Skip to main content

Cytotoxic Effects of the Clostridium difficile Toxins

  • 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.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-662-06272-2_4
  • Chapter length: 12 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   149.00
Price excludes VAT (USA)
  • ISBN: 978-3-662-06272-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   199.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • 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 2761

    Google Scholar 

  • Caron E, Hall A (1998) Identification of two distinct mechanisms of phagocylosis controlled by different Rho GTPases. Science 282: 1717 1720

    Google Scholar 

  • 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: 657 665

    Google Scholar 

  • 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:(; 333 343

    Google Scholar 

  • 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: 4758–4793

    CrossRef  Google Scholar 

  • 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 6932

    Google Scholar 

  • 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: 1734–1741

    CAS  Google Scholar 

  • 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: 11046–11052

    CAS  Google Scholar 

  • 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 I6026

    Google Scholar 

  • 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 1160

    Google Scholar 

  • 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: 313–321

    Google Scholar 

  • 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: 375 382

    Google Scholar 

  • 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: 100 105

    Google Scholar 

  • Fiorentini C, Thelestam M (1991) Clostridium di//irite toxin A and its ellects on cells. Toxicon 29: 543 567

    Google Scholar 

  • 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: 1209–1218

    Google Scholar 

  • 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: 2329–2336

    Google Scholar 

  • 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: 292–297

    Google Scholar 

  • 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 2665

    Google Scholar 

  • 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: 23784–23791

    PubMed  CrossRef  CAS  Google Scholar 

  • Florin 1, Thelestam M (1986) Lysosomal involvement in cellular intoxication with Clostridium (Wile toxin B. Microb Pathogen 1: 373–385

    CrossRef  CAS  Google Scholar 

  • 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: 4063–4071

    PubMed  CAS  Google Scholar 

  • Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279: 509–514

    PubMed  CrossRef  CAS  Google Scholar 

  • 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 1524

    CrossRef  Google Scholar 

  • 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: 416–423

    Google Scholar 

  • Henriques B, Florin I, Thelestam M (1987) Cellular internalisation of Clostridium difficile toxin A. Microb Pathogen 2: 455–463

    CrossRef  CAS  Google Scholar 

  • 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 11078

    Google Scholar 

  • 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 

  • 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: 1393213936

    Google Scholar 

  • 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 2182

    Google Scholar 

  • Kelly C’P, Pothoulakis (’, LaMont.IT (1994) Clostridium difficile colitis. N Engl J Med 330: 257–262

    Google Scholar 

  • 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: 573–581

    PubMed  CAS  Google Scholar 

  • Kushnaryov VM, Sedmak JJ (1989) Effect of Clostridium dif/idle enterotoxin A on ultrastructure of Chinese hamster ovary cells. Infect Immun 57: 3914 3921

    Google Scholar 

  • 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: 5096–5099

    PubMed  CAS  Google Scholar 

  • 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: 61333–1340

    Google Scholar 

  • Lyerly DM, Wilkins TD (1995) Clostridium difficile. In: Blaser MJ Infections of the Gastrointestinal Tract. Raven Press Ltd., New York, pp. 867–891

    Google Scholar 

  • 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: 614–620

    CrossRef  CAS  Google Scholar 

  • Mazuski JE, Panesar N, Tolman K, Longo WE (1998) In vitro effects of Clostridium di/ficik’ toxins on hepatocytes..1 Surg Res 79: 170 178

    Google Scholar 

  • 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: 5315–5319

    CrossRef  Google Scholar 

  • 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: 3007–3010

    Google Scholar 

  • 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: 10629–1063

    PubMed  CrossRef  CAS  Google Scholar 

  • 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: 641–649

    CrossRef  CAS  Google Scholar 

  • Pothoulakis C. Castagliuolo I, LaMont JT (1998) Nerves and intestinal mast cells modulate responses to enterotoxins. News Physiol Sci 13: 58–63

    PubMed  Google Scholar 

  • 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: 2004–2011

    Google Scholar 

  • 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 1022

    Google Scholar 

  • 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 2746

    Google Scholar 

  • 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: 2240–2247

    PubMed  Google Scholar 

  • 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 85–92

    CrossRef  Google Scholar 

  • 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: 216–225

    Google Scholar 

  • 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 510–511

    Google Scholar 

  • 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: 45–54

    Google Scholar 

  • 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: 357–363

    CAS  Google Scholar 

  • 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: 281–258

    CrossRef  Google Scholar 

  • 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: 599–609

    PubMed  CrossRef  CAS  Google Scholar 

  • Thelestam M, Brönnegiird M (1980) Interaction of cytopathogenic toxin from Clostridium di(tied(’ with cells in tissue culture. Scand J Inf Dis Suppl 22: 16–29

    CAS  Google Scholar 

  • 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 141 158

    Google Scholar 

  • 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 

  • Tucker KD, Wilkins TD (1991) Toxin A of Clostridium difficile hinds to the human carbohydrate antigens I, X and Y. Infect Immun 59: 73–78

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2000 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Thelestam, M., Chaves-Olarte, E. (2000). Cytotoxic Effects of the Clostridium difficile Toxins. In: Aktories, K., Wilkins, T.D. (eds) Clostridium difficile. Current Topics in Microbiology and Immunology, vol 250. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-06272-2_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-06272-2_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-08668-7

  • Online ISBN: 978-3-662-06272-2

  • eBook Packages: Springer Book Archive