Critical roles of Clostridium difficile toxin B enzymatic activities in pathogenesis

Infection and Immunity

Volumn 83, Issue 2, 2015, Pages 502-513

  Li, Shan ^a   Shi, Lianfa ^a   Yang, Zhiyong ^a   Zhang, Yongrong ^a   Perez Cordon, Gregorio ^a   Huang, Tuxiong ^a   Ramsey, Jeremy ^a   Oezguen, Numan ^b   Savidge, Tor C ^b   Feng, Hanping ^a  

^a UNIVERSITY OF MARYLAND DENTAL SCHOOL   (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7F ANTIBODY; CLOSTRIDIUM DIFFICILE TOXIN B; CYSTEINE PROTEINASE; E3 ANTIBODY; GLUCOSYLTRANSFERASE; PHYTIC ACID; RAC PROTEIN; UNCLASSIFIED DRUG; BACTERIAL PROTEIN; BACTERIAL TOXIN; CYSTEINE PROTEINASE INHIBITOR; IMMUNOGLOBULIN HEAVY CHAIN; NANOBODY; TOXB PROTEIN, CLOSTRIDIUM DIFFICILE; VIRULENCE FACTOR;

ADULT; AMINO ACID SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL DEATH; CELL MEDIATED CYTOTOXICITY; CONTROLLED STUDY; CYTOPATHOGENIC EFFECT; CYTOSOL; CYTOSOLIC FRACTION; ENZYME ACTIVITY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; HEAVY CHAIN; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; PATHOGENESIS; PHASE CONTRAST MICROSCOPY; PRIORITY JOURNAL; PROTEIN GLYCOSYLATION; QUANTITATIVE ANALYSIS; TARGET CELL; VERO CELL LINE; WESTERN BLOTTING; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL LINE; CHLOROCEBUS AETHIOPS; ENZYMOLOGY; IMMUNOLOGY; METABOLISM; MICROBIOLOGY; PATHOGENICITY; PEPTOCLOSTRIDIUM DIFFICILE; PROTEIN TERTIARY STRUCTURE; PSEUDOMEMBRANOUS COLITIS;

AMINO ACID SEQUENCE; ANIMALS; BACTERIAL PROTEINS; BACTERIAL TOXINS; CELL LINE; CERCOPITHECUS AETHIOPS; CLOSTRIDIUM DIFFICILE; CYSTEINE PROTEASES; CYSTEINE PROTEINASE INHIBITORS; ENTEROCOLITIS, PSEUDOMEMBRANOUS; GLUCOSYLTRANSFERASES; HUMANS; IMMUNOGLOBULIN HEAVY CHAINS; MICE; PROTEIN STRUCTURE, TERTIARY; SINGLE-DOMAIN ANTIBODIES; VERO CELLS; VIRULENCE FACTORS;

EID: 84921366455     PISSN: 00199567     EISSN: 10985522     Source Type: Journal    
DOI: 10.1128/IAI.02316-14     Document Type: Article

References (62)

1. Kelly CP, LaMont JT. 2008. Clostridium difficile-more difficult than ever. N Engl J Med 359:1932-1940. http://dx.doi.org/10.1056/NEJMra0707500.
2. Zilberberg MD. 2009. Clostridium difficile-related hospitalizations among US adults, 2006. Emerg Infect Dis 15:122-124. http://dx.doi.org/10.3201/eid1501.080793.
3. Voth DE, Ballard JD. 2005. Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18:247-263. http://dx.doi.org/10.1128/CMR.18.2.247-263.2005.
4. Jank T, Aktories K. 2008. Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol 16:222-229. http://dx.doi.org/10.1016/j.tim.2008.01.011.
5. Albesa-Jove D, Bertrand T, Carpenter EP, Swain GV, Lim J, Zhang J, Haire LF, Vasisht N, Braun V, Lange A, von Eichel-Streiber C, Svergun DI, Fairweather NF, Brown KA. 2010. Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS. J Mol Biol 396: 1260-1270. http://dx.doi.org/10.1016/j.jmb.2010.01.012.
6. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB. 2010. Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A 107:13467-13472. http://dx.doi.org/10.1073/pnas.1002199107.
7. Schorch B, Song S, van Diemen FR, Bock HH, May P, Herz J, Brummelkamp TR, Papatheodorou P, Aktories K. 2014. LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proc Natl Acad Sci U S A 111:6431-6436. http://dx.doi.org/10.1073/pnas.1323790111.
8. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500-503. http://dx.doi.org/10.1038/375500a0.
9. Nam HJ, Kang JK, Kim SK, Ahn KJ, Seok H, Park SJ, Chang JS, Pothoulakis C, Lamont JT, Kim H. 2010. 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 285:32888-32896. http://dx.doi.org/10.1074/jbc.M110.162743.
10. Pothoulakis C, Lamont JT. 2001. Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins.AmJ Physiol Gastrointest Liver Physiol 280:G178-G183.
11. Qa'Dan M, Ramsey M, Daniel J, Spyres LM, Safiejko-Mroczka B, Ortiz-Leduc W, Ballard JD. 2002. Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells. Cell Microbiol 4:425-434. http://dx.doi.org/10.1046/j.1462-5822.2002.00201.x.
12. 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. 2009. Toxin B is essential for virulence of Clostridium difficile. Nature 458:1176-1179. http://dx.doi.org/10.1038/nature07822.
13. Rupnik M, Wilcox MH, Gerding DN. 2009. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7:526-536. http://dx.doi.org/10.1038/nrmicro2164.
14. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP. 2010. The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711-713. http://dx.doi.org/10.1038/nature09397.
15. Chaves-Olarte E, Weidmann M, Eichel-Streiber C, Thelestam M. 1997. Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells. J Clin Invest 100:1734-1741. http://dx.doi.org/10.1172/JCI119698.
16. Lanis JM, Hightower LD, Shen A, Ballard JD. 2012. TcdB from hypervirulent Clostridium difficile exhibits increased efficiency of autoprocessing. Mol Microbiol 84:66-76. http://dx.doi.org/10.1111/j.1365-2958.2012.08009.x.
17. Giesemann T, Egerer M, Jank T, Aktories K. 2008. Processing of Clostridium difficile toxins. J Med Microbiol 57:690-696. http://dx.doi.org/10.1099/jmm.0.47742-0.
18. von Eichel-Streiber C, Sauerborn M, Kuramitsu HK. 1992. Evidence for a modular structure of the homologous repetitive C-terminal carbohydrate-binding sites of Clostridium difficile toxins and Streptococcus mutans glucosyltransferases. J Bacteriol 174:6707-6710.
19. Ho JG, Greco A, Rupnik M, Ng KK. 2005. Crystal structure of receptorbinding C-terminal repeats from Clostridium difficile toxin A. Proc Natl Acad Sci U S A 102:18373-18378. http://dx.doi.org/10.1073/pnas.0506391102.
20. Papatheodorou P, Zamboglou C, Genisyuerek S, Guttenberg G, Aktories K. 2010. Clostridial glucosylating toxins enter cells via clathrinmediated endocytosis. PLoS One 5:e10673. http://dx.doi.org/10.1371/journal.pone.0010673.
21. Qa'Dan M, Spyres LM, Ballard JD. 2000. pH-induced conformational changes in Clostridium difficile toxin B. Infect Immun 68:2470-2474. http://dx.doi.org/10.1128/IAI.68.5.2470-2474.2000.
22. Barth H, Pfeifer G, Hofmann F, Maier E, Benz R, Aktories K. 2001. Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells. J Biol Chem 276:10670-10676. http://dx.doi.org/10.1074/jbc.M009445200.
23. Pfeifer G, Schirmer J, Leemhuis J, Busch C, Meyer DK, Aktories K, Barth H. 2003. Cellular uptake of Clostridium difficile toxin B. Translocation of the N-terminal catalytic domain into the cytosol of eukaryotic cells. J Biol Chem 278:44535-44541. http://dx.doi.org/10.1074/jbc.M307540200.
24. Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O, Schrattenholz A, Schild H, von Eichel-Streiber C. 2007. Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446:415-419. http://dx.doi.org/10.1038/nature05622.
25. Egerer M, Giesemann T, Jank T, Satchell KJ, Aktories K. 2007. Autocatalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity. J Biol Chem 282:25314-25321. http://dx.doi.org/10.1074/jbc.M703062200.
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 Chem 272:11074-11078. http://dx.doi.org/10.1074/jbc.272.17.11074.
27. Nottrott S, Schoentaube J, Genth H, Just I, Gerhard R. 2007. Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases. Apoptosis 12:1443-1453. http://dx.doi.org/10.1007/s10495-007-0074-8.
28. 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. 2011. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat Med 17:1136-1141. http://dx.doi.org/10.1038/nm.2405.
29. Egerer M, Giesemann T, Herrmann C, Aktories K. 2009. Autocatalytic processing of Clostridium difficile toxin B. Binding of inositol hexakisphosphate. J Biol Chem 284:3389-3395. http://dx.doi.org/10.1074/jbc.M806002200.
30. Li S, Shi L, Yang Z, Feng H. 2013. Cytotoxicity of Clostridium difficile toxin B does not require cysteine protease-mediated autocleavage and release of the glucosyltransferase domain into the host cell cytosol. Pathog Dis 67:11-18. http://dx.doi.org/10.1111/2049-632X.12016.
31. Kreimeyer I, Euler F, Marckscheffel A, Tatge H, Pich A, Olling A, Schwarz J, Just I, Gerhard R. 2011. Autoproteolytic cleavage mediates cytotoxicity of Clostridium difficile toxin A. Naunyn Schmiedebergs Arch Pharmacol 383:253-262. http://dx.doi.org/10.1007/s00210-010-0574-x.
32. Kim H, Rhee SH, Pothoulakis C, LaMont JT. 2009. Clostridium difficile toxin A binds colonocyte Src causing dephosphorylation of focal adhesion kinase and paxillin. Exp Cell Res 315:3336-3344. http://dx.doi.org/10.1016/j.yexcr.2009.05.020.
33. Kim H, Rhee SH, Kokkotou E, Na X, Savidge T, Moyer MP, Pothoulakis C, LaMont JT. 2005. 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 280:21237-21245. http://dx.doi.org/10.1074/jbc.M413842200.
34. Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Haslam DB, Goldenring JR, Lacy DB. 2012. Clostridium difficile toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. PLoS Pathog 8:e1003072. http://dx.doi.org/10.1371/journal.ppat.1003072.
35. Farrow MA, Chumbler NM, Lapierre LA, Franklin JL, Rutherford SA, Goldenring JR, Lacy DB. 2013. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Proc Natl Acad Sci U S A 110:18674-18679. http://dx.doi.org/10.1073/pnas.1313658110.
36. Donald RG, Flint M, Kalyan N, Johnson E, Witko SE, Kotash C, Zhao P, Megati S, Yurgelonis I, Lee PK, Matsuka YV, Severina E, Deatly A, Sidhu M, Jansen KU, Minton NP, Anderson AS. 2013. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 159:1254-1266. http://dx.doi.org/10.1099/mic.0.066712-0.
37. Wohlan K, Goy S, Olling A, Srivaratharajan S, Tatge H, Genth H, Gerhard R. 2014. Pyknotic cell death induced by Clostridium difficile TcdB: Chromatin condensation and nuclear blister are induced independently of the glucosyltransferase activity. Cell Microbiol 16:1678-1692. http://dx.doi.org/10.1111/cmi.12317.
38. Zhang Z, Park M, Tam J, Auger A, Beilhartz GL, Lacy DB, Melnyk RA. 2014. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Proc Natl Acad Sci U S A 111:3721-3726. http://dx.doi.org/10.1073/pnas.1400680111.
39. Li H, Carrion-Vazquez M, Oberhauser AF, Marszalek PE, Fernandez JM. 2000. Point mutations alter the mechanical stability of immunoglobulin modules. Nat Struct Biol 7:1117-1120. http://dx.doi.org/10.1038/81964.
40. Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R. 1993. Naturally occurring antibodies devoid of light chains. Nature 363:446-448. http://dx.doi.org/10.1038/363446a0.
41. Arbabi Ghahroudi M, Desmyter A, Wyns L, Hamers R, Muyldermans S. 1997. Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett 414:521-526. http://dx.doi.org/10.1016/S0014-5793(97)01062-4.
42. Hussack G, Arbabi-Ghahroudi M, van Faassen H, Songer JG, Ng KK, MacKenzie R, Tanha J. 2011. Neutralization of Clostridium difficile toxin A with single-domain antibodies targeting the cell receptor binding domain. J Biol Chem 286:8961-8976. http://dx.doi.org/10.1074/jbc.M110.198754.
43. Dumoulin M, Conrath K, Van Meirhaeghe A, Meersman F, Heremans K, Frenken LG, Muyldermans S, Wyns L, Matagne A. 2002. Singledomain antibody fragments with high conformational stability. Protein Sci 11:500-515. http://dx.doi.org/10.1110/ps.34602.
44. Arbabi-Ghahroudi M, Tanha J, MacKenzie R. 2009. Isolation of monoclonal antibody fragments from phage display libraries. Methods Mol Biol 502:341-364. http://dx.doi.org/10.1007/978-1-60327-565-1_20.
45. Koide A, Tereshko V, Uysal S, Margalef K, Kossiakoff AA, Koide S. 2007. Exploring the capacity of minimalist protein interfaces: interface energetics and affinity maturation to picomolar KD of a single-domain antibody with a flat paratope. J Mol Biol 373:941-953. http://dx.doi.org/10.1016/j.jmb.2007.08.027.
46. De Genst E, Silence K, Decanniere K, Conrath K, Loris R, Kinne J, Muyldermans S, Wyns L. 2006. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc Natl Acad SciUS A 103:4586-4591. http://dx.doi.org/10.1073/pnas.0505379103.
47. Koch-Nolte F, Reyelt J, Schossow B, Schwarz N, Scheuplein F, Rotherburg S, Haag F, Alzogaray V, Cauerhff A, Goldbaum FA. 2007. Single domain antibodies from llama effectively and specifically block T cell ecto-ADP-ribosyltransferase ART2.2 in vivo. FASEB J 21:3490-3498. http://dx.doi.org/10.1096/fj.07-8661com.
48. Adams H, Brummelhuis W, Maassen B, van Egmond N, El Khattabi M, Detmers F, Hermans P, Braam B, Stam J, Verrips T. 2009. Specific immuno capturing of the staphylococcal superantigen toxic-shock syndrome toxin-1 in plasma. Biotechnol Bioeng 104:143-151. http://dx.doi.org/10.1002/bit.22365.
49. Tremblay JM, Mukherjee J, Leysath CE, Debatis M, Ofori K, Baldwin K, Boucher C, Peters R, Beamer G, Sheoran A, Bedenice D, Tzipori S, Shoemaker CB. 2013. A single VHH-based toxin neutralizing agent and an effector antibody protects mice against challenge with Shiga toxins 1 and 2. Infect Immun 81:4592-4603. http://dx.doi.org/10.1128/IAI.01033-13.
50. Hussack G, Arbabi-Ghahroudi M, Mackenzie CR, Tanha J. 2012. Isolation and characterization of Clostridium difficile toxin-specific singledomain antibodies. Methods Mol Biol 911:211-239. http://dx.doi.org/10.1007/978-1-61779-968-6_14.
51. Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, Chen K, Yu H, Tremblay JM, Chen X, Piepenbrink KH, Sundberg EJ, Kelly CP, Bai G, Shoemaker CB, Feng H. 2014. A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis 210:964-972. http://dx.doi.org/10.1093/infdis/jiu196.
52. Yang G, Zhou B, Wang J, He X, Sun X, Nie W, Tzipori S, Feng H. 2008. Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium. BMC Microbiol 8:192. http://dx.doi.org/10.1186/1471-2180-8-192.
53. Wang H, Sun X, Zhang Y, Li S, Chen K, Shi L, Nie W, Kumar R, Tzipori S, Wang J, Savidge T, Feng H. 2012. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun 80:2678-2688. http://dx.doi.org/10.1128/IAI.00215-12.
54. Zhang Y, Shi L, Li S, Yang Z, Standley C, ZhuGe R, Savidge T, Wang X, Feng H. 2013. A segment of 97 amino acids within the translocation domain of Clostridium difficile toxin B is essential for toxicity. PLoS One 8:e58634. http://dx.doi.org/10.1371/journal.pone.0058634.
55. Steele J, Chen K, Sun X, Zhang Y, Wang H, Tzipori S, Feng H. 2012. Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models. J Infect Dis 205:384-391. http://dx.doi.org/10.1093/infdis/jir748.
56. Rupnik M, Pabst S, Rupnik M, von Eichel-Streiber C, Urlaub H, Soling HD. 2005. Characterization of the cleavage site and function of resulting cleavage fragments after limited proteolysis of Clostridium difficile toxin B (TcdB) by host cells. Microbiology 151:199-208. http://dx.doi.org/10.1099/mic.0.27474-0.
57. Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE, Garcia KC, Bogyo M. 2011. Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat Struct Mol Biol 18:364-371. http://dx.doi.org/10.1038/nsmb.1990.
58. Lanis JM, Heinlen LD, James JA, Ballard JD. 2013. Clostridium difficile 027/BI/NAP1 encodes a hypertoxic and antigenically variable form of TcdB. PLoS Pathog 9:e1003523. http://dx.doi.org/10.1371/journal.ppat.1003523.
59. Just I, Selzer J, von Eichel-Streiber C, Aktories K. 1995. The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. J Clin Invest 95:1026-1031. http://dx.doi.org/10.1172/JCI117747.
60. Alzogaray V, Danquah W, Aquirre A, Urrutia M, Berquer P, Garcia Vescovi E, Haag F, Koch-Nolte F, Goldbaum FA. 2011. Single-domain llama antibodies as specific intracellular inhibitors of SpvB, the actin ADPribosylating toxin of Salmonella typhimurium. FASEB J 25:526-534. http://dx.doi.org/10.1096/fj.10-162958.
61. He X, Wang J, Steele J, Sun X, Nie W, Tzipori S, Feng H. 2009. An ultrasensitive rapid immunocytotoxicity assay for detecting Clostridium difficile toxins. J Microbiol Methods 78:97-100. http://dx.doi.org/10.1016/j.mimet.2009.04.007.
62. Qualman SJ, Petric M, Karmali MA, Smith CR, Hamilton SR. 1990. Clostridium difficile invasion and toxin circulation in fatal pediatric pseudomembranous colitis. Am J Clin Pathol 94:410-416.