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The molecular pathogenesis of Clostridium difficile-associated disease

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Abstract

Clostridium difficile-associated disease is a reemerging nosocomial disease of paramount importance not only in the United States, but most of the world as well. Recently, C. difficile-associated disease appears to be on the rise, with a parallel increase noted in its severity and extent. Although the main virulence factors, the large exotoxins known as toxin A and toxin B, have long been identified, only in the past few years has a near explosion of new information regarding the details of the toxin-mediated pathogenicity come to light. This update gives an overview of some of the more exciting and insightful reports published in the recent literature.

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References and Recommended Reading

  1. Bartlett JG: Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006, 145:758–764.

    PubMed  Google Scholar 

  2. Blossom DB, McDonald LC: The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 2007, 45:222–227.

    Article  PubMed  Google Scholar 

  3. Cloud J, Kelly CP: Update on Clostridium difficile associated disease. Curr Opin Gastroenterol 2007, 23:4–9.

    PubMed  Google Scholar 

  4. McMaster-Baxter NL, Musher DM: Clostridium difficile: recent epidemiologic findings and advances in therapy. Pharmacotherapy 2007, 27:1029–1039.

    Article  PubMed  CAS  Google Scholar 

  5. Voth DE, Ballard JD: Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 2005, 18:247–263.

    Article  PubMed  CAS  Google Scholar 

  6. Jank T, Giesemann T, Aktories K: Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 2007, 17:15R–22R.

    Article  PubMed  CAS  Google Scholar 

  7. Cohen SH, Tang YJ, Silva J Jr: Analysis of the pathogenicity locus in Clostridium difficile strains. J Infect Dis 2000, 181:659–663.

    Article  PubMed  CAS  Google Scholar 

  8. Spigaglia P, Mastrantonio P: Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol 2002, 40:3470–3475.

    Article  PubMed  CAS  Google Scholar 

  9. McDonald LC, Killgore GE, Thompson A, et al.: An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005, 353:2433–2441.

    Article  PubMed  CAS  Google Scholar 

  10. Curry SR, Marsh JW, Muto CA, et al.: tcdC genotypes associated with severe TcdC truncation in an epidemic clone and other strains of Clostridium difficile. J Clin Microbiol 2007, 45:215–221.

    Article  PubMed  CAS  Google Scholar 

  11. Stabler RA, Gerding DN, Songer JG, et al.: Comparative phylogenomics of Clostridium difficile reveals clade specificity and microevolution of hypervirulent strains. J Bacteriol 2006, 188:7297–7305.

    Article  PubMed  CAS  Google Scholar 

  12. Sebaihia M, Wren BW, Mullany P, et al.: The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet 2006, 38:779–786.

    Article  PubMed  CAS  Google Scholar 

  13. Carter GP, Purdy D, Williams P, Minton NP: Quorum sensing in Clostridium difficile: analysis of a luxS-type signalling system. J Med Microbiol 2005, 54:1119–1127.

    Article  CAS  Google Scholar 

  14. Cookson B: Hypervirulent strains of Clostridium difficile. Postgrad Med J 2007, 83:291–295.

    Article  PubMed  Google Scholar 

  15. Drudy D, Fanning S, Kyne L: Toxin A-negative, toxin B-positive Clostridium difficile. Int J Infect Dis 2007, 11:5–10.

    Article  PubMed  CAS  Google Scholar 

  16. Matamouros S, England P, Dupuy B: Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol Microbiol 2007, 64:1274–1288.

    Article  PubMed  CAS  Google Scholar 

  17. Heap JT, Pennington OJ, Cartman ST, et al.: The ClosTron: a universal gene knock-out system for the genus Clostridium. J Microbiol Methods 2007, 70:452–464.

    Article  PubMed  CAS  Google Scholar 

  18. Ho JG, Greco A, Rupnik M, Ng KK: Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. Proc Natl Acad Sci U S A 2005, 102:18373–18378.

    Article  PubMed  CAS  Google Scholar 

  19. Greco A, Ho JG, Lin SJ, et al.: Carbohydrate recognition by Clostridium difficile toxin A. Nat Struct Mol Biol 2006, 13:460–461.

    Article  PubMed  CAS  Google Scholar 

  20. Stubbe H, Berdoz J, Kraehenbuhl JP, Corthésy B: Polymeric IgA is superior to monomeric IgA and IgG carrying the same variable domain in preventing Clostridium difficile toxin A damaging of T84 monolayers. J Immunol 2000, 164:1952–1960.

    PubMed  CAS  Google Scholar 

  21. Giesemann T, Jank T, Gerhard R, et al.: Cholesterol-dependent pore formation of Clostridium difficile toxin A. J Biol Chem 2006, 281:10808–10815.

    Article  PubMed  CAS  Google Scholar 

  22. Pfeifer G, Schirmer J, Leemhuis J, et al.: Cellular uptake of Clostridium difficile toxin B. Translocation of the N-terminal catalytic domain into the cytosol of eukaryotic cells. J Biol Chem 2003, 278:44535–44541.

    Article  PubMed  CAS  Google Scholar 

  23. Rupnik M, Pabst S, Rupnik M, et al.: Characterization of the cleavage site and function of resulting cleavage fragments after limited proteolysis of Clostridium difficile toxin B (TcdB) by host cells. Microbiology 2005, 151:199–208.

    Article  PubMed  CAS  Google Scholar 

  24. Reineke J, Tenzer S, Rupnik M, et al.: Autocatalytic cleavage of Clostridium difficile toxin B. Nature 2007, 446:415–419.

    Article  PubMed  CAS  Google Scholar 

  25. Egerer M, Giesemann T, Jank T, et al.: Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity. J Biol Chem 2007, 282:25314–25321.

    Article  PubMed  CAS  Google Scholar 

  26. Jaffe AB, Hall A: Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005, 21:247–269.

    Article  PubMed  CAS  Google Scholar 

  27. Bustelo XR, Sauzeau V, Berenjeno IM: GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 2007, 29:356–370.

    Article  PubMed  CAS  Google Scholar 

  28. Reinert DJ, Jank T, Aktories K, Schulz GE: Structural basis for the function of Clostridium difficile toxin B. J Mol Biol 2005, 351:973–981.

    Article  PubMed  CAS  Google Scholar 

  29. Jank T, Reinert DJ, Giesemann T, et al.: Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J Biol Chem 2005, 280:37833–37838.

    Article  PubMed  CAS  Google Scholar 

  30. Jank T, Pack U, Giesemann T, et al.: Exchange of a single amino acid switches the substrate properties of RhoA and RhoD toward glucosylating and transglutaminating toxins. J Biol Chem 2006, 281:19527–19535.

    Article  PubMed  CAS  Google Scholar 

  31. Jank T, Giesemann T, Aktories K: Clostridium difficile glucosyltransferase toxin B-essential amino acids for substrate binding. J Biol Chem 2007, 282:35222–35231.

    Article  PubMed  CAS  Google Scholar 

  32. Barth H, Aktories K, Popoff MR, Stiles BG: Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol Mol Biol Rev 2004, 68:373–402.

    Article  PubMed  CAS  Google Scholar 

  33. Geric B, Carman RJ, Rupnik M, et al.: Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J Infect Dis 2006, 193:1143–1145.

    Article  PubMed  CAS  Google Scholar 

  34. Matarrese P, Falzano L, Fabbri A, et al.: Clostridium difficile toxin B causes apoptosis in epithelial cells by thrilling mitochondria. Involvement of ATP-sensitive mitochondrial potassium channels. J Biol Chem 2007, 282:9029–9041.

    Article  PubMed  CAS  Google Scholar 

  35. Huelsenbeck J, Dreger S, Gerhard R, et al.: Difference in the cytotoxic effects of toxin B from Clostridium difficile strain VPI 10463 and toxin B from variant Clostridium difficile strain 1470. Infect Immun 2007, 75:801–809.

    Article  PubMed  CAS  Google Scholar 

  36. Chaves-Olarte E, Freer E, Parra A, et al.: R-Ras glucosylation and transient RhoA activation determine the cytopathic effect produced by toxin B variants from toxin A-negative strains of Clostridium difficile. J Biol Chem 2003, 278:7956–7963.

    Article  PubMed  CAS  Google Scholar 

  37. Gerhard R, Tatge H, Genth H, et al.: Clostridium difficile toxin A induces expression of the stress-induced early gene product RhoB. J Biol Chem 2005, 280:1499–1505.

    Article  PubMed  CAS  Google Scholar 

  38. Chae S, Eckmann L, Miyamoto Y, et al.: Epithelial cell I kappa B-kinase beta has an important protective role in Clostridium difficile toxin A-induced mucosal injury. J Immunol 2006, 177:1214–1220.

    PubMed  CAS  Google Scholar 

  39. Huelsenbeck J, Dreger SC, Gerhard R, et al.: Upregulation of the immediate early gene product RhoB by exoenzyme C3 from Clostridium limosum and toxin B from Clostridium difficile. Biochemistry 2007, 46:4923–4931.

    Article  PubMed  CAS  Google Scholar 

  40. Kim H, Rhee SH, Kokkotou E, et al.: Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 MAPK. J Biol Chem 2005, 280:21237–21245.

    Article  PubMed  CAS  Google Scholar 

  41. Lee JY, Park HR, Oh YK, et al.: Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin A. J Mol Med 2007, 85:1393–1404.

    Article  PubMed  CAS  Google Scholar 

  42. Anton PM, Gay J, Mykoniatis A, et al.: Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Proc Natl Acad Sci U S A 2004, 101:8503–8508.

    Article  PubMed  CAS  Google Scholar 

  43. Tait AS, Dalton M, Geny B, et al.: The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity. Infect Immun 2007, 75:3935–3940.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to David A. Bobak.

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Bobak, D.A. The molecular pathogenesis of Clostridium difficile-associated disease. Curr Infect Dis Rep 10, 111–115 (2008). https://doi.org/10.1007/s11908-008-0020-0

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