Virulence factors of Clostridium difficile and their role during infection

Anaerobe

Volumn 37, Issue , 2016, Pages 13-24

  Janoir, Claire ^a  

^a University Paris Sud   (France)

Author keywords

Adhesion; Clostridium difficile; Colonization; Toxins; Virulence

Indexed keywords

ADHESIN; BACTERIAL PROTEIN; BACTERIAL TOXIN; CHAPERONIN 60; CLOSTRIDIUM DIFFICILE BINARY TOXIN; CLOSTRIDIUM DIFFICILE TOXIN A; CLOSTRIDIUM DIFFICILE TOXIN B; CLOSTRIDIUM DIFFICILE VIRULENCE FACTOR; COLLAGEN BINDING PROTEIN; COLLAGEN BINDING PROTEIN CBPA; CWP PROTEIN; CWP66 ADHESIN; CWPV PROTEIN; CYCLIC DI GMP; CYCLIC GMP DERIVATIVE; CYSTEINE PROTEINASE; CYSTEINE PROTEINASE CWP84; FIBRONECTIN BINDING PROTEIN; FIBRONECTIN BINDING PROTEIN FBP68; LIPOPROTEIN CD630 08730; MICROBIAL SURFACE COMPONENT RECOGNIZING ADHESIVE MATRIX MOLECULE; PROTEINASE; SLP PROTEIN; UNCLASSIFIED DRUG; VIRULENCE FACTOR;

ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL COLONIZATION; BACTERIAL FLAGELLUM; BACTERIAL GENE; BACTERIAL STRAIN; BACTERIAL VIRULENCE; BACTERIUM ADHERENCE; BACTERIUM PILUS; BIOFILM; CLOSTRIDIUM DIFFICILE INFECTION; HOST PATHOGEN INTERACTION; HOST RESISTANCE; HUMAN; NONHUMAN; PATHOPHYSIOLOGY; PEPTOCLOSTRIDIUM DIFFICILE; PRIORITY JOURNAL; PROTEIN FUNCTION; SECOND MESSENGER; TOXICITY; TOXIN SYNTHESIS; TYPE IV PILUS; ANIMAL; CLOSTRIDIUM INFECTION; IMMUNOLOGY; MICROBIOLOGY; PATHOGENICITY; PHYSIOLOGY;

ANIMALS; BACTERIAL ADHESION; BACTERIAL PROTEINS; BACTERIAL TOXINS; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; HUMANS; VIRULENCE FACTORS;

EID: 84957045548     PISSN: 10759964     EISSN: 10958274     Source Type: Journal    
DOI: 10.1016/j.anaerobe.2015.10.009     Document Type: Article

References (166)

1. Rupnik M., Wilcox M.H., Gerding D.N. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat. Rev. Microbiol. 2009, 7:526-536.
2. Zacharioudakis I.M., Zervou F.N., Pliakos E.E., Ziakas P.D., Mylonakis E. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis. Am. J. Gastroenterol. 2015, 110:381-390.
3. Rousseau C., Poilane I., De Pontual L., Maherault A.C., Le Monnier A., Collignon A. Clostridium difficile carriage in healthy infants in the community: a potential reservoir for pathogenic strains. Clin. Infect. Dis. 2012, 55:1209-1215.
4. McDonald L.C., Killgore G.E., Thompson A., Owens R.C., Kazakova S.V., Sambol S.P., et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 2005, 353:2433-2441.
5. Warny M., Pepin J., Fang A., Killgore G., Thompson A., Brazier J., et al. 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.
6. Poxton I.R. The changing faces of Clostridium difficile: a personal reflection of the past 34 years. Anaerobe 2013, 24:124-127.
7. Goorhuis A., Bakker D., Corver J., Debast S.B., Harmanus C., Notermans D.W., et al. Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin. Infect. Dis. 2008, 47:1162-1170.
8. Knetsch C.W., Connor T.R., Mutreja A., van Dorp S.M., Sanders I.M., Browne H.P., et al. Whole genome sequencing reveals potential spread of Clostridium difficile between humans and farm animals in the Netherlands, 2002 to 2011. Euro Surveill. 2014, 19:20954.
9. Sarker M.R., Paredes-Sabja D. Molecular basis of early stages of Clostridium difficile infection: germination and colonization. Future Microbiol. 2012, 7:933-943.
10. Seekatz A.M., Young V.B. Clostridium difficile and the microbiota. J. Clin. Investig. 2014, 124:4182-4189.
11. Wright A., Wait R., Begum S., Crossett B., Nagy J., Brown K., Fairweather N. Proteomic analysis of cell surface proteins from Clostridium difficile. Proteomics 2005, 5:2443-2452.
12. Davis K.M., Weiser J.N. Modifications to the peptidoglycan backbone help bacteria to establish infection. Infect. Immun. 2011, 79:562-570.
13. Peltier J., Courtin P., El Meouche I., Lemée L., Chapot-Chartier M.P., Pons J.L. Clostridium difficile has an original peptidoglycan structure with a high level of N-acetylglucosamine deacetylation and mainly 3-3 cross-links. J. Biol. Chem. 2011, 286:29053-29062.
14. Ho T.D., Williams K.B., Chen Y., Helm R.F., Popham D.L., Ellermeier C.D. Clostridium difficile extracytoplasmic function σ factor σV regulates lysozyme resistance and is necessary for pathogenesis in the hamster model of infection. Infect. Immun. 2014, 82:2345-2355.
15. Ho T.D., Ellermeier C.D. PrsW is required for colonization, resistance to antimicrobial peptides, and expression of extracytoplasmic function σ factors in Clostridium difficile. Infect. Immun. 2011, 79:3229-3238.
16. McQuade R., Roxas B., Viswanathan V.K., Vedantam G. Clostridium difficile clinical isolates exhibit variable susceptibility and proteome alterations upon exposure to mammalian cationic antimicrobial peptides. Anaerobe 2012, 18:614-620.
17. Furci L., Baldan R., Bianchini V., Trovato A., Ossi C., Cichero P., Cirillo D.M. New role for human α-defensin 5 in the fight against hypervirulent Clostridium difficile strains. Infect. Immun. 2015, 83:986-995.
18. Revilla-Guarinos A., Gebhard S., Mascher T., Zúñiga M. Defence against antimicrobial peptides: different strategies in Firmicutes. Environ. Microbiol. 2014, 16:1225-1237.
19. McBride S.M., Sonenshein A.L. The dlt operon confers resistance to cationic antimicrobial peptides in Clostridium difficile. Microbiology 2011, 157:1457-1465.
20. McBride S.M., Sonenshein A.L. Identification of a genetic locus responsible for antimicrobial peptide resistance in Clostridium difficile. Infect. Immun. 2011, 79:167-176.
21. Giesemann T., Guttenberg G., Aktories K. Human alpha-defensins inhibit Clostridium difficile toxin B. Gastroenterology 2008, 134:2049-2058.
22. Hing T.C., Ho S., Shih D.Q., Ichikawa R., Cheng M., Chen J. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut 2013, 62:1295-1305.
23. Naaber P., Lehto E., Salminen S., Mikelsaar M. Inhibition of adhesion of Clostridium difficile to Caco-2 cells. FEMS Immunol. Med. Microbiol. 1996, 14:205-209.
24. Drudy D., O'Donoghue D.P., Baird A., Fenelon L., O'Farrelly C. Flow cytometric analysis of Clostridium difficile adherence to human intestinal epithelial cells. J. Med. Microbiol. 2001, 50:526-534.
25. Karjalainen T., Barc M.C., Collignon A., Trollé S., Boureau H., Cotte-Laffitte, Bourlioux P. Cloning of a genetic determinant from Clostridium difficile involved in adherence to tissue culture cells and mucus. Infect. Immun. 1994, 62:4347-4355.
26. Cerquetti M., Serafino A., Sebastianelli A., Mastrantonio P. Binding of Clostridium difficile to Caco-2 epithelial cell line and to extracellular matrix proteins. FEMS Immunol. Med. Microbiol. 2002, 32:211-218.
27. Borriello S.P., Welch A.R., Barclay F.E., Davies H.A. Mucosal association by Clostridium difficile in the hamster gastrointestinal tract. J. Med. Microbiol. 1988, 25:191-196.
28. Lawley T.D., Clare S., Walker A.W., Goulding D., Stabler R.A., Croucher N., et al. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 2009, 77:3661-3669.
29. Spigaglia P., Barketi-Klai A., Collignon A., Mastrantonio P., Barbanti F., Rupnik M., et al. Surface-layer (S-layer) of human and animal Clostridium difficile strains and their behaviour in adherence to epithelial cells and intestinal colonization. J. Med. Microbiol. 2013, 62:1386-1393.
30. Borriello S.P. Clostridium difficile and its toxin in the gastrointestinal tract in health and disease. Res. Clin. Forums 1979, 1:33-35.
31. Lyra A., Forssten S., Rolny P., Wettergren Y., Lahtinen S.J., Salli K., et al. Comparison of bacterial quantities in left and right colon biopsies and faeces. World J. Gastroenterol. 2012, 18:4404-4411.
32. Fagan R.P., Janoir C., Collignon A., Mastrantonio P., Poxton I.R., Fairweather N.F. A proposed nomenclature for cell wall proteins of Clostridium difficile. J. Med. Microbiol. 2011, 60:1225-1228.
33. Willing S.E., Candela T., Shaw H.A., Seager Z., Mesnage S., Fagan R.P., Fairweather N.F. Clostridium difficile surface proteins are anchored to the cell wall using CWB2 motifs that recognise the anionic polymer PSII. Mol. Microbiol. 2015, 96:596-608.
34. Fagan R.P., Fairweather N.F. Clostridium difficile has two parallel and essential Sec secretion systems. J. Biol. Chem. 2011, 286:27483-27493.
35. Karjalainen T., Saumier N., Barc M.C., Delmée M., Collignon A. Clostridium difficile genotyping based on slpA variable region in S-layer gene sequence: an alternative to serotyping. J. Clin. Microbiol. 2002, 40:2452-2458.
36. Savariau-Lacomme M.P., Lebarbier C., Karjalainen T., Collignon A., Janoir C. Transcription and analysis of polymorphism in a cluster of genes encoding surface-associated proteins of Clostridium difficile. J. Bacteriol. 2003, 185:4461-4470.
37. Dingle K.E., Didelot X., Ansari M.A., Eyre D.W., Vaughan A., Griffiths D., et al. Recombinational switching of the Clostridium difficile S-layer and a novel glycosylation gene cluster revealed by large-scale whole-genome sequencing. J. Infect. Dis. 2013, 207:675-686.
38. Biazzo M., Cioncada R., Fiaschi L., Tedde V., Spigaglia P., Mastrantonio P., et al. Diversity of cwp loci in clinical isolates of Clostridium difficile. J. Med. Microbiol. 2013, 62:1444-1452.
39. Drudy D., Calabi E., Kyne L., Sougioultzis S., Kelly E., Fairweather N., Kelly C.P. Human antibody response to surface layer proteins in Clostridium difficile infection. FEMS Immunol. Med. Microbiol. 2004, 41:237-242.
40. Péchiné S., Gleizes A., Janoir C., Gorges-Kergot R., Barc M.C., Delmée M., Collignon A. Immunological properties of surface proteins of Clostridium difficile. J. Med. Microbiol. 2005, 54:193-196.
41. Péchiné S., Janoir C., Collignon A. Variability of Clostridium difficile surface proteins and specific serum antibody response in patients with Clostridium difficile-associated disease. J. Clin. Microbiol. 2005, 43:5018-5025.
42. Wright A., Drudy D., Kyne L., Brown K., Fairweather N.F. Immunoreactive cell wall proteins of Clostridium difficile identified by human sera. J. Med. Microbiol. 2008, 57:750-756.
43. Calabi E., Ward S., Wren B., Paxton T., Panico M., Morris H., et al. Molecular characterization of the surface layer proteins from Clostridium difficile. Mol. Microbiol. 2001, 40:1187-1199.
44. Kirby J.M., Ahern H., Roberts A.K., Kumar V., Freeman Z., Acharya K.R., Shone C.C. Cwp84, a surface-associated cysteine protease, plays a role in the maturation of the surface layer of Clostridium difficile. J. Biol. Chem. 2009, 284:34666-34673.
45. Dang T.T.H., de la Riva L., Fagan R.P., Storck E.M., Heal W.P., Janoir C., et al. Chemical probes of surface layer biogenesis in Clostridium difficile. ACS Chem. Biol. 2010, 5:279-285.
46. Fagan R.P., Albesa-Jové D., Qazi O., Svergun D.I., Brown K.A., Fairweather N.F. Structural insights into the molecular organization of the S-layer from Clostridium difficile. Mol. Microbiol. 2009, 71:1308-1322.
47. Qazi O., Hitchen P., Tissot B., Panico M., Morris H.R., Dell A., Fairweather N. Mass spectrometric analysis of the S-layer proteins from Clostridium difficile demonstrates the absence of glycosylation. J. Mass Spectrom. 2009, 44:368-374.
48. Calabi E., Calabi F., Phillips A.D., Fairweather N.F. Binding of Clostridium difficile surface layer proteins to gastrointestinal tissues. Infect. Immun. 2002, 70:5770-5778.
49. Merrigan M.M., Venugopal A., Roxas J.L., Anwar F., Mallozzi M.J., Roxas B.A., et al. Surface-layer protein A (SlpA) is a major contributor to host-cell adherence of Clostridium difficile. PLoS One 2013, 8:e78404.
50. Ryan A., Lynch M., Smith S.M., Amu S., Nel H.J., McCoy C.E., et al. A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. PLoS Pathog. 2011, 7:e1002076.
51. Collins L.E., Lynch M., Marszalowska I., Kristek M., Rochfort K., O'Connell M., et al. Surface layer proteins isolated from Clostridium difficile induce clearance responses in macrophages. Microbes Infect. 2014, 16:391-400.
52. Bianco M., Fedele G., Quattrini A., Spigaglia P., Barbanti F., Mastrantonio P., Ausiello C.M. Immunomodulatory activities of surface-layer proteins obtained from epidemic and hypervirulent Clostridium difficile strains. J. Med. Microbiol. 2011, 60:1162-1167.
53. Vohra P., Poxton I.R. Induction of cytokines in a macrophage cell line by proteins of Clostridium difficile. FEMS Immunol. Med. Microbiol. 2012, 65:96-104.
54. Dembek M., Barquist L., Boinett C.J., Cain A.K., Mayho M., Lawley T.D., et al. High-throughput analysis of gene essentiality and sporulation in Clostridium difficile. MBio 2015, 6:e02383.
55. Bradshaw W.J., Kirby J.M., Thiyagarajan N., Chambers C.J., Davies A.H., Roberts A.K., et al. The structure of the cysteine protease and lectin-like domains of Cwp84, a surface layer-associated protein from Clostridium difficile. Acta Crystallogr. D. Biol. Crystallogr. 2014, 70:1983-1993.
56. Bradshaw W.J., Roberts A.K., Shone C.C., Acharya K.R. Cwp84, a Clostridium difficile cysteine protease, exhibits conformational flexibility in the absence of its propeptide. Acta Crystallogr. F. Struct. Biol. Commun. 2015, 71:295-303.
57. de la Riva L., Willing S.E., Tate E.W., Fairweather N.F. Roles of cysteine proteases Cwp84 and Cwp13 in biogenesis of the cell wall of Clostridium difficile. J. Bacteriol. 2011, 193:3276-3285.
58. Chapetón-Montes D., Candela T., Collignon A., Janoir C. Localization of the Clostridium difficile cysteine protease Cwp84 and insights into its maturation process. J. Bacteriol. 2011, 193:5314-5321.
59. Janoir C., Péchiné S., Grosdidier C., Collignon A. Cwp84, a surface-associated protein of Clostridium difficile, is a cysteine protease with degrading activity on extracellular matrix proteins. J. Bacteriol. 2007, 189:7174-7180.
60. Waligora A.J., Hennequin C., Mullany P., Bourlioux P., Collignon A., Karjalainen T. Characterization of a cell surface protein of Clostridium difficile with adhesive properties. Infect. Immun. 2001, 69:2144-2153.
61. Waligora A.J., Barc M.C., Bourlioux P., Collignon A., Karjalainen T. Clostridium difficile cell attachment is modified by environmental factors. Appl. Environ. Microbiol. 1999, 65:4234-4238.
62. Reynolds C.B., Emerson J.E., de la Riva L., Fagan R.P., Fairweather N.F. The Clostridium difficile cell wall protein CwpV is antigenically variable between strains, but exhibits conserved aggregation-promoting function. PLoS Pathog. 2011, 7:e1002024.
63. Dembek M., Reynolds C.B., Fairweather N.F. Clostridium difficile cell wall protein CwpV undergoes enzyme-independent intramolecular autoproteolysis. J. Biol. Chem. 2012, 287:1538-1544.
64. Emerson J.E., Reynolds C.B., Fagan R.P., Shaw H.A., Goulding D., Fairweather N.F. A novel genetic switch controls phase variable expression of CwpV, a Clostridium difficile cell wall protein. Mol. Microbiol. 2009, 74:541-556.
65. Martin M.J., Clare S., Goulding D., Faulds-Pain A., Barquist L., Browne H.P., et al. The agr locus regulates virulence and colonization genes in Clostridium difficile 027. J. Bacteriol. 2013, 195:3672-3681.
66. Sekulovic O., Bedoya M.O., Fivian-Hughes A.S., Fairweather N.F., Fortier L.C. The Clostridium difficile cell wall protein CwpV confers phase-variable phage resistance. Mol. Microbiol. 2015, 98:329-342.
67. Sekulovic O., Fortier L.C. Global transcriptional response of Clostridium difficile carrying the CD38 prophage. Appl. Environ. Microbiol. 2015, 81:1364-1374.
68. Hennequin C., Janoir C., Barc M.C., Collignon A., Karjalainen T. Identification and characterization of a fibronectin-binding protein from Clostridium difficile. Microbiology 2003, 149:2779-2787.
69. Lin Y.P., Kuo C.J., Koleci X., McDonough S.P., Chang Y.F. Manganese binds to Clostridium difficile Fbp68 and is essential for fibronectin binding. J. Biol. Chem. 2011, 286:3957-3969.
70. Barketi-Klai A., Hoys S., Lambert-Bordes S., Collignon A., Kansau I. Role of fibronectin-binding protein A in Clostridium difficile intestinal colonization. J. Med. Microbiol. 2011, 60:1155-1161.
71. Janvilisri T., Scaria J., Thompson A.D., Nicholson A., Limbago B.M., Arroyo L.G., et al. Microarray identification of Clostridium difficile core components and divergent regions associated with host origin. J. Bacteriol. 2009, 191:3881-3891.
72. Donahue E.H., Dawson L.F., Valiente E., Firth-Clark S., Major M.R., Littler E., et al. Clostridium difficile has a single sortase, SrtB, that can be inhibited by small-molecule inhibitors. BMC Microbiol. 2014, 14:219.
73. Tulli L., Marchi S., Petracca R., Shaw H.A., Fairweather N.F., Scarselli M., et al. CbpA: a novel surface exposed adhesin of Clostridium difficile targeting human collagen. Cell. Microbiol. 2013, 15:1674-1687.
74. Janoir C., Denève C., Bouttier S., Barbut F., Hoys S., Caleechum L., et al. Adaptive strategies and pathogenesis of Clostridium difficile from in vivo transcriptomics. Infect. Immun. 2013, 81:3757-3769.
75. Sebaihia M., Wren B.W., Mullany P., Fairweather N.F., Minton N., Stabler R., et al. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat. Genet. 2006, 38:779-786.
76. Kovacs-Simon A., Leuzzi R., Kasendra M., Minton N., Titball R.W., Michell S.L. Lipoprotein CD0873 is a novel adhesin of Clostridium difficile. J. Infect. Dis. 2014, 210:274-284.
77. Hennequin C., Porcheray F., Waligora-Dupriet A., Collignon A., Barc M., Bourlioux P., Karjalainen T. GroEL (Hsp60) of Clostridium difficile is involved in cell adherence. Microbiology 2001, 147:87-96.
78. Péchiné S., Hennequin C., Boursier C., Hoys S., Collignon A. Immunization using GroEL decreases Clostridium difficile intestinal colonization. PLoS One 2013, 8:e81112.
79. Cafardi V., Biagini M., Martinelli M., Leuzzi R., Rubino J.T., Cantini F., et al. Identification of a novel zinc metalloprotease through a global analysis of Clostridium difficile extracellular proteins. PLoS One 2013, 8:e81306.
80. Hensbergen P.J., Klychnikov O.I., Bakker D., van Winden V.J., Ras N., Kemp A.C., et al. A novel secreted metalloprotease (CD2830) from Clostridium difficile cleaves specific proline sequences in LPXTG cell surface proteins. Mol. Cell. Proteom. 2014, 13:1231-1244.
81. Bordeleau E., Fortier L.C., Malouin F., Burrus V. c-di-GMP turn-over in Clostridium difficile is controlled by a plethora of diguanylate cyclases and phosphodiesterases. PLoS Genet. 2011, 7:e1002039.
82. Sudarsan N., Lee E.R., Weinberg Z., Moy R.H., Kim J.N., Link K.H., Breaker R.R. Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science 2008, 321:411-413.
83. Soutourina O.A., Monot M., Boudry P., Saujet L., Pichon C., Sismeiro O., et al. Genome-wide identification of regulatory RNAs in the human pathogen Clostridium difficile. PLoS Genet. 2013, 9:e1003493.
84. Tasteyre A., Barc M.C., Karjalainen T., Dodson P., Hyde S., Bourlioux P., Borriello P. A Clostridium difficile gene encoding flagellin. Microbiology 2000, 146:957-966.
85. Tasteyre A., Karjalainen T., Avesani V., Delmée M., Collignon A., Bourlioux P., Barc M.C. Molecular characterization of fliD gene encoding flagellar cap and its expression among Clostridium difficile isolates from different serogroups. J. Clin. Microbiol. 2001, 39:1178-1183.
86. Twine S.M., Reid C.W., Aubry A., McMullin D.R., Fulton K.M., Austin J., Logan S.M. Motility and flagellar glycosylation in Clostridium difficile. J. Bacteriol. 2009, 191:7050-7062.
87. Faulds-Pain A., Twine S.M., Vinogradov E., Strong P.C., Dell A., Buckley A.M., et al. The post-translational modification of the Clostridium difficile flagellin affects motility, cell surface properties and virulence. Mol. Microbiol. 2014, 94:272-289.
88. Stabler R.A., Gerding D.N., Songer J.G., Drudy D., Brazier J.S., Trinh H.T., et al. Comparative phylogenomics of Clostridium difficile reveals clade specificity and microevolution of hypervirulent strains. J. Bacteriol. 2006, 188:7297-7305.
89. Dawson L.F., Valiente E., Wren B.W. Clostridium difficile - a continually evolving and problematic pathogen. Infect. Genet. Evol. 2009, 9:1410-1417.
90. Derman Y., Söderholm H., Lindström M., Korkeala H. Role of csp genes in NaCl, pH, and ethanol stress response and motility in Clostridium botulinum ATCC 3502. Food Microbiol. 2015, 46:463-470.
91. Soutourina O.A., Bertin P.N. Regulation cascade of flagellar expression in gram-negative bacteria. FEMS Microbiol. Rev. 2003, 27:505-523.
92. Saujet L., Monot M., Dupuy B., Soutourina O., Martin-Verstraete I. The key sigma factor of transition phase, SigH, controls sporulation, metabolism, and virulence factor expression in Clostridium difficile. J. Bacteriol. 2011, 193:3186-3196.
93. Scaria J., Janvilisri T., Fubini S., Gleed R.D., McDonough S.P., Chang Y.F. Clostridium difficile transcriptome analysis using pig ligated loop model reveals modulation of pathways not modulated in vitro. J. Infect. Dis. 2011, 203:1613-1620.
94. Tasteyre A., Barc M.C., Collignon A., Boureau H., Karjalainen T. Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization. Infect. Immun. 2001, 69:7937-7940.
95. Dingle T.C., Mulvey G.L., Armstrong G.D. Mutagenic analysis of the Clostridium difficile flagellar proteins, FliC and FliD, and their contribution to virulence in hamsters. Infect. Immun. 2011, 79:4061-4067.
96. Baban S.T., Kuehne S.A., Barketi-Klai A., Cartman S.T., Kelly M.L., Hardie K.R., et al. The role of flagella in Clostridium difficile pathogenesis: comparison between a non-epidemic and an epidemic strain. PLoS One 2013, 8:e73026.
97. Barketi-Klai A., Monot M., Hoys S., Lambert-Bordes S., Kuehne S.A., Minton N., et al. The flagellin FliC of Clostridium difficile is responsible for pleiotropic gene regulation during in vivo infection. PLoS One 2014, 9:e96876.
98. Aubry A., Hussack G., Chen W., KuoLee R., Twine S.M., Fulton K.M., et al. Modulation of toxin production by the flagellar regulon in Clostridium difficile. Infect. Immun. 2012, 80:3521-3532.
99. McKee R.W., Mangalea M.R., Purcell E.B., Borchardt E.K., Tamayo R. The second messenger cyclic Di-GMP regulates Clostridium difficile toxin production by controlling expression of sigD. J. Bacteriol. 2013, 195:5174-5185.
100. El Meouche I., Peltier J., Monot M., Soutourina O., Pestel-Caron M., Dupuy B., Pons J.L. Characterization of the SigD regulon of C. difficile and its positive control of toxin production through the regulation of tcdR. PLoS One 2013, 8:e83748.
101. Purcell E.B., McKee R.W., McBride S.M., Waters C.M., Tamayo R. Cyclic diguanylate inversely regulates motility and aggregation in Clostridium difficile. J. Bacteriol. 2012, 194:3307-3316.
102. Yoshino Y., Kitazawa T., Ikeda M., Tatsuno K., Yanagimoto S., Okugawa S., et al. Clostridium difficile flagellin stimulates toll-like receptor 5, and toxin B promotes flagellin-induced chemokine production via TLR5. Life Sci. 2013, 92:211-217.
103. Stevenson E., Minton N.P., Kuehne S.A. The role of flagella in Clostridium difficile pathogenicity. Trends Microbiol. 2015, 23:275-282.
104. Borriello S.P., Davies H.A., Barclay F.E. Detection of fimbriae amongst strains of Clostridium difficile. FEMS Microbiol. Lett. 1988, 49:65-67.
105. Goulding D., Thompson H., Emerson J., Fairweather N.F., Dougan G., Douce G.R. Distinctive profiles of infection and pathology in hamsters infected with Clostridium difficile strains 630 and B1. Infect. Immun. 2009, 77:5478-5485.
106. Maldarelli G.A., De Masi L., von Rosenvinge E.C., Carter M., Donnenberg M.S. Identification, immunogenicity, and cross-reactivity of type IV pilin and pilin-like proteins from Clostridium difficile. Pathog. Dis. 2014, 71:302-314.
107. Piepenbrink K.H., Maldarelli G.A., Martinez de la Peña C.F., Dingle T.C., Mulvey G.L., Lee A., et al. Structural and evolutionary analyses show unique stabilization strategies in the type IV pili of Clostridium difficile. Structure 2015, 23:385-396.
108. Bordeleau E., Purcell E.B., Lafontaine D.A., Fortier L.C., Tamayo R., Burrus V. Cyclic di-GMP riboswitch-regulated type IV pili contribute to aggregation of Clostridium difficile. J. Bacteriol. 2015, 197:819-832.
109. Dawson L.F., Valiente E., Faulds-Pain A., Donahue E.H., Wren B.W. Characterisation of Clostridium difficile biofilm formation, a role for Spo0A. PLoS One 2012, 7:e50527.
110. Dapa T., Leuzzi R., Ng Y.K., Baban S.T., Adamo R., Kuehne S.A., et al. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile. J. Bacteriol. 2013, 195:545-555.
111. Pantaléon V., Soavelomandroso A.P., Bouttier S., Briandet R., Roxas B., Chu M., et al. The Clostridium difficile protease Cwp84 modulates both biofilm formation and cell-surface properties. PLoS One 2015, 1:e0124971.
112. Semenyuk E.G., Laning M.L., Foley J., Johnston P.F., Knight K.L., Gerding D.N., Driks A. Spore formation and toxin production in Clostridium difficile biofilms. PLoS One 2014, 9:e87757.
113. Buckley A, Spencer J, Jukes C, Candlish D, Irvine J, Douce G. Biofilm formation in Clostridium difficile. P84, 5th International Clostridium difficile Symposium. Bled, Slovenia, 19-21 May 2015.
114. Soavelomandroso AP, Bouttier S, Hoys S, Candela T, Janoir C. Spatial organization of tissue-associated bacteria in a Clostridium difficile monoxenic mouse model. P95, 5th International Clostridium difficile Symposium. Bled, Slovenia, 19-21 May 2015.
115. Semenyuk E.G., Poroyko V.A., Johnston P.F., Jones S.E., Knight K.L., Gerding D.N., Driks A. Analysis of bacterial communities during Clostridium difficile infection in the mouse. Infect. Immun. 2015, 83:4383-4391.
116. Crowther G.S., Chilton C.H., Todhunter S.L., Nicholson S., Freeman J., Baines S.D., Wilcox M.H. Comparison of planktonic and biofilm-associated communities of Clostridium difficile and indigenous gut microbiota in a triple-stage chemostat gut model. J. Antimicrob. Chemother. 2014, 69:2137-2147.
117. Hundsberger T., Braun V., Weidmann M., Leukel P., Sauerborn M., von Eichel-Streiber C. Transcription analysis of the genes tcdA-E of the pathogenicity locus of Clostridium difficile. Eur. J. Biochem. 1997, 244:735-742.
118. Mani N., Dupuy B. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:5844-5849.
119. Govind R., Dupuy B. Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS Pathog. 2012, 8:e1002727.
120. Oling A., Seehase S., Minton N.P., Tatge H., Schröter S., Kohlscheen S., et al. Release of TcdA and TcdB from Clostridium difficile cdi 630 is not affected by functional inactivation of the tcdE gene. Microb. Pathog. 2012, 52:92-100.
121. Govind R., Fitzwater L., Nichols R. Observations on the role of TcdE isoforms in Clostridium difficile toxin secretion. J. Bacteriol. 2015, 197:2600-2609.
122. Matamouros S., England P., Dupuy B. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol. Microbiol. 2007, 64:1274-1288.
123. Carter G.P., Douce G.R., Govind R., Howarth P.M., Mackin K.E., Spencer J., et al. The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile. PLoS Pathog. 2011, 7:e1002317.
124. Bakker D., Smits W.K., Kuijper E.J., Corver J. TcdC does not significantly repress toxin expression in Clostridium difficile 630δErm. PLoS One 2012, 7:e43247.
125. Cartman S.T., Kelly M.L., Heeg D., Heap J.T., Minton N.P. Precise manipulation of the Clostridium difficile chromosome reveals a lack of association between the tcdC genotype and toxin production. Appl. Environ. Microbiol. 2012, 78:4683-4690.
126. Murray R., Boyd D., Levett P.N., Mulvey M.R., Alfa M.J. Truncation in the tcdC region of the Clostridium difficile PathLoc of clinical isolates does not predict increased biological activity of Toxin B or Toxin A. BMC Infect. Dis. 2009, 9:103.
127. Goldenberg S.D., French G.L. Lack of association of tcdC type and binary toxin status with disease severity and outcome in toxigenic Clostridium difficile. J. Infect. 2011, 62:355-362.
128. van Leeuwen H.C., Bakker D., Steindel P., Kuijper E.J., Corver J. Clostridium difficile TcdC protein binds four-stranded G-quadruplex structures. Nucleic Acids Res. 2013, 41:2382-2393.
129. Brouwer M.S., Roberts A.P., Hussain H., Williams R.J., Allan E., Mullany P. Horizontal gene transfer converts non-toxigenic Clostridium difficile strains into toxin producers. Nat. Commun. 2013, 4:2601.
130. Bouillaut L., Dubois T., Sonenshein A.L., Dupuy B. Integration of metabolism and virulence in Clostridium difficile. Res. Microbiol. 2015, 166:375-383.
131. Pruitt R.N., Lacy D.B. Toward a structural understanding of Clostridium difficile toxins A and B. Front. Cell Infect. Microbiol. 2012, 2:1-14.
132. Oezguen N., Power T.D., Urvil P., Feng H., Pothoulakis C., Stamler J.S., et al. Clostridial toxins: sensing a target in a hostile gut environment. Gut Microbes 2012, 3:35-41.
133. Shen A. Clostridium difficile toxins: mediators of inflammation. J. Innate Immun. 2012, 4:149-158.
134. Sun X., Hirota S.A. The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection. Mol. Immunol. 2015, 63:193-202.
135. Papatheodorou P., Zamboglou C., Genisyuerek S., Guttenberg G., Aktories K. Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLoS One 2010, 5:e10673.
136. Na X., Kim H., Moyer M.P., Pothoulakis C., LaMont J.T. gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A. Infect. Immun. 2008, 76:2862-2871.
137. 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.
138. Gerhard R., Frenzel E., Goy S., Olling A. Cellular uptake of Clostridium difficile TcdA and truncated TcdA lacking the receptor binding domain. J. Med. Microbiol. 2013, 62:1414-1422.
139. 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. Erratum in: Mol Microbiol 2012;84:1189-90.
140. Yuan P., Zhang H., Cai C., Zhu S., Zhou Y., Yang X., et al. Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. Cell Res. 2015, 25:157-168.
141. LaFrance M.E., Farrow M.A., Chandrasekaran R., Sheng J., Rubin D.H., Lacy D.B. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc. Natl. Acad. Sci. U. S. A. 2015, 112:7073-7078.
142. Schorch B., Song S., van Diemen F.R., Bock H.H., May P., Herz J., et al. 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. 2014, 111:6431-6436.
143. Stabler R.A., He M., Dawson L., Martin M., Valiente E., Corton C., et al. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol. 2009, 10:R102.
144. Stabler R.A., Dawson L.F., Phua L.T., Wren B.W. Comparative analysis of BI/NAP1/027 hypervirulent strains reveals novel toxin B-encoding gene (tcdB) sequences. J. Med. Microbiol. 2008, 57:771-775.
145. Lanis J.M., Barua S., Ballard J.D. Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathog. 2010, 6:e1001061.
146. Lanis J.M., Hightower L.D., Shen A., Ballard J.D. TcdB from hypervirulent Clostridium difficile exhibits increased efficiency of autoprocessing. Mol. Microbiol. 2012, 84:66-76.
147. Lyerly D.M., Saum K.E., MacDonald D.K., Wilkins T.D. Effects of Clostridium difficile toxins given intragastrically to animals. Infect. Immun. 1985, 47:349-352.
148. Sutton P.A., Li S., Webb J., Solomon K., Brazier J., Mahida Y.R. Essential role of toxin A in C. difficile 027 and reference strain supernatant-mediated disruption of Caco-2 intestinal epithelial barrier function. Clin. Exp. Immunol. 2008, 153:439-447.
149. Feltis B.A., Wiesner S.M., Kim A.S., Erlandsen S.L., Lyerly D.L., Wilkins T.D., Wells C.L. Clostridium difficile toxins A and B can alter epithelial permeability and promote bacterial paracellular migration through HT-29 enterocytes. Shock 2000, 14:629-634.
150. Kasendra M., Barrile R., Leuzzi R., Soriani M. Clostridium difficile toxins facilitate bacterial colonization by modulating the fence and gate function of colonic epithelium. J. Infect. Dis. 2014, 209:1095-1104.
151. Lyras D., O'Connor J.R., Howarth P.M., Sambol S.P., Carter G.P., Phumoonna T., et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009, 458:1176-1179.
152. Kuehne S.A., Cartman S.T., Heap J.T., Kelly M.L., Cockayne A., Minton N.P. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010, 467:711-713.
153. Kuehne S.A., Collery M.M., Kelly M.L., Cartman S.T., Cockayne A., Minton N.P. Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J. Infect. Dis. 2014, 209:83-86.
154. Carter G.P., Chakravorty A., Pham Nguyen T.A., Mileto S., Schreiber F., Li L., et al. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. MBio 2015, 6. pii: e00551-15.
155. Perelle S., Gibert M., Bourlioux P., Corthier G., Popoff M.R. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect. Immun. 1997, 65:1402-1407.
156. Carter G.P., Lyras D., Allen D.L., Mackin K.E., Howarth P.M., O'Connor J.R., Rood J.I. Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator. J. Bacteriol. 2007, 189:7290-7301.
157. Papatheodorou P., Carette J.E., Bell G.W., Schwan C., Guttenberg G., Brummelkamp T.R., Aktories K. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc. Natl. Acad. Sci. U. S. A. 2011, 108:16422-16427.
158. Hemmasi S., Czulkies B.A., Schorch B., Veit A., Aktories K., Papatheodorou P. Interaction of the Clostridium difficile binary toxin CDT and its host cell receptor, lipolysis-stimulated lipoprotein receptor (LSR). J. Biol. Chem. 2015, 290:14031-14044.
159. Papatheodorou P., Hornuss D., Nölke T., Hemmasi S., Castonguay J., Picchianti M., Aktories K. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. MBio 2013, 4:e00244-13.
160. Aktories K., Schwan C., Papatheodorou P., Lang A.E. Bidirectional attack on the actin cytoskeleton. Bacterial protein toxins causing polymerization or depolymerization of actin. Toxicon 2012, 60:572-581.
161. Schwan C., Stecher B., Tzivelekidis T., van Ham M., Rohde M., Hardt W.D., et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog. 2009, 5:e1000626.
162. Schwan C., Kruppke A.S., Nölke T., Schumacher L., Koch-Nolte F., Kudryashev M., et al. Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. Proc. Natl. Acad. Sci. U. S. A. 2014, 111:2313-2318.
163. Geric B., Carman R.J., Rupnik M., Genheimer C.W., Sambol S.P., Lyerly D.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, 193:1143-1150.
164. Gerding D.N., Johnson S., Rupnik M., Aktories K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 2014, 5:15-27.
165. Eckert C., Emirian A., Le Monnier A., Cathala L., De Montclos H., Goret J., et al. Prevalence and pathogenicity of binary toxin-positive Clostridium difficile strains that do not produce toxins A and B. New Microbes New Infect. 2014, 3:12-17.
166. Darkoh C., DuPont H.L., Norris S.J., Kaplan H.B. Toxin synthesis by Clostridium difficile is regulated through quorum signaling. MBio 2015, 6:e02569.