encoding Escherichia coli cytolethal distending toxin. Infect Immun62:244–251[PubMed]
    [Google Scholar]
  154. Shen Z., Xu S., Dewhirst F. E., Paster B. J., Pena J. A., Modlin I. M., Kidd M., Fox J. G.. ( 2005;). A novel enterohepatic Helicobacter species ‘Helicobacter mastomyrinus’ isolated from the liver and intestine of rodents. Helicobacter10:59–70 [CrossRef][PubMed]
    [Google Scholar]
  155. Shen Z., Feng Y., Rogers A. B., Rickman B., Whary M. T., Xu S., Clapp K. M., Boutin S. R., Fox J. G.. ( 2009;). Cytolethal distending toxin promotes Helicobacter cinaedi-associated typhlocolitis in interleukin-10-deficient mice. Infect Immun77:2508–2516 [CrossRef][PubMed]
    [Google Scholar]
  156. 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 Immunol162:4773–4780[PubMed]
    [Google Scholar]
  157. 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 Immunol167:435–441[PubMed][CrossRef]
    [Google Scholar]
  158. Shenker B. J., Besack D., McKay T., Pankoski L., Zekavat A., Demuth D. R.. ( 2005;). Induction of cell cycle arrest in lymphocytes by Actinobacillus actinomycetemcomitans cytolethal distending toxin requires three subunits for maximum activity. J Immunol174:2228–2234[PubMed][CrossRef]
    [Google Scholar]
  159. Shenker B. J., Dlakic M., Walker L. P., Besack D., Jaffe E., LaBelle E., Boesze-Battaglia K.. ( 2007;). A novel mode of action for a microbial-derived immunotoxin: the cytolethal distending toxin subunit B exhibits phosphatidylinositol 3,4,5-triphosphate phosphatase activity. J Immunol178:5099–5108[PubMed][CrossRef]
    [Google Scholar]
  160. Shigematsu M., Harada Y., Sekizuka T., Murayama O., Takamiya S., Millar B. C., Moore J. E., Matsuda M.. ( 2006;). Genetic heterogeneity of the cytolethal distending toxin B (cdtB) gene locus among isolates of Campylobacter lari . Br J Biomed Sci63:179–181[PubMed]
    [Google Scholar]
  161. Smith J. L., Bayles D. O.. ( 2006;). The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol32:227–248 [CrossRef][PubMed]
    [Google Scholar]
  162. Solnick J. V., Schauer D. B.. ( 2001;). Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin Microbiol Rev14:59–97 [CrossRef][PubMed]
    [Google Scholar]
  163. Song J., Willinger T., Rongvaux A., Eynon E. E., Stevens S., Manz M. G., Flavell R. A., Galán J. E.. ( 2010;). A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe8:369–376 [CrossRef][PubMed]
    [Google Scholar]
  164. Spanò S., Ugalde J. E., Galán J. E.. ( 2008;). Delivery of a Salmonella Typhi exotoxin from a host intracellular compartment. Cell Host Microbe3:30–38 [CrossRef][PubMed]
    [Google Scholar]
  165. 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 Immun67:3900–3908[PubMed]
    [Google Scholar]
  166. Suerbaum S., Josenhans C., Sterzenbach T., Drescher B., Brandt P., Bell M., Droge M., Fartmann B., Fischer H. P. et al. ( 2003;). The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus . Proc Natl Acad Sci U S A100:7901–7906 [CrossRef][PubMed]
    [Google Scholar]
  167. 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 Immun66:5008–5019[PubMed]
    [Google Scholar]
  168. Taylor N. S., Ge Z., Shen Z., Dewhirst F. E., Fox J. G.. ( 2003;). Cytolethal distending toxin: a potential virulence factor for Helicobacter cinaedi . J Infect Dis188:1892–1897 [CrossRef][PubMed]
    [Google Scholar]
  169. Taylor R. C., Cullen S. P., Martin S. J.. ( 2008;). Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol9:231–241 [CrossRef][PubMed]
    [Google Scholar]
  170. 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 Microbiol41:4285–4291 [CrossRef][PubMed]
    [Google Scholar]
  171. Tóth I., Nougayrède J. P., Dobrindt U., Ledger T. N., Boury M., Morabito S., Fujiwara T., Sugai M., Hacker J., Oswald E.. ( 2009;). Cytolethal distending toxin type I and type IV genes are framed with lambdoid prophage genes in extraintestinal pathogenic Escherichia coli . Infect Immun77:492–500 [CrossRef][PubMed]
    [Google Scholar]
  172. Ueno Y., Ohara M., Kawamoto T., Fujiwara T., Komatsuzawa H., Oswald E., Sugai M.. ( 2006;). Biogenesis of the Actinobacillus actinomycetemcomitans cytolethal distending toxin holotoxin. Infect Immun74:3480–3487 [CrossRef][PubMed]
    [Google Scholar]
  173. Weiss R. S., Leder P., Vaziri C.. ( 2003;). Critical role for mouse Hus1 in an S-phase DNA damage cell cycle checkpoint. Mol Cell Biol23:791–803 [CrossRef][PubMed]
    [Google Scholar]
  174. 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 Immun66:1934–1940[PubMed]
    [Google Scholar]
  175. 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 Pathog33:49–62 [CrossRef][PubMed]
    [Google Scholar]
  176. Wising C., Azem J., Zetterberg M., Svensson L. A., Ahlman K., Lagergård T.. ( 2005;). Induction of apoptosis/necrosis in various human cell lineages by Haemophilus ducreyi cytolethal distending toxin. Toxicon45:767–776 [CrossRef][PubMed]
    [Google Scholar]
  177. Xu B., Kim S. T., Lim D. S., Kastan M. B.. ( 2002;). Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol Cell Biol22:1049–1059 [CrossRef][PubMed]
    [Google Scholar]
  178. Xynogala I., Volgina A., DiRienzo J. M., Korostoff J.. ( 2009;). Evaluation of the humoral immune response to the cytolethal distending toxin of Aggregatibacter actinomycetemcomitans Y4 in subjects with localized aggressive periodontitis. Oral Microbiol Immunol24:116–123 [CrossRef][PubMed]
    [Google Scholar]
  179. Yamada T., Komoto J., Saiki K., Konishi K., Takusagawa F.. ( 2006;). Variation of loop sequence alters stability of cytolethal distending toxin (CDT): crystal structure of CDT from Actinobacillus actinomycetemcomitans . Protein Sci15:362–372 [CrossRef][PubMed]
    [Google Scholar]
  180. Yamamoto K., Tominaga K., Sukedai M., Okinaga T., Iwanaga K., Nishihara T., Fukuda J.. ( 2004;). Delivery of cytolethal distending toxin B induces cell cycle arrest and apoptosis in gingival squamous cell carcinoma in vitro. Eur J Oral Sci112:445–451 [CrossRef][PubMed]
    [Google Scholar]
  181. Yamano R., Ohara M., Nishikubo S., Fujiwara T., Kawamoto T., Ueno Y., Komatsuzawa H., Okuda K., Kurihara H. et al. ( 2003;). Prevalence of cytolethal distending toxin production in periodontopathogenic bacteria. J Clin Microbiol41:1391–1398 [CrossRef][PubMed]
    [Google Scholar]
  182. Young V. B., Mansfield L. S.. ( 2005;). Campylobacter infection –clinical context. Campylobacter: New Perspectives in Molecular and Cellular Biology1–12 Ketley J. M., Konkel M. E.. Oxford, UK: Taylor & Francis;
    [Google Scholar]
  183. Young V. B., Chien C. C., Knox K. A., Taylor N. S., Schauer D. B., Fox J. G.. ( 2000a;). Cytolethal distending toxin in avian and human isolates of Helicobacter pullorum . J Infect Dis182:620–623 [CrossRef][PubMed]
    [Google Scholar]
  184. Young V. B., Knox K. A., Schauer D. B.. ( 2000b;). Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus . Infect Immun68:184–191 [CrossRef][PubMed]
    [Google Scholar]
  185. Young R. S., Fortney K. R., Gelfanova V., Phillips C. L., Katz B. P., Hood A. F., Latimer J. L., Munson R. S. Jr, Hansen E. J., Spinola S. M.. ( 2001;). Expression of cytolethal distending toxin and hemolysin is not required for pustule formation by Haemophilus ducreyi in human volunteers. Infect Immun69:1938–1942 [CrossRef][PubMed]
    [Google Scholar]
  186. 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 Immun72:2521–2527 [CrossRef][PubMed]
    [Google Scholar]
  187. Young K. T., Davis L. M., Dirita V. J.. ( 2007;). Campylobacter jejuni: molecular biology and pathogenesis. Nat Rev Microbiol5:665–679 [CrossRef][PubMed]
    [Google Scholar]
  188. Yue M., Yang F., Yang J., Bei W., Cai X., Chen L., Dong J., Zhou R., Jin M. et al. ( 2009;). Complete genome sequence of Haemophilus parasuis SH0165. J Bacteriol191:1359–1360 [CrossRef][PubMed]
    [Google Scholar]
  189. Zamzami N., Susin S. A., Marchetti P., Hirsch T., Gómez-Monterrey I., Castedo M., Kroemer G.. ( 1996;). Mitochondrial control of nuclear apoptosis. J Exp Med183:1533–1544 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.049536-0
Loading
/content/journal/micro/10.1099/mic.0.049536-0
Loading

Data & Media loading...

Most cited this month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error