Clostridium difficile toxins: Mediators of inflammation

Journal of Innate Immunity

Volumn 4, Issue 2, 2012, Pages 149-158

  Shen, Aimee ^a  

^a UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

Author keywords

Binary toxin; Clostridium difficile infection; Glucosylating toxin; Hypervirulence

Indexed keywords

ANTIBIOTIC AGENT; ANTIINFLAMMATORY AGENT; CELL PROTEIN; CLOSTRIDIUM DIFFICILE TOXIN A; CLOSTRIDIUM DIFFICILE TOXIN B;

ACTIN FILAMENT; BACTERIAL VIRULENCE; CELL FUNCTION; CELL MEMBRANE; CLOSTRIDIUM DIFFICILE INFECTION; DISEASE SEVERITY; GLYCOSYLATION; HUMAN; IMMUNOSTIMULATION; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; REVIEW;

BACTERIAL TOXINS; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; HUMANS; INFLAMMATION; TRANSFERASES;

EID: 84857790535     PISSN: 1662811X     EISSN: 16628128     Source Type: Journal    
DOI: 10.1159/000332946     Document Type: Review

References (78)

1. Carroll KC, Bartlett JG: Biology of Clostridium difficile : Implications for epidemiology and diagnosis. Annu Rev Microbiol 2011; 65: 501-521.
2. Rupnik M, Wilcox MH, Gerding DN: Clostridium difficile infection: New developments in epidemiology and pathogenesis. Nature Rev 2009; 7: 526-536.
3. Voth DE, Ballard JD: Clostridium difficile toxins: Mechanism of action and role in disease. Clin Microbiol Rev 2005; 18: 247-263. (Pubitemid 40548293)
4. Gerding DN, Johnson S: Management of Clostridium difficile infection: Thinking inside and outside the box. Clin Infect Dis 2010; 51: 1306-1313.
5. Bartlett JG: Clinical practice: Antibiotic-associated diarrhea. N Engl J Med 2002; 346: 334-339.
6. McGlone SM, Bailey RR, Zimmer SM, Popovich MJ, Tian Y, Ufberg P, Muder RR, Lee BY: The economic burden of Clostridium difficile Clin Microbiol Infect 2011, E-pub ahead of print.
7. O'Brien JA, Lahue BJ, Caro JJ, Davidson DM: The emerging infectious challenge of Clostridium difficile -associated disease in Massachusetts hospitals: Clinical and economic consequences. Infect Control Hosp Epidemiol 2007; 28: 1219-1227. (Pubitemid 47596558)
8. McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN: An epidemic, toxin genevariant strain of Clostridium difficile N Engl J Med 2005; 353: 2433-2441. (Pubitemid 41770164)
9. Akerlund T, Persson I, Unemo M, Noren T, Svenungsson B, Wullt M, Burman LG: Increased sporulation rate of epidemic Clostridium difficile type 027/nap1. J Clin Microbiol 2008; 46: 1530-1533. (Pubitemid 351563610)
10. Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, Frost E, McDonald LC: Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366: 1079-1084. (Pubitemid 41338761)
11. Lanis JM, Barua S, Ballard JD: Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile PLoS Pathog 2010; 6:e1001061.
12. Stabler RA, Dawson LF, Phua LT, Wren BW: Comparative analysis of bi/nap1/027 hypervirulent strains reveals novel toxin B-encoding gene (TcdB) sequences. J Med Microbiol 2008; 57: 771-775. (Pubitemid 351842071)
13. Bacci S, Molbak K, Kjeldsen MK, Olsen KE: Binary toxin and death after Clostridium difficile infection. Emerg Infect Dis 2011; 17: 976-982.
14. Schirmer J, Aktories K: Large clostridial cytotoxins: Cellular biology of Rho/Ras-glucosylating toxins. Biochim Biophys Acta 2004; 1673: 66-74. (Pubitemid 38844795)
15. Kelly CP, Kyne L: The host immune response to Clostridium difficile J Med Microbiol 2011; 60: 1070-1079.
16. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N, Stack AM, Lowy I, Graziano R, Molrine D, Ambrosino DM, Thomas WD Jr: Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile -induced mortality in hamsters. Infect Immun 2006; 74: 6339-6347. (Pubitemid 44657416)
17. Johnson S: Antibody responses to clostridial infection in humans. Clin Infect Dis 1997; 25(suppl 2):S173-S177.
18. Pothoulakis C: Effects of Clostridium difficile toxins on epithelial cell barrier. Ann NY Acad Sci 2000; 915: 347-356. (Pubitemid 32059401)
19. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, Qamar A, Pothoulakis C, LaMont JT, Kelly CP: P38 map kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 2000; 105: 1147-1156. (Pubitemid 30217700)
20. Savidge TC, Pan WH, Newman P, O'Brien M, Anton PM, Pothoulakis C: Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 2003; 125: 413-420. (Pubitemid 36929422)
21. Pepin J, Vo TT, Boutros M, Marcotte E, Dial S, Dube S, Vasilevsky CA, McFadden N, Patino C, Labbe AC: Risk factors for mortality following emergency colectomy for fulminant Clostridium difficile infection. Dis Colon Rectum 2009; 52: 400-405.
22. Lamkanfi M, Dixit VM: Inflammasomes: Guardians of cytosolic sanctity. Immunol Rev 2009; 227: 95-105.
23. Ng J, Hirota SA, Gross O, Li Y, Ulke-Lemee A, Potentier MS, Schenck LP, Vilaysane A, Seamone ME, Feng H, Armstrong GD, Tschopp J, Macdonald JA, Muruve DA, Beck PL: Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 2010; 139: 542-552.
24. Davies AH, Roberts AK, Shone CC, Acharya KR: Super toxins from a super bug: Structure and function of Clostridium difficile toxins. Biochem J 2011; 436: 517-526.
25. Lyerly DM, Saum KE, MacDonald DK, Wilkins TD: Effects of Clostridium difficile toxins given intragastrically to animals. Infect Immun 1985; 47: 349-352. (Pubitemid 15169828)
26. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP: The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467: 711-713.
27. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R, Adams V, Vedantam G, Johnson S, Gerding DN, Rood JI: Toxin B is essential for virulence of Clostridium difficile Nature 2009; 458: 1176-1179.
28. Carter GP, Rood JI, Lyras D: The role of toxin A and toxin B in Clostridium difficile -associated disease: Past and present perspectives. Gut Microbes 2010; 1: 58-64.
29. Drudy D, Fanning S, Kyne L: Toxin A-negative, toxin B-positive Clostridium difficile Int J Infect Dis 2007; 11: 5-10. (Pubitemid 44937660)
30. Jank T, Aktories K: Structure and mode of action of clostridial glucosylating toxins: The ABCD model. Trends Microbiol 2008; 16: 222-229.
31. Dingle T, Wee S, Mulvey GL, Greco A, Kitova EN, Sun J, Lin S, Klassen JS, Palcic MM, Ng KK, Armstrong GD: Functional properties of the carboxy-terminal host cell-binding domains of the two toxins, TcdA and TcdB, expressed by Clostridium difficile Glycobiology 2008; 18: 698-706.
32. El-Hawiet A, Kitova EN, Kitov P, Eugenio L, Ng KK, Mulvey GL, Dingle TC, Szpacenko A, Armstrong GD, Klassen JS: Binding of Clostridium difficile toxins to human milk oligosaccharides. Glycobiology 2011; 21: 1217-1227.
33. 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 USA 2005; 102: 18373-18378. (Pubitemid 43011233)
34. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB: Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci USA 2010; 107: 13467-13472.
35. Jank T, Giesemann T, Aktories K: Clostridium difficile glucosyltransferase toxin B-essential amino acids for substrate binding. J Biol Chem 2007; 282: 35222-35231. (Pubitemid 350232434)
36. Stabler RA, He M, Dawson L, Martin M, Valiente E, Corton C, Lawley TD, Sebaihia M, Quail MA, Rose G, Gerding DN, Gibert M, Popoff MR, Parkhill J, Dougan G, Wren BW: Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol 2009; 10:R102.
37. Papatheodorou P, Zamboglou C, Genisyuerek S, Guttenberg G, Aktories K: Clostridial glucosylating toxins enter cells via clathrinmediated endocytosis. PloS One 2010; 5:e10673.
38. Olling A, Goy S, Hoffmann F, Tatge H, Just I, Gerhard R: The repetitive oligopeptide sequences modulate cytopathic potency but are not crucial for cellular uptake of Clostridium difficile toxin A. PloS One 2011; 6:e17623.
39. Qa'Dan M, Spyres LM, Ballard JD: PH-Induced conformational changes in Clostridium difficile toxin B. Infect Immun 2000; 68: 2470-2474. (Pubitemid 30253815)
40. Genisyuerek S, Papatheodorou P, Guttenberg G, Schubert R, Benz R, Aktories K: Structural determinants for membrane insertion, pore formation and translocation of Clostridium difficile toxin B. Mol Microbiol 2011; 79: 1643-1654.
41. Egerer M, Giesemann T, Jank T, Satchell KJ, Aktories K: Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity. J Biol Chem 2007; 282: 25314-25321. (Pubitemid 47372781)
42. Rawlings ND, Barrett AJ, Bateman A: MEROPS: The peptidase database. Nucleic Acids Res 2010; 38:D227-D233.
43. Egerer M, Satchell KJ: Inositol hexakisphosphate-induced autoprocessing of large bacterial protein toxins. PLoS Pathog 2010; 6:e1000942.
44. Shen A: Allosteric regulation of protease activity by small molecules. Mol Biosystems 2010; 6: 1431-1443.
45. Shen A, Lupardus PJ, Albrow VE, Guzzetta A, Powers JC, Garcia KC, Bogyo M: Mechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin. Nat Chem Biol 2009; 5: 469-478.
46. Pruitt RN, Chagot B, Cover M, Chazin WJ, Spiller B, Lacy DB: Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem 2009; 284: 21934-21940.
47. Puri AW, Lupardus PJ, Deu E, Albrow VE, Garcia KC, Bogyo M, Shen A: Rational design of inhibitors and activity-based probes targeting Clostridium difficile virulence factor TcdB. Chem Biol 2010; 17: 1201-1211.
48. Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE, Garcia KC, Bogyo M: Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat Struct Mol Biol 2011; 18: 364-371.
49. Kreimeyer I, Euler F, Marckscheffel A, Tatge H, Pich A, Olling A, Schwarz J, Just I, Gerhard R: Autoproteolytic cleavage mediates cytotoxicity of Clostridium difficile toxin A. Naunyn Schmiedebergs Arch Pharmacol 2010; 383: 253-262.
50. Rupnik M, Pabst S, Rupnik M, von Eichel-Streiber C, Urlaub H, Soling HD: 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. (Pubitemid 40214335)
51. Heasman SJ, Ridley AJ: Mammalian Rho GTPases: New insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008; 9: 690-701.
52. Genth H, Aktories K, Just I: Monoglucosylation of RhoA at threonine 37 blocks cytosolmembrane cycling. J Biol Chem 1999; 274: 29050-29056.
53. Herrmann C, Ahmadian MR, Hofmann F, Just I: Functional consequences of monoglucosylation of Ha-Ras at effector domain amino acid threonine 35. J Biol Chem 1998; 273: 16134-16139. (Pubitemid 28311384)
54. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K: Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375: 500-503.
55. Gerhard R, Nottrott S, Schoentaube J, Tatge H, Olling A, Just I: Glucosylation of Rho GTPases by Clostridium difficile toxin a triggers apoptosis in intestinal epithelial cells. J Med Microbiol 2008; 57: 765-770. (Pubitemid 351842070)
56. Huelsenbeck J, Dreger S, Gerhard R, Barth H, Just I, Genth H: 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. (Pubitemid 46203443)
57. Nottrott S, Schoentaube J, Genth H, Just I, Gerhard R: Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases. Apoptosis 2007; 12: 1443-1453. (Pubitemid 46988281)
58. Qa'Dan M, Ramsey M, Daniel J, Spyres LM, Safiejko-Mroczka B, Ortiz-Leduc W, Ballard JD: Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells. Cell Microbiol 2002; 4: 425-434. (Pubitemid 34830925)
59. Nam HJ, Kang JK, Kim SK, Ahn KJ, Seok H, Park SJ, Chang JS, Pothoulakis C, Lamont JT, Kim H: Clostridium difficile toxin A decreases acetylation of tubulin, leading to microtubule depolymerization through activation of histone deacetylase 6, and this mediates acute inflammation. J Biol Chem 2010; 285: 32888-32896.
60. 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. (Pubitemid 41133445)
61. Jank T, Reinert DJ, Giesemann T, Schulz GE, Aktories K: Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J Biol Chem 2005; 280: 37833-37838. (Pubitemid 41642394)
62. Geissler B, Tungekar R, Satchell KJ: Identification of a conserved membrane localization domain within numerous large bacterial protein toxins. Proc Natl Acad Sci USA 2010; 107: 5581-5586.
63. Aktories K, Barth H: Clostridium botulinum C2 toxin -new insights into the cellular uptake of the actin-ADP-ribosylating toxin. Int J Med Microbiol 2004; 293: 557-564. (Pubitemid 38667579)
64. Barbut F, Decre D, Lalande V, Burghoffer B, Noussair L, Gigandon A, Espinasse F, Raskine L, Robert J, Mangeol A, Branger C, Petit JC: Clinical features of Clostridium difficile -associated diarrhoea due to binary toxin (actinspecific ADP-ribosyltransferase)-producing strains. J Med Microbiol 2005; 54: 181-185. (Pubitemid 40868005)
65. Geric B, Carman RJ, Rupnik M, Genheimer CW, Sambol SP, Lyerly DM, Gerding DN, Johnson S: Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J Infect Dis 2006; 193: 1143-1150.
66. Heap JT, Kuehne SA, Ehsaan M, Cartman ST, Cooksley CM, Scott JC, Minton NP: The clostron: Mutagenesis in Clostridium refined and streamlined. J Microbiol Methods 2010; 80: 49-55.
67. Sundriyal A, Roberts AK, Shone CC, Acharya KR: Structural basis for substrate recognition in the enzymatic component of ADP-ribosyltransferase toxin CDTa from Clostridium difficile J Biol Chem 2009; 284: 28713-28719.
68. Perelle S, Gibert M, Bourlioux P, Corthier G, Popoff MR: Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect Immun 1997; 65: 1402-1407. (Pubitemid 27146631)
69. Sundriyal A, Roberts AK, Ling R, Mc-Glashan J, Shone CC, Acharya KR: Expression, purification and cell cytotoxicity of actin-modifying binary toxin from Clostridium difficile Protein Expr Purif 2010; 74: 42-48.
70. Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M, Fischer G, Buchner J, Aktories K, Barth H: Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by cyclophilin A and Hsp90. Infect Immun 2011; 79: 3913-3921.
71. Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt WD, Wehland J, Aktories K: Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 2009; 5:e1000626.
72. Schwan C, Noelke T, Kruppke AS, Schubert DM, Lang AE, Aktories K: Cholesterol-and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase CDT. J Biol Chem 2011; 286: 29356-29365.
73. Jarchum I, Liu M, Lipuma L, Pamer EG: Tolllike receptor 5 stimulation protects mice from acute Clostridium difficile colitis. Infect Immun 2011; 79: 1498-1503.
74. Lawley TD, Clare S, Walker AW, Goulding D, Stabler RA, Croucher N, Mastroeni P, Scott P, Raisen C, Mottram L, Fairweather NF, Wren BW, Parkhill J, Dougan G: Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, sporemediated transmission, and severe disease in immunocompromised hosts. Infect Immun 2009; 77: 3661-3669.
75. Lee GM, Craik CS: Trapping moving targets with small molecules. Science 2009; 324: 213-215.
76. Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A, Acharya V, Pinchuk I, Torres AG, English RD, Wiktorowicz JE, Loeffelholz M, Kumar R, Shi L, Nie W, Braun W, Herman B, Hausladen A, Feng H, Stamler JS, Pothoulakis C: Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat Med 2011; 17: 1136-1141.
77. Muller AJ, Hoffmann C, Hardt WD: Caspase-1 activation via Rho GTPases: A common theme in mucosal infections? PLoS Pathog 2010; 6:e1000795.
78. Hamm EE, Voth DE, Ballard JD: Identification of Clostridium difficile toxin B cardiotoxicity using a zebrafish embryo model of intoxication. Proc Natl Acad Sci USA 2006; 103: 14176-14181. (Pubitemid 44452999)