Advertisement

Cytotoxic Effects of the Clostridium difficile Toxins

  • M. Thelestam
  • E. Chaves-Olarte
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 250)

Abstract

Clostridium difficile-induced antibiotic-associated diarrhea and pseudomembranous colitis are typical toxin diseases elicited by actions of the two major toxins A and B (TcdA, TcdB) in the intestine. TcdA and TcdB are cytotoxic to intestinal and other cells because they glucosylate small GTP-binding proteins. These GTPases are crucial proteins controlling the actin cytoskeleton (ACSK) and the molecular signaling pathways involved in cell proliferation and cell death. Besides the two “classic” toxins produced by most strains of C. difficile, certain strains produce variant toxins whose pathophysiological significance is still unclear (Kato et al. 1998; Rlpnik et al. 1998). The C. difficile toxins are prototypes of the family of so-called Large Clostridial cytoToxins (LCTs). The LCTs glucosylate a variety of small GTPases thereby inducing a collapse of the ACSK (Eichel-Streiber et al. 1996).

Keywords

Dorsal Root Ganglion Fluid Secretion Lethal Toxin Cytotoxic Potency Mucosal Necrosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Calderún GM, Torres-Löpez J. Lin Ti. (’haves B, Hernandez M. Munoz O. Betas Al). Ilnciso JA (1998) Effects of toxin A from Clostridium difficile on mast cell activation and survival. Infect Immun 66: 2755 2761Google Scholar
  2. Caron E, Hall A (1998) Identification of two distinct mechanisms of phagocylosis controlled by different Rho GTPases. Science 282: 1717 1720Google Scholar
  3. Castagliuolo I. LaMont.IT, Letourneau R, Kelly CP, O’Keane K“, Jailer A. Thcoharides TC. Pothoulakis C (1994) Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Fihrio choierne enterotoxin in rat ileum. (ìustroenterol 107: 657 665Google Scholar
  4. Castagliuolo I, Kelly CP, Qiu BS, Nikulasson ST, LaMont.IT, Pothoulakis C (1997a) IL-11 inhibits Clostridium difficile toxin A enteroloxicity in rat ileum. Ain J Physiol 273:(; 333 343Google Scholar
  5. Castagliuolo I, Keates AC, Qiu B. Kelly CP, Nikulasson S, Leeman SE, Pothoulakis C (1997h) Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci USA 94: 4758–4793CrossRefGoogle Scholar
  6. Chaves-Olarte E. Florin I, Boquet P. Popoff M, Eichel-Streiber (r. Thelestam M (1996) tJDP-Glucose deficiency in a mutant cell line protects against glucosyltransferase toxins from Clostridium difficile and Clostridium sordellii.. Biol Chein 271: 6925 6932Google Scholar
  7. Chaves-Olarte E, Weidmann M, Eichel-Streiber (’V, Thelestam M (1997) Toxins A and B from Clostridium difficile dil(er with respect to enzymatic potencies, cellular substrate specificities. and surface binding to cultured cells. J Clin Invest 100: 1734–1741Google Scholar
  8. Chaves-Olarte E, Löw P, Freer E, Norlin T, Weidman!) M. Iiichel-Streiber CV, Thelestam M (1999) A novel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins. J Bio! Chem 274: 11046–11052Google Scholar
  9. Ciesla WP, Bobak DA (1998) Clostridium difficile toxins A and It are cation-dependent FDP-glucose hydrolases with dill’ering catalytic activities. J Biol Chem 273: 16 1121 I6026Google Scholar
  10. Eichel-Streiber(’V, Warfolomeow I, Knautz D, Sauerborn M. Fladding U(1991) Morphological changes in adherent cells induced by Clostridium difficile toxins. Biochem Soc Trans 19: 1154 1160Google Scholar
  11. Eichel-Streiber CV, Meyer Z[J, Heringdorf M, Habermann lì, Harlingen S t 1995 ) Closing in on the toxic domain through analysis of a variant Clostridium dif/indi’ cytotoxin B. Mol Microbiol 17: 313–321Google Scholar
  12. Eichel-Streiber CV, Boguet P, Sauerborn M, Thelestam M (1996) Large clostridia’ cytotoxins a family of glycosyltransferases modifying small (iTP-binding proteins. Trends Microbiol 4: 375 382Google Scholar
  13. Faust C, Ye B, Song KP (1998) The enzymatic domain of Clostridium di//)rile toxin A is located within its N-terminal region. Biochem Biophys Res Commun 251: 100 105Google Scholar
  14. Fiorentini C, Thelestam M (1991) Clostridium di//irite toxin A and its ellects on cells. Toxicon 29: 543 567Google Scholar
  15. Fiorentini C, Arancia G, Paradisi S, Donelli G, Giuliano M. Piemonte E, Mastrantonio I’ (1989) [’fleets of Clostridium dif/icile toxins A and B cytoskeleton organization in IIEp-2 cells: a comparative morphological study. Toxicon 27: 1209–1218Google Scholar
  16. Fiorentini C, Malorni W, Paradisi S, Giuliano M, Mastrantonio P, Donelli (ì 11990) Interaction of Om/rid/um dif/icile toxin A with cultured cells: cytoskeletal changes and nuclear polarization. Infect Immun 58: 2329–2336Google Scholar
  17. Fiorentini C, (’how SC, Mastrantonio P, Jeddi-Tehrani M, Thelestam M (1992) Clos ridium dì//irite toxin A induces multinucleation in the human leukemic T cell line.II)RKA’F. Fur.I (’cll Biol 57: 292–297Google Scholar
  18. Fiorentini C, Donelli G, Nicotera P, Thelestam M (1993) (’kavrirlium dif/iri/e toxin A elicits (a2 independent cytotoxic effects in cultured normal rat intestinal crypt cells. infect Inunun 61:3988 3993 Fiorentini C, Fabbri A, Esilzano L. Fattorossi A, Matarrese I’, Rivabene R. Donelli G (1998) (’/ostridiunr difficils toxin B induces apoptosis in intestinal cultured cells. infect lmmun 66: 2660 2665Google Scholar
  19. Flores-Diaz M, Alapc-Girón A. Pcrsson B, Pollescllo P, Moos M, Eichel-Streibcr CV, Thelestam M, Florin I (1997) Cellular UDP-glucose deficiency caused by a single point mutation in the UDPglucose pyrophosphorylase gene. J Biol Chem 272: 23784–23791PubMedCrossRefGoogle Scholar
  20. Florin 1, Thelestam M (1986) Lysosomal involvement in cellular intoxication with Clostridium (Wile toxin B. Microb Pathogen 1: 373–385CrossRefGoogle Scholar
  21. Giry M, Popoff MR, Eichel-Streibcr CV, Boquet P (1995) Transient expression of RhoA, -B, and -(’ GTPases in HeLa cells potentiates resistance to Clostridium difficile toxins A and B but not to Clostridium sorde/lii lethal toxin. Infect Immun 63: 4063–4071PubMedGoogle Scholar
  22. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279: 509–514PubMedCrossRefGoogle Scholar
  23. Hecht G, Pothoulakis C, LaMont JT, Madam J (1988) Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 82: 1516 1524CrossRefGoogle Scholar
  24. Hecht G, Koutsouris A, Pothoulakis C, LaMont JT, Madura J (1992) Clostridium di//kite toxin B disrupts the barrier function of TM monolayers. Gastroenterol 102: 416–423Google Scholar
  25. Henriques B, Florin I, Thelestam M (1987) Cellular internalisation of Clostridium difficile toxin A. Microb Pathogen 2: 455–463CrossRefGoogle Scholar
  26. Hofmann F, Busch C, Prepens U, Just I, Aktories K (1997) Localization of the glucosyltransferase activity of Clostridium difficile toxin B to the N-terminal part of the holotoxin. J Biol (’hein 272: 11074 11078Google Scholar
  27. Just I, Selzer J, Wilm M. Eichel-Streiber CV, Mann M, Aktories K (1995a) Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500–503.Google Scholar
  28. Just I. Wilco M, Selzer J. Rex G, Eichel-Streiher Cv, Mann M, Aktories K (1995b) The enterotoxin from C/osiridium di//idle ( ToxA) monoglucosylates the Rho proteins. J Biol Chem 270: 1393213936Google Scholar
  29. Kato Il. Kato N. Watanabe K, Iwai N, Nakamura II, Yamamoto T, Suzuki K, Kim SM, Chong Y, Wasito EB (1998) Identification of toxin A-negative, toxin B-positive Clostridium difficile by PC’R. J Clin Microbiol 36: 2178 2182Google Scholar
  30. Kelly C’P, Pothoulakis (’, LaMont.IT (1994) Clostridium difficile colitis. N Engl J Med 330: 257–262Google Scholar
  31. Krivan HC, Clark GF, Smith DE, Wilkins TD (1986) Cell surface binding site for Clostridium difficile enterotoxin: evidence for glycoconjugate containing the sequence Galal-3Gal(3t-4GIcNAc. Infect Immun 53: 573–581PubMedGoogle Scholar
  32. Kushnaryov VM, Sedmak JJ (1989) Effect of Clostridium dif/idle enterotoxin A on ultrastructure of Chinese hamster ovary cells. Infect Immun 57: 3914 3921Google Scholar
  33. Kushnaryov VM, Redlich PN, Sedmak JJ, Lyerly DM, Wilkins TD (1992) C’ytotoxicity of Clostridium c/i//ici/e toxin A for human colonic and pancreatic carcinoma cell lines. Cancer Res 52: 5096–5099PubMedGoogle Scholar
  34. Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, LaMont IT, Kelly CP (1997) IL-8 release and neutrophil activation by Clostridium cli//kilo toxin-exposed human monocytes. Am J Physiol 273: 61333–1340Google Scholar
  35. Lyerly DM, Wilkins TD (1995) Clostridium difficile. In: Blaser MJ Infections of the Gastrointestinal Tract. Raven Press Ltd., New York, pp. 867–891Google Scholar
  36. Mantyh CR, Maggio JE, Mantyh PW, Vigna SR, Pappas TN (1996) Increased substance P receptor expression by blood vessels and lymphoid aggregates in Clostridium di/fici/e-induced pseudomembranous colitis. Dig Dis & Sci 41: 614–620CrossRefGoogle Scholar
  37. Mazuski JE, Panesar N, Tolman K, Longo WE (1998) In vitro effects of Clostridium di/ficik’ toxins on hepatocytes..1 Surg Res 79: 170 178Google Scholar
  38. Merlon M, Schlesinger P, Brooks RM, Moehring JM, Moehring Ti, Sly WS (1983) Defective acidification of endosomes in Chinese banister ovary cell mutants cross-resistant to toxins and viruses. Proc Natl Acad Sci USA 80: 5315–5319CrossRefGoogle Scholar
  39. Miller II, Eichel-Streiher (’V, Habermann E (1992) Morphological changes of cultured endothelial cells after microinjection of toxins that act on the cytoskeleton. Infect Immun 60: 3007–3010Google Scholar
  40. Nusrat A, Giry M, Turner JR, Colgan SP, Parkos CA, Carnes D, Lemichez E, Boquet P, Madam JL (1995) Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. Proc Natl Acad Sci USA 92: 10629–1063PubMedCrossRefGoogle Scholar
  41. Pothoulakis C, Gilbert R.I. Cladaras C. Castagliuolo 1, Semenza G, Hitti Y, Montcrief JS, Linevsky J, Kelly (’P, Nikulasson S, Desai IIP, Wilkins TD, LaMont JT (1996) Rabbit sucrase-isomaltase contains a functional intestinal receptor I’or Clostridium difficile toxin A. J (’lin Invest 98: 641–649CrossRefGoogle Scholar
  42. Pothoulakis C. Castagliuolo I, LaMont JT (1998) Nerves and intestinal mast cells modulate responses to enterotoxins. News Physiol Sci 13: 58–63PubMedGoogle Scholar
  43. Riegler M, Sedivy R, Pothoulakis C, Hamilton G, Zacherl J, Bischof G. Cosentini F. Feil W, Schiessel R, LaMont JT, Wenzl E (1995) Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 95: 2004–2011Google Scholar
  44. Riegler M, Sedivy R, Sogukoglu T, Castagliuolo 1, Pothoulakis C, Cosentini I, Bischof G, I Iamihon G. Teleky B, Feil W, LaMont JT, Wenzl E (1997) Epidermal growth factor attenuates Clostridium difficile toxin A- and I3-induced damage of human colonic mucosa. Atn J Physiol 273: 01014 1022Google Scholar
  45. Rocha MF, Maie ME, Bezerr LR, Lyerly DM, Guerrant RL, Ribeiro RA, Lima AA (1997) Clostridium difficile toxin A induces the release of neutrophil chemotactic factors From rat peritoneal macrophages: role of interleukin-1 I), tumor necrosis factor alpha, and Ieukotrienes. Infect Immun 65: 2740 2746Google Scholar
  46. Rupnik M. Avesani V, Jane M, Eichel-Streiher CV, Dclmée M (1998) A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium dilficile isolates. J Clin Microbiol 36: 2240–2247PubMedGoogle Scholar
  47. Saito Y, Narumiya S (1997) Preparation of Clostridium boodinum C3 exoenzynie and application of ADP-ribosylation of Rho proteins in biological systems. In: Aktories K (ed) Bacterial toxins tools in cell biology and pharmacology. Chapman & Hall. Weinheim, pp 85–92CrossRefGoogle Scholar
  48. Santos MF, McCormack SA, Guo Z, Okolicany J, Zheng Y, Johnson LR. “figyi G (1997) Rho proteins play a critical role in cell migration during the early phase of mucosal restitution..1 (’lit Invest 100: 216–225Google Scholar
  49. Sauerborn M, Hegenbarth S, Laufenberg-Feldmann R, Leukel P, Eichel-Streiher CV (1994) Monoclonal antibodies discriminating between Clostridium difficile toxins A and B. In: Freer J et al. (eds) Bacterial protein toxins. Gustav Fischer Verlag, Stuttgart, pp 510–511Google Scholar
  50. Sauerborn M, Leukel P. Eichel-Streiher C’v (1997) The C-terminal ligand-binding domain of Clostridium (Wilde toxin A (TcdA) abrogates TcdA-specific binding to cells and prevents mouse lethality. I F: MS Microbiol Lett 155: 45–54Google Scholar
  51. Shoshan MC, Aman P. Skoog 5, Florin I, Thelestam M (1990) Microfilament-disrupting Clostridium difficile toxin B causes multinucleation of transformed cells but does not block capping of membrane Ig. Fur J Cell Biol 53: 357–363Google Scholar
  52. Souza Mil, Melo-Filho AA, Rocha MF, Lyerly DM, Cunha FQ, Luna AA, Ribeiro RA (1997) The involvement of macrophage-derived tumour necrosis factor and lipoxygenase products on the neutrophil recruitment induced by Clostridium ffifficilc toxin B. Immunology 91: 281–258CrossRefGoogle Scholar
  53. Teneberg S, Lönnroth I, Torres Lopez JF, Galili U, I lalvarsson MO. Angström J. Karlsson KA (1996) Molecular mimicry in the recognition of glycosphingolipids by (ìala3-GaI14-GIcNAc-binding Clostridium difficile toxin A, a human natural anti a-galactosyl IgG and the monoclonal antibody Gal-1 3:characterization of a binding-active human glycosphingolipid, non-identical with the animal receptor. Glycobiology 6: 599–609PubMedCrossRefGoogle Scholar
  54. Thelestam M, Brönnegiird M (1980) Interaction of cytopathogenic toxin from Clostridium di(tied(’ with cells in tissue culture. Scand J Inf Dis Suppl 22: 16–29Google Scholar
  55. Thelestam M, Florin I, Chaves-Olarte E (1997) (lo.itridiunt difficile toxins. In: Aktories K (ed) Bacterial toxins - tools in cell biology and pharmacology. Chapman & Hall, Weinheim. pp 141 158Google Scholar
  56. Thelestam M, Chaves-Olarte E, Moos M, Fichel-Streiher CV (1999) Clostridia] toxins acting on the cytoskeleton. In: Alouf JE, Freer.1 (eds) Sourcebook of Bacterial Toxins. Academic Press (in press)Google Scholar
  57. Tucker KD, Wilkins TD (1991) Toxin A of Clostridium difficile hinds to the human carbohydrate antigens I, X and Y. Infect Immun 59: 73–78Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • M. Thelestam
    • 1
  • E. Chaves-Olarte
    • 1
  1. 1.Microbiology and Tumorbiology CenterKarolinska InstitutetStockholmSweden

Personalised recommendations