1887

Abstract

is the primary cause for nosocomial infective diarrhoea. For a successful infection, must navigate between resident gut bacteria and the harsh host environment. The perturbation of the intestinal microbiota by broad-spectrum antibiotics alters the composition and the geography of the gut microbiota, deterring colonization resistance, and enabling to colonize. This review will discuss how interacts with and exploits the microbiota and the host epithelium to infect and persist. We provide an overview of virulence factors and their interactions with the gut to aid adhesion, cause epithelial damage and mediate persistence. Finally, we document the host responses to , describing the immune cells and host pathways that are associated and triggered during infection.

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2023-02-27
2024-05-03
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References

  1. Weese JS. Clostridium (Clostridioides) difficile in animals. J Vet Diagnostic Investig 2020; 32:213–221 [View Article]
    [Google Scholar]
  2. Janezic S, Potocnik M, Zidaric V, Rupnik M. Highly divergent Clostridium difficile strains isolated from the environment. PLoS One 2016; 11:e0167101 [View Article]
    [Google Scholar]
  3. Public Health England Annual epidemiological commentary: Gram-negative, MRSA, MSSA bacteraemia and C. difficile infections, up to and including financial year 2021 to 2022. Vol. GOV-9331. NHS National statistics; 2022
  4. Guh AY, Mu Y, Winston LG, Johnston H, Olson D et al. Trends in U.S. Burden of Clostridioides difficile infection and outcomes. N Engl J Med 2020; 382:1320–1330 [View Article]
    [Google Scholar]
  5. Schäffler H, Breitrück A. Clostridium difficile – from colonization to infection. Front Microbiol 2018; 9:1–12 [View Article]
    [Google Scholar]
  6. Wilcox MH, Ahir H, Coia JE, Dodgson A, Hopkins S et al. Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life. J Antimicrob Chemother 2017; 72:2647–2656 [View Article]
    [Google Scholar]
  7. Britton RA, Young VB. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol 2012; 20:313–319 [View Article]
    [Google Scholar]
  8. Pike CM, Theriot CM. Mechanisms of colonization resistance against Clostridioides difficile. J Infect Dis 2021; 223:S194–S200 [View Article]
    [Google Scholar]
  9. Kirk JA, Banerji O, Fagan RP. Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics. Microb Biotechnol 2017; 10:76–90 [View Article]
    [Google Scholar]
  10. Burns DA, Heap JT, Minton NP. Clostridium difficile spore germination: an update. Res Microbiol 2010; 161:730–734 [View Article]
    [Google Scholar]
  11. Howerton A, Ramirez N, Abel-Santos E. Mapping interactions between germinants and Clostridium difficile spores. J Bacteriol 2011; 193:274–282 [View Article]
    [Google Scholar]
  12. Paredes-Sabja D, Shen A, Sorg JA. Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. Trends Microbiol 2014; 22:406–416 [View Article]
    [Google Scholar]
  13. Crobach MJT, Vernon JJ, Loo VG, Kong LY, Péchiné S et al. Understanding Clostridium difficile colonization. Clin Microbiol Rev 2018; 31:1–29 [View Article]
    [Google Scholar]
  14. Barbut F, Jones G, Eckert C. Epidemiology and control of Clostridium difficile infections in healthcare settings: an update. Curr Opin Infect Dis 2011; 24:370–376 [View Article]
    [Google Scholar]
  15. Zhu D, Sorg JA, Sun X. Clostridioides difficile biology: sporulation, germination, and corresponding therapies for C. difficile infection. Front Cell Infect Microbiol 2018; 8:1–10 [View Article]
    [Google Scholar]
  16. Heinlen L, Ballard JD. Clostridium difficile infection. Am J Med Sci 2010; 340:247–252 [View Article]
    [Google Scholar]
  17. Francino MP. Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front Microbiol 2016; 6:1543 [View Article]
    [Google Scholar]
  18. Anonye BO, Hassall J, Patient J, Detamornrat U, Aladdad AM et al. Probing Clostridium difficile infection in complex human gut cellular models. Front Microbiol 2019; 10:1–15 [View Article]
    [Google Scholar]
  19. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009; 7:526–536 [View Article]
    [Google Scholar]
  20. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372:1539–1548 [View Article]
    [Google Scholar]
  21. Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 2016; 14:20–32 [View Article]
    [Google Scholar]
  22. Wetzel D, McBride SM. The impact of pH on Clostridioides difficile sporulation and physiology. Appl Environ Microbiol 2019; 86:1–13 [View Article]
    [Google Scholar]
  23. Manda-Handzlik A, Demkow U. Neutrophils: the role of oxidative and nitrosative stress in health and disease. In Advances in Experimental Medicine and Biology Springer New York LLC; 2015 pp 51–60 http://link.springer.com/10.1007/5584_2015_117
    [Google Scholar]
  24. Schairer DO, Chouake JS, Nosanchuk JD, Friedman AJ. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 2012; 3:271–279 [View Article]
    [Google Scholar]
  25. Adlerberth I, Cerquetti M, Poilane I, Wold A, Collignon A. Mechanisms of colonisation and colonisation resistance of the digestive tract Part 1: bacteria/host interactions. Microb Ecol Health Dis 2000; 12:223–239 [View Article]
    [Google Scholar]
  26. Fons M, Gomez A, Karjalainen T. Mechanisms of colonisation and colonisation resistance of the digestive tract Part 2: bacteria/bacteria interactions. Microb Ecol in Health and Dis 2000; 12:240–246 [View Article]
    [Google Scholar]
  27. Lawley TD, Walker AW. Intestinal colonization resistance. Immunology 2013; 138:1–11 [View Article]
    [Google Scholar]
  28. Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect Immun 2012; 80:62–73 [View Article]
    [Google Scholar]
  29. Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197:435–438 [View Article]
    [Google Scholar]
  30. Milani C, Ticinesi A, Gerritsen J, Nouvenne A, Lugli GA et al. Gut microbiota composition and Clostridium difficile infection in hospitalized elderly individuals: a metagenomic study. Sci Rep 2016; 6:1–12 [View Article]
    [Google Scholar]
  31. Gu S, Chen Y, Zhang X, Lu H, Lv T et al. Identification of key taxa that favor intestinal colonization of Clostridium difficile in an adult Chinese population. Microbes and Infect 2016; 18:30–38 [View Article]
    [Google Scholar]
  32. Zhang L, Dong D, Jiang C, Li Z, Wang X et al. Insight into alteration of gut microbiota in Clostridium difficile infection and asymptomatic C. difficile colonization. Anaerobe 2015; 34:1–7 [View Article]
    [Google Scholar]
  33. Amrane S, Hocquart M, Afouda P, Kuete E, Pham TPT et al. Metagenomic and culturomic analysis of gut microbiota dysbiosis during Clostridium difficile infection. Sci Rep 2019; 9:1–8 [View Article]
    [Google Scholar]
  34. Fachi JL, Sécca C, Rodrigues PB, Mato F de, Di Luccia B et al. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. J Exp Med 2020; 217: [View Article]
    [Google Scholar]
  35. Corrêa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MAR. Regulation of immune cell function by short-chain fatty acids. Clin Trans Immunol 2016; 5:e73 [View Article]
    [Google Scholar]
  36. Gregory AL, Pensinger DA, Hryckowian AJ. A short chain fatty acid-centric view of Clostridioides difficile pathogenesis. PLoS Pathog 2021; 17:1–15 [View Article]
    [Google Scholar]
  37. Hayashi A, Nagao-Kitamoto H, Kitamoto S, Kim CH, Kamada N. The butyrate-producing bacterium Clostridium butyricum suppresses Clostridioides difficile infection via neutrophil- and antimicrobial cytokine-dependent but GPR43/109a-independent mechanisms. J Immunol 2021; 206:1576–1585 [View Article]
    [Google Scholar]
  38. Fachi JL, Felipe J de S, Pral LP, da Silva BK, Corrêa RO et al. Butyrate protects mice from Clostridium difficile-induced colitis through an HIF-1-dependent mechanism. Cell Rep 2019; 27:750–761 [View Article]
    [Google Scholar]
  39. Hryckowian AJ, Van Treuren W, Smits SA, Davis NM, Gardner JO et al. Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model. Nat Microbiol 2018; 3:662–669 [View Article]
    [Google Scholar]
  40. Ferreyra JA, Wu KJ, Hryckowian AJ, Bouley DM, Weimer BC et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe 2014; 16:770–777 [View Article]
    [Google Scholar]
  41. Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011; 469:543–547 [View Article]
    [Google Scholar]
  42. Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 2015; 517:205–208 [View Article]
    [Google Scholar]
  43. Becattini S, Littmann ER, Carter RA, Kim SG, Morjaria SM et al. Commensal microbes provide first line defense against Listeria monocytogenes infection. J Exp Med 2017; 214:1973–1989 [View Article]
    [Google Scholar]
  44. Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 2017; 357:570–575 [View Article]
    [Google Scholar]
  45. Gillor O, Etzion A, Riley MA. The dual role of bacteriocins as anti- and probiotics. Appl Microbiol Biotechnol 2008; 81:591–606 [View Article]
    [Google Scholar]
  46. Dobson A, Cotter PD, Ross RP, Hill C. Bacteriocin production: a probiotic trait?. Appl Environ Microbiol 2012; 78:1–6 [View Article]
    [Google Scholar]
  47. Garcia-Gutierrez E, O’Connor PM, Colquhoun IJ, Vior NM, Rodríguez JM et al. Production of multiple bacteriocins, including the novel bacteriocin gassericin M, by Lactobacillus gasseri LM19, a strain isolated from human milk. Appl Microbiol Biotechnol 2020; 53:1689–1699 [View Article]
    [Google Scholar]
  48. Rea MC, Sit CS, Clayton E, O’Connor PM, Whittal RM et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc Natl Acad Sci 2010; 107:9352–9357 [View Article]
    [Google Scholar]
  49. Cleusix V, Lacroix C, Vollenweider S, Duboux M, Le Blay G. Inhibitory activity spectrum of reuterin produced by Lactobacillus reuteri against intestinal bacteria. BMC Microbiol 2007; 7:101 [View Article]
    [Google Scholar]
  50. Shen A. Clostridioides difficile spore formation and germination: new insights and opportunities for intervention. Annu Rev Microbiol 2020; 74:545–566 [View Article]
    [Google Scholar]
  51. Sorg JA, Sonenshein AL. Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol 2008; 190:2505–2512 [View Article]
    [Google Scholar]
  52. Sorg JA, Sonenshein AL. Chenodeoxycholate is an inhibitor of Clostridium difficile spore germination. J Bacteriol 2009; 191:1115–1117 [View Article]
    [Google Scholar]
  53. Wang S, Shen A, Setlow P, Li Y. Characterization of the dynamic germination of individual Clostridium difficile spores using Raman spectroscopy and differential interference contrast microscopy. J Bacteriol 2015; 197:2361–2373 [View Article]
    [Google Scholar]
  54. Thanissery R, Winston JA, Theriot CM. Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids. Anaerobe 2017; 45:86–100 [View Article]
    [Google Scholar]
  55. Studer N, Desharnais L, Beutler M, Brugiroux S, Terrazos MA et al. Functional intestinal bile acid 7α-dehydroxylation by Clostridium scindens associated with protection from Clostridium difficile infection in a Gnotobiotic Mouse Model. Front Cell Infect Microbiol 2016; 6:1–15 [View Article]
    [Google Scholar]
  56. Marion S, Studer N, Desharnais L, Menin L, Escrig S et al. In vitro and in vivo characterization of Clostridium scindens bile acid transformations. Gut Microbes 2019; 10:481–503
    [Google Scholar]
  57. Aguirre AM, Adegbite AO, Sorg JA. Clostridioides difficile bile salt hydrolase activity has substrate specificity and affects biofilm formation. NPJ Biofilms Microbiomes 2022; 8:94 [View Article]
    [Google Scholar]
  58. Dubois T, Tremblay YDN, Hamiot A, Martin-Verstraete I, Deschamps J et al. A microbiota-generated bile salt induces biofilm formation in Clostridium difficile. NPJ Biofilms Microbiomes 2019; 5:14 [View Article]
    [Google Scholar]
  59. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467:711–713 [View Article]
    [Google Scholar]
  60. Chandrasekaran R, Lacy DB. The role of toxins in Clostridium difficile infection. FEMS Microbiol Rev 2017; 41:723–750 [View Article]
    [Google Scholar]
  61. Rupnik M, Janezic S, Kraft CS. An update on Clostridium difficile toxinotyping. J Clin Microbiol 2016; 54:13–18 [View Article]
    [Google Scholar]
  62. Moncrief JS, Barroso LA, Wilkins TD. Positive regulation of Clostridium difficile toxins. Infect Immun 1997; 65:1105–1108 [View Article]
    [Google Scholar]
  63. Mani N, Dupuy B. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. Proc Natl Acad Sci 2001; 98:5844–5849 [View Article]
    [Google Scholar]
  64. Matamouros S, England P, Dupuy B. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol Microbiol 2007; 64:1274–1288 [View Article]
    [Google Scholar]
  65. McDonald LC, Killgore GE, Thompson A, Owens RC, Kazakova SV et al. An epidemic, toxin gene–variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433–2441 [View Article]
    [Google Scholar]
  66. Warny M, Pepin J, Fang A, Killgore G, Thompson A 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 [View Article]
    [Google Scholar]
  67. MacCannell DR, Louie TJ, Gregson DB, Laverdiere M, Labbe A-C et al. Molecular analysis of Clostridium difficile PCR ribotype 027 isolates from Eastern and Western Canada. J Clin Microbiol 2006; 44:2147–2152 [View Article]
    [Google Scholar]
  68. Curry SR, Marsh JW, Muto CA, O’Leary MM, Pasculle AW 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 [View Article]
    [Google Scholar]
  69. Carter GP, Douce GR, Govind R, Howarth PM, Mackin KE 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 [View Article]
    [Google Scholar]
  70. Bakker D, Smits WK, Kuijper EJ, Corver J. TcdC does not significantly repress toxin expression in Clostridium difficile 630ΔErm. PLoS One 2012; 7:e43247 [View Article]
    [Google Scholar]
  71. Cartman ST, Kelly ML, Heeg D, Heap JT, Minton NP. 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 [View Article]
    [Google Scholar]
  72. Tan KS, Wee BY, Song KP. Evidence for holin function of tcdE gene in the pathogenicity of Clostridium difficile. J Med Microbiol 2001; 50:613–619 [View Article]
    [Google Scholar]
  73. Govind R, Dupuy B, Cheung A. Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS Pathog 2012; 8:e1002727 [View Article]
    [Google Scholar]
  74. Govind R, Fitzwater L, Nichols R. Observations on the role of TcdE isoforms in Clostridium difficile toxin secretion. J Bacteriol 2015; 197:2600–2609 [View Article]
    [Google Scholar]
  75. Voth DE, Ballard JD. Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 2005; 18:247–263 [View Article]
    [Google Scholar]
  76. Frisch C, Gerhard R, Aktories K, Hofmann F, Just I. The complete receptor-binding domain of Clostridium difficile toxin A is required for endocytosis. Biochem Biophys Res Commun 2003; 300:706–711 [View Article]
    [Google Scholar]
  77. Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci 2011; 108:16422–16427 [View Article]
    [Google Scholar]
  78. Chandrasekaran R, Kenworthy AK, Lacy DB, Blanke SR. Clostridium difficile toxin A undergoes Clathrin-independent, PACSIN2-dependent endocytosis. PLoS Pathog 2016; 12:e1006070 [View Article]
    [Google Scholar]
  79. Pfeifer G, Schirmer J, Leemhuis J, Busch C, Meyer DK et al. Cellular uptake of Clostridium difficile toxin B. J Biol Chemist 2003; 278:44535–44541 [View Article]
    [Google Scholar]
  80. Geny B, Popoff MR. Bacterial protein toxins and lipids: pore formation or toxin entry into cells. Biol Cell 2006; 98:667–678 [View Article]
    [Google Scholar]
  81. Genisyuerek S, Papatheodorou P, Guttenberg G, Schubert R, Benz R et al. Structural determinants for membrane insertion, pore formation and translocation of Clostridium difficile toxin B. Mol Microbiol 2011; 79:1643–1654 [View Article]
    [Google Scholar]
  82. Zhang Z, Park M, Tam J, Auger A, Beilhartz GL et al. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Proc Natl Acad Sci 2014; 111:3721–3726 [View Article]
    [Google Scholar]
  83. Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature 2007; 446:415–419 [View Article]
    [Google Scholar]
  84. Gerding DN, Johnson S, Rupnik M, Aktories K. Clostridium difficile binary toxin CDT. Gut Microbes 2014; 5:15–27 [View Article]
    [Google Scholar]
  85. Olling A, Hüls C, Goy S, Müller M, Krooss S et al. The combined repetitive oligopeptides of Clostridium difficile toxin A counteract premature cleavage of the glucosyl-transferase domain by stabilizing protein conformation. Toxins 2014; 6:2162–2176 [View Article]
    [Google Scholar]
  86. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420:629–635 [View Article]
    [Google Scholar]
  87. 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 [View Article]
    [Google Scholar]
  88. Chang TW, Lin PS, Gorbach SL, Bartlett JG. Ultrastructural changes of cultured human amnion cells by Clostridium difficile toxin. Infect Immun 1979; 23:795–798 [View Article]
    [Google Scholar]
  89. Hecht G, Pothoulakis C, LaMont JT, Madara JL. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 1988; 82:1516–1524 [View Article]
    [Google Scholar]
  90. Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375:500–503 [View Article]
    [Google Scholar]
  91. Just I, Wilm M, Selzer J, Rex G, von Eichel-Streiber C et al. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J Biol Chem 1995; 270:13932–13936 [View Article]
    [Google Scholar]
  92. Sehr P, Joseph G, Genth H, Just I, Pick E et al. Glucosylation and ADP ribosylation of Rho proteins: effects on nucleotide binding, GTPase activity, and effector coupling. Biochem 1998; 37:5296–5304 [View Article]
    [Google Scholar]
  93. 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 [View Article]
    [Google Scholar]
  94. Genth H, Aktories K, Just I. Monoglucosylation of RhoA at threonine 37 blocks cytosol-membrane cycling. J Biol Chem 1999; 274:29050–29056 [View Article]
    [Google Scholar]
  95. 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 [View Article]
    [Google Scholar]
  96. Carter GP, Lyras D, Allen DL, Mackin KE, Howarth PM et al. Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator. J Bacteriol 2007; 189:7290–7301 [View Article]
    [Google Scholar]
  97. 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 [View Article]
    [Google Scholar]
  98. Gibert M, Monier M-N, Ruez R, Hale ML, Stiles BG et al. Endocytosis and toxicity of clostridial binary toxins depend on a clathrin-independent pathway regulated by Rho-GDI. Cell Microbiol 2011; 13:154–170 [View Article]
    [Google Scholar]
  99. Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M et al. 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 [View Article]
    [Google Scholar]
  100. Papatheodorou P, Hornuss D, Nölke T, Hemmasi S, Castonguay J et al. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. mBio 2013; 4:1–8 [View Article]
    [Google Scholar]
  101. Ernst K, Schmid J, Beck M, Hägele M, Hohwieler M et al. Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells. Sci Rep 2017; 7:2724 [View Article]
    [Google Scholar]
  102. Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH et al. Botulinum C2 toxin ADP-ribosylates actin. Nature 1986; 322:390–392 [View Article] [PubMed]
    [Google Scholar]
  103. Aktories K, Wegner A. Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. Mol Microbiol 1992; 6:2905–2908 [View Article]
    [Google Scholar]
  104. Gülke I, Pfeifer G, Liese J, Fritz M, Hofmann F et al. Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect Immun 2001; 69:6004–6011 [View Article]
    [Google Scholar]
  105. Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 2009; 5:e1000626 [View Article]
    [Google Scholar]
  106. 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 [View Article]
    [Google Scholar]
  107. 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 [View Article]
    [Google Scholar]
  108. Sundriyal A, Roberts AK, Ling R, McGlashan J, Shone CC et al. Expression, purification and cell cytotoxicity of actin-modifying binary toxin from Clostridium difficile. Protein Expr Purif 2010; 74:42–48 [View Article]
    [Google Scholar]
  109. Anderson DM, Sheedlo MJ, Jensen JL, Lacy DB. Structural insights into the transition of Clostridioides difficile binary toxin from prepore to pore. Nat Microbiol 2020; 5:102–107 [View Article]
    [Google Scholar]
  110. Xu X, Godoy-Ruiz R, Adipietro KA, Peralta C, Ben-Hail D et al. Structure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assembly. Proc Natl Acad Sci 2020; 117:9642 [View Article]
    [Google Scholar]
  111. Hemmasi S, Czulkies BA, Schorch B, Veit A, Aktories K et al. 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 [View Article]
    [Google Scholar]
  112. Perieteanu AA, Visschedyk DD, Merrill AR, Dawson JF. ADP-ribosylation of cross-linked actin generates barbed-end polymerization-deficient F-actin oligomers. Biochem 2010; 49:8944–8954 [View Article]
    [Google Scholar]
  113. Savidge TC, Pan W-H, Newman P, O’brien M, Anton PM et al. Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 2003; 125:413–420 [View Article]
    [Google Scholar]
  114. Schwan C, Kruppke AS, Nölke T, Schumacher L, Koch-Nolte F et al. Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. Proc Natl Acad Sci 2014; 111:2313–2318 [View Article]
    [Google Scholar]
  115. Aktories K, Papatheodorou P, Schwan C. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe 2018; 53:21–29 [View Article]
    [Google Scholar]
  116. Hennequin C, Janoir C, Barc M-C, Collignon A, Karjalainen T. Identification and characterization of a fibronectin-binding protein from Clostridium difficile. Microbiol 2003; 149:2779–2787 [View Article]
    [Google Scholar]
  117. Lin Y-P, Kuo C-J, Koleci X, McDonough SP, Chang Y-F. Manganese binds to Clostridium difficile Fbp68 and is essential for fibronectin binding. J Biol Chem 2011; 286:3957–3969 [View Article]
    [Google Scholar]
  118. Baban ST, Kuehne SA, Barketi-Klai A, Cartman ST, Kelly ML et al. The role of flagella in Clostridium difficile pathogenesis: comparison between a non-epidemic and an epidemic strain. PLoS One 2013; 8:e73026 [View Article]
    [Google Scholar]
  119. Ghose C. Clostridium difficile infection in the twenty-first century. Emerg Microbes Infect 2013; 2:e62 [View Article]
    [Google Scholar]
  120. Stevenson E, Minton NP, Kuehne SA. The role of flagella in Clostridium difficile pathogenicity. Trends Microbiol 2015; 23:275–282 [View Article]
    [Google Scholar]
  121. Faulds-Pain A, Twine SM, Vinogradov E, Strong PCR, Dell A et al. The post-translational modification of the Clostridium difficile flagellin affects motility, cell surface properties and virulence. Mol Microbiol 2014; 94:272–289 [View Article]
    [Google Scholar]
  122. Merino S, Tomás JM. Gram-negative flagella glycosylation. Int J Mol Sci 2014; 15:2840–2857 [View Article]
    [Google Scholar]
  123. Twine SM, Reid CW, Aubry A, McMullin DR, Fulton KM et al. Motility and flagellar glycosylation in Clostridium difficile. J Bacteriol 2009; 191:7050–7062 [View Article]
    [Google Scholar]
  124. Anjuwon-Foster BR, Maldonado-Vazquez N, Tamayo R. Characterization of flagellum and toxin phase variation in Clostridioides difficile ribotype 012 isolates. J Bacteriol 2018; 200:1–15 [View Article]
    [Google Scholar]
  125. Aubry A, Hussack G, Chen W, KuoLee R, Twine SM et al. Modulation of toxin production by the flagellar regulon in Clostridium difficile. Infect Immun 2012; 80:3521–3532 [View Article]
    [Google Scholar]
  126. El Meouche I, Peltier J, Monot M, Soutourina O, Pestel-Caron M et al. 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 [View Article]
    [Google Scholar]
  127. McKee RW, Harvest CK, Tamayo R. Cyclic diguanylate regulates virulence factor genes via multiple riboswitches in Clostridium difficile. mSphere 2018; 3:1–15 [View Article]
    [Google Scholar]
  128. Dingle TC, Mulvey GL, Armstrong GD. Mutagenic analysis of the Clostridium difficile flagellar proteins, FliC and FliD, and their contribution to virulence in Hamsters. Infect Immun 2011; 79:4061–4067 [View Article]
    [Google Scholar]
  129. Barketi-Klai A, Monot M, Hoys S, Lambert-Bordes S, Kuehne SA et al. The flagellin FliC of Clostridium difficile is responsible for pleiotropic gene regulation during in vivo infection. PLoS One 2014; 9:e96876 [View Article]
    [Google Scholar]
  130. Borriello SP. Pathogenesis of Clostridium difficile infection. J Antimicrob Chemother 1998; 41:13–19 [View Article]
    [Google Scholar]
  131. Maldarelli GA, Piepenbrink KH, Scott AJ, Freiberg JA, Song Y et al. Type IV pili promote early biofilm formation by Clostridium difficile. Pathog Dis 2016; 74:ftw061 [View Article]
    [Google Scholar]
  132. Crawshaw AD, Baslé A, Salgado PS. A practical overview of molecular replacement: Clostridioides difficile PilA1, a difficult case study. Acta Crystallogr Sect D Struct Biol 2020; 76:261–271 [View Article]
    [Google Scholar]
  133. Purcell EB, McKee RW, Bordeleau E, Burrus V, Tamayo R. Regulation of type IV pili contributes to surface behaviors of historical and epidemic strains pili contributes to surface behaviors of historical and epidemic strains of Clostridium difficile. J Bacteriol 2016; 198:565–577 [View Article]
    [Google Scholar]
  134. Awad MM, Johanesen PA, Carter GP, Rose E, Lyras D. Clostridium difficile virulence factors: insights into an anaerobic spore-forming pathogen. Gut Microbes 2014; 5:579–593 [View Article]
    [Google Scholar]
  135. McKee RW, Aleksanyan N, Garrett EM, Tamayo R, Young VB. Type IV pili promote Clostridium difficile adherence and persistence in a mouse model of infection adherence and persistence in a mouse model of infection. Infect Immun 2018; 86: [View Article]
    [Google Scholar]
  136. Goulding D, Thompson H, Emerson J, Fairweather NF, Dougan G. Distinctive profiles of infection and pathology in hamsters infected with Clostridium difficile strains 630 and B1. Infect Immun 2009; 77:5478–5485 [View Article]
    [Google Scholar]
  137. DiRita VJ, Karjalainen T, Waligora-Dupriet A-J, Cerquetti M, Spigaglia P et al. Molecular and genomic analysis of genes encoding surface-anchored proteins from Clostridium difficile. Infect Immun 2001; 69:3442–3446 [View Article]
    [Google Scholar]
  138. Fagan RP, Fairweather NF. Clostridium difficile has two parallel and essential sec secretion systems. J Biol Chem 2011; 286:27483–27493 [View Article]
    [Google Scholar]
  139. Ryan A, Lynch M, Smith SM, Amu S, Nel HJ et al. A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. PLoS Pathog 2011; 7:e1002076 [View Article]
    [Google Scholar]
  140. Dingle KE, Didelot X, Ansari MA, Eyre DW, Vaughan A 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 [View Article]
    [Google Scholar]
  141. Bradshaw WJ, Roberts AK, Shone CC, Acharya KR. The structure of the S-layer of Clostridium difficile. J Cell Commun Signal 2018; 12:319–331 [View Article]
    [Google Scholar]
  142. Lanzoni-Mangutchi P, Banerji O, Wilson J, Barwinska-Sendra A, Kirk JA et al. Structure and assembly of the S-layer in C. difficile. Nat Commun 2022; 13:970 [View Article]
    [Google Scholar]
  143. Calabi E, Fairweather N. Patterns of sequence conservation in the S-Layer proteins and related sequences in Clostridium difficile. J Bacteriol 2002; 184:3886–3897 [View Article]
    [Google Scholar]
  144. Fagan RP, Albesa-Jové D, Qazi O, Svergun DI, Brown KA et al. Structural insights into the molecular organization of the S-layer from Clostridium difficile. Mol Microbiol 2009; 71:1308–1322 [View Article]
    [Google Scholar]
  145. Calabi E, Calabi F, Phillips AD, Fairweather NF. Binding of Clostridium difficile surface layer proteins to gastrointestinal tissues. Infect Immun 2002; 70:5770–5778 [View Article]
    [Google Scholar]
  146. Dang THT, de la Riva L, Fagan RP, Storck EM, Heal WP et al. Chemical probes of surface layer biogenesis in Clostridium difficile. ACS Chem Biol 2010; 5:279–285 [View Article]
    [Google Scholar]
  147. Merrigan MM, Venugopal A, Roxas JL, Anwar F, Mallozzi MJ et al. Surface-layer protein A (SlpA) is a major contributor to host-cell adherence of Clostridium difficile. PLoS One 2013; 8:e78404 [View Article]
    [Google Scholar]
  148. Dembek M, Barquist L, Boinett CJ, Cain AK, Mayho M et al. High-throughput analysis of gene essentiality and sporulation in Clostridium difficile. mBio 2015; 6:1–13 [View Article]
    [Google Scholar]
  149. Kirk JA, Gebhart D, Buckley AM, Lok S, Scholl D et al. New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability. Sci Transl Med 2017; 9:eaah6813 [View Article]
    [Google Scholar]
  150. Calabi E, Ward S, Wren B, Paxton T, Panico M et al. Molecular characterization of the surface layer proteins from Clostridium difficile. Mol Microbiol 2001; 40:1187–1199 [View Article]
    [Google Scholar]
  151. Kirby JM, Ahern H, Roberts AK, Kumar V, Freeman Z et al. 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 [View Article]
    [Google Scholar]
  152. de la Riva L, Willing SE, Tate EW, Fairweather NF. Roles of cysteine proteases Cwp84 and Cwp13 in biogenesis of the cell wall of Clostridium difficile. J Bacteriol 2011; 193:3276–3285 [View Article]
    [Google Scholar]
  153. 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 [View Article]
    [Google Scholar]
  154. DiRita VJ, Waligora A-J, Hennequin C, Mullany P, Bourlioux P et al. Characterization of a cell surface protein of Clostridium difficile with adhesive properties. Infect Immun 2001; 69:2144–2153 [View Article]
    [Google Scholar]
  155. Emerson JE, Reynolds CB, Fagan RP, Shaw HA, Goulding D et al. A novel genetic switch controls phase variable expression of CwpV, a Clostridium difficile cell wall protein. Mol Microb 2009; 74:541–556 [View Article]
    [Google Scholar]
  156. Reynolds CB, Emerson JE, de la Riva L, Fagan RP, Fairweather NF et al. The Clostridium difficile cell wall protein CwpV is antigenically variable between strains, but exhibits conserved aggregation-promoting function. PLoS Pathog 2011; 7:e1002024 [View Article]
    [Google Scholar]
  157. Sekulovic O, Ospina Bedoya M, Fivian-Hughes AS, Fairweather NF, Fortier L-C. The Clostridium difficile cell wall protein CwpV confers phase‐variable phage resistance. Mol Microbiol 2015; 98:329–342 [View Article]
    [Google Scholar]
  158. Bradshaw WJ, Kirby JM, Roberts AK, Shone CC, Acharya KR. Cwp2 from Clostridium difficile exhibits an extended three domain fold and cell adhesion in vitro. FEBS J 2017; 284:2886–2898 [View Article]
    [Google Scholar]
  159. Zhu D, Bullock J, He Y, Sun X. Cwp22, a novel peptidoglycan cross-linking enzyme, plays pleiotropic roles in Clostridioides difficile. Environ Microbiol 2019; 21:3076–3090 [View Article]
    [Google Scholar]
  160. Wydau-Dematteis S, El Meouche I, Courtin P, Hamiot A, Lai-Kuen R et al. Cwp19 is a novel lytic transglycosylase involved in stationary-phase autolysis resulting in toxin release in Clostridium difficile. mBio 2018; 9:1–19 [View Article]
    [Google Scholar]
  161. Janoir C, Denève C, Bouttier S, Barbut F, Hoys S et al. Adaptive strategies and pathogenesis of Clostridium difficile from in vivo transcriptomics. Infect Immun 2013; 81:3757–3769 [View Article]
    [Google Scholar]
  162. Tulli L, Marchi S, Petracca R, Shaw HA, Fairweather NF et al. CbpA: a novel surface exposed adhesin of Clostridium difficile targeting human collagen. Cell Microbiol 2013; 15:n/a-n/a [View Article]
    [Google Scholar]
  163. Arato V, Gasperini G, Giusti F, Ferlenghi I, Scarselli M et al. Dual role of the colonization factor CD2831 in Clostridium difficile pathogenesis. Sci Rep 2019; 9:5554 [View Article]
    [Google Scholar]
  164. 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 [View Article]
    [Google Scholar]
  165. Kovacs-Simon A, Leuzzi R, Kasendra M, Minton N, Titball RW et al. Lipoprotein CD0873 is a novel adhesin of Clostridium difficile. J Infect Dis 2014; 210:274–284 [View Article]
    [Google Scholar]
  166. Bradshaw WJ, Bruxelle J-F, Kovacs-Simon A, Harmer NJ, Janoir C et al. Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile. J Biol Chem 2019; 294:15850–15861 [View Article]
    [Google Scholar]
  167. Cafardi V, Biagini M, Martinelli M, Leuzzi R, Rubino JT et al. Identification of a novel zinc metalloprotease through a global analysis of Clostridium difficile extracellular proteins. PLoS ONE 2013; 8:e81306 [View Article]
    [Google Scholar]
  168. Hensbergen PJ, Klychnikov OI, Bakker D, van Winden VJC, Ras N et al. A novel secreted metalloprotease (CD2830) from Clostridium difficile cleaves specific proline sequences in LPXTG cell surface proteins. Mol CellProteomics 2014; 13:1231–1244 [View Article]
    [Google Scholar]
  169. Matsushita O, Okabe A. Clostridial hydrolytic enzymes degrading extracellular components. Toxicon 2001; 39:1769–1780 [View Article]
    [Google Scholar]
  170. Steffen EK, Hentges DJ. Hydrolytic enzymes of anaerobic bacteria isolated from human infections. J Clin Microbiol 1981; 14:153–156 [View Article]
    [Google Scholar]
  171. Seddon SV, Krishna M, Davies HA, Borriello SP. Effect of nutrition on the expression of known and putative virulence factors of Clostridium difficile. Microb Ecol Health Dis 1991; 4:303–309 [View Article]
    [Google Scholar]
  172. Hynes WL, Walton SL. Hyaluronidases of Gram-positive bacteria. FEMS Microbiology Letters 2000; 183:201–207 [View Article]
    [Google Scholar]
  173. Malavaki C, Mizumoto S, Karamanos N, Sugahara K. Recent advances in the structural study of functional chondroitin sulfate and dermatan sulfate in health and disease. Connect Tissue Res 2008; 49:133–139 [View Article]
    [Google Scholar]
  174. Wang S, Sugahara K, Li F. Chondroitin sulfate/dermatan sulfate sulfatases from mammals and bacteria. Glycoconj J 2016; 33:841–851
    [Google Scholar]
  175. Lawler AJ, Lambert PA, Worthington T. A revised understanding of Clostridioides difficile spore germination. Trends in Microbiol 2020; 28:744–752 [View Article]
    [Google Scholar]
  176. Deakin LJ, Clare S, Fagan RP, Dawson LF, Pickard DJ et al. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect Immun 2012; 80:2704–2711 [View Article]
    [Google Scholar]
  177. Fimlaid KA, Bond JP, Schutz KC, Putnam EE, Leung JM. n.d. Global analysis of the sporulation pathway of Clostridium difficile. PLoS Genet 9:e1003660 [View Article]
    [Google Scholar]
  178. Pettit LJ, Browne HP, Yu L, Smits WK, Fagan RP et al. Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism. BMC Genomics 2014; 15:160 [View Article]
    [Google Scholar]
  179. Pereira FC, Saujet L, Tomé AR, Serrano M, Monot M. The spore differentiation pathway in the enteric pathogen spore differentiation pathway in the enteric pathogen Clostridium difficile. PLoS Genet 2013; 9:e1003782 [View Article]
    [Google Scholar]
  180. Saujet L, Pereira FC, Serrano M, Soutourina O, Monot M. Genome-wide analysis of cell type-specific gene transcription during spore formation in Clostridium difficile. PLoS Genet 2013; 9:e1003756 [View Article]
    [Google Scholar]
  181. Mackin KE, Carter GP, Howarth P, Rood JI, Lyras D. Spo0A differentially regulates toxin production in evolutionarily diverse strains of Clostridium difficile. PLoS ONE 2013; 8:e79666 [View Article]
    [Google Scholar]
  182. Dhungel BA, Govind R, Ellermeier CD. Spo0A suppresses sin locus expression in Clostridioides difficile. mSphere 2020; 5:1–10 [View Article]
    [Google Scholar]
  183. Edwards AN, Krall EG, McBride SM. Strain-dependent RstA regulation of Clostridioides difficile toxin production and sporulation. J Bacteriol 2020; 202:1–17 [View Article]
    [Google Scholar]
  184. DiCandia MA, Edwards AN, Jones JB, Swaim GL, Mills BD et al. Identification of functional spo0A residues critical for sporulation in Clostridioides difficile. J Mol Biol 2022; 434:167641 [View Article]
    [Google Scholar]
  185. Edwards AN, Wetzel D, DiCandia MA, McBride SM. Three orphan histidine kinases inhibit Clostridioides difficile sporulation. J Bacteriol 2022; 204:49–58 [View Article]
    [Google Scholar]
  186. Antunes A, Camiade E, Monot M, Courtois E, Barbut F et al. Global transcriptional control by glucose and carbon regulator CcpA in Clostridium difficile. Nucleic Acids Res 2012; 40:10701–10718 [View Article]
    [Google Scholar]
  187. Daou N, Wang Y, Levdikov VM, Nandakumar M, Livny J et al. Impact of CodY protein on metabolism, sporulation and virulence in Clostridioides difficile ribotype 027. PLoS One 2019; 14:e0206896 [View Article]
    [Google Scholar]
  188. Nawrocki KL, Edwards AN, Daou N, Bouillaut L, McBride SM. CodY-dependent regulation of sporulation in Clostridium difficile. J Bacteriol 2016; 198:2113–2130 [View Article]
    [Google Scholar]
  189. Viswanathan VK, Mallozzi M, Vedantam G. Clostridium difficile infection. Gut Microbes 2010; 1:234–242 [View Article]
    [Google Scholar]
  190. Lawley TD, Croucher NJ, Yu L, Clare S, Sebaihia M et al. Proteomic and genomic characterization of highly infectious Clostridium difficile 630 spores. J Bacteriol 2009; 191:5377–5386 [View Article]
    [Google Scholar]
  191. Merrigan M, Venugopal A, Mallozzi M, Roxas B, Viswanathan VK et al. Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol 2010; 192:4904–4911 [View Article]
    [Google Scholar]
  192. Gómez S, Chaves F, Orellana MA. Clinical, epidemiological and microbiological characteristics of relapse and re-infection in Clostridium difficile infection. Anaerobe 2017; 48:147–151 [View Article]
    [Google Scholar]
  193. Carlson PE, Kaiser AM, McColm SA, Bauer JM, Young VB et al. Variation in germination of Clostridium difficile clinical isolates correlates to disease severity. Anaerobe 2015; 33:64–70 [View Article]
    [Google Scholar]
  194. Paredes-Sabja D, Cofre-Araneda G, Brito-Silva C, Pizarro- M, Sarker MR et al. Clostridium difficile spore-macrophage interactions: spore survival. PLoS One 2012; 7:e43635 [View Article]
    [Google Scholar]
  195. Chiu P-J, Rathod J, Hong Y-P, Tsai P-J, Hung Y-P et al. Clostridioides difficile spores stimulate inflammatory cytokine responses and induce cytotoxicity in macrophages. Anaerobe 2021; 70:102381 [View Article]
    [Google Scholar]
  196. Castro-Córdova P, Mora-Uribe P, Reyes-Ramírez R, Cofré-Araneda G, Orozco-Aguilar J et al. Entry of spores into intestinal epithelial cells contributes to recurrence of Clostridioides difficile infection. Nat Commun 2021; 12:1140 [View Article]
    [Google Scholar]
  197. Mora-Uribe P, Miranda-Cárdenas C, Castro-Córdova P, Gil F, Calderón I et al. Characterization of the adherence of Clostridium difficile spores: the integrity of the outermost layer affects adherence properties of spores of the epidemic strain R20291 to components of the intestinal mucosa. Front Cell Infect Microbiol 2016; 6:1–16 [View Article]
    [Google Scholar]
  198. Paredes-Sabja D, Sarker MR. Adherence of Clostridium difficile spores to Caco-2 cells in culture. J Med Microbiol 2012; 61:1208–1218 [View Article]
    [Google Scholar]
  199. Tumbarello M, Fiori B, Trecarichi EM, Posteraro P, Losito AR et al. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One 2012; 7:e33705 [View Article]
    [Google Scholar]
  200. Donelli G, Vuotto C, Cardines R, Mastrantonio P. Biofilm-growing intestinal anaerobic bacteria. FEMS Immunol Med Microbiol 2012; 65:318–325 [View Article]
    [Google Scholar]
  201. Percival SL, Suleman L, Vuotto C, Donelli G. Healthcare-associated infections, medical devices and biofilms: risk, tolerance and control. J Med Microbiol 2015; 64:323–334 [View Article]
    [Google Scholar]
  202. Normington C, Moura IB, Bryant JA, Ewin DJ, Clark EV et al. Biofilms harbour Clostridioides difficile, serving as a reservoir for recurrent infection. NPJ Biofilms Microbiomes 2021; 7:16 [View Article]
    [Google Scholar]
  203. Frost LR, Cheng JKJ, Unnikrishnan M. Clostridioides difficile biofilms: a mechanism of persistence in the gut?. PLoS Pathog 2021; 17:e1009348 [View Article]
    [Google Scholar]
  204. Dawson LF, Valiente E, Faulds-Pain A, Donahue EH, Wren BW. Characterisation of Clostridium difficile biofilm formation, a role for Spo0A. PLoS One 2012; 7:e50527 [View Article]
    [Google Scholar]
  205. Semenyuk EG, Poroyko VA, Johnston PF, Jones SE, Knight KL et al. Analysis of bacterial communities during Clostridium difficile infection in the mouse. Infect Immun 2015; 83:4383–4391 [View Article]
    [Google Scholar]
  206. Ðapa T, Leuzzi R, Ng YK, Baban ST, Adamo R et al. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile. J Bacteriol 2013; 195:545–555 [View Article]
    [Google Scholar]
  207. Soavelomandroso AP, Gaudin F, Hoys S, Nicolas V, Vedantam G et al. Biofilm structures in a mono-associated mouse model of Clostridium difficile infection. Front Microbiol 2017; 8:1–10 [View Article]
    [Google Scholar]
  208. Semenyuk EG, Laning ML, Foley J, Johnston PF, Knight KL et al. Spore formation and toxin production in Clostridium difficile biofilms. PLoS One 2014; 9:e87757 [View Article]
    [Google Scholar]
  209. Pantaléon V, Soavelomandroso AP, Bouttier S, Briandet R, Roxas B et al. The Clostridium difficile protease Cwp84 modulates both biofilm formation and cell-surface properties. PLoS One 2015; 10:e0124971 [View Article]
    [Google Scholar]
  210. Slater RT, Frost LR, Jossi SE, Millard AD, Unnikrishnan M. Clostridioides difficile LuxS mediates inter-bacterial interactions within biofilms. Sci Rep 2019; 9:9903 [View Article]
    [Google Scholar]
  211. Dapa T, Unnikrishnan M. Biofilm formation by Clostridium difficile. Gut Microbes 2013; 4:397–402 [View Article]
    [Google Scholar]
  212. Vuotto C, Moura I, Barbanti F, Donelli G, Spigaglia P. Subinhibitory concentrations of metronidazole increase biofilm formation in Clostridium difficile strains. Pathog Dis 2016; 74:ftv114 [View Article]
    [Google Scholar]
  213. Piotrowski M, Wultańska D, Obuch-Woszczatyński P, Pituch H. Fructooligosaccharides and mannose affect Clostridium difficile adhesion and biofilm formation in a concentration-dependent manner. Eur J Clin Microbiol Infect Dis 2019; 38:1975–1984 [View Article]
    [Google Scholar]
  214. Hall CW, Mah T-F. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol Rev 2017; 41:276–301 [View Article]
    [Google Scholar]
  215. Chiang W-C, Nilsson M, Jensen , Høiby N, Nielsen TE et al. Extracellular DNA shields against aminoglycosides in Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother 2013; 57:2352–2361 [View Article]
    [Google Scholar]
  216. Mah T-F, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 2001; 9:34–39 [View Article]
    [Google Scholar]
  217. Roy R, Tiwari M, Donelli G, Tiwari V. Strategies for combating bacterial biofilms: a focus on anti-biofilm agents and their mechanisms of action. Virulence 2018; 9:522–554 [View Article]
    [Google Scholar]
  218. Taggart MG, Snelling WJ, Naughton PJ, La Ragione RM, Dooley JSG et al. Biofilm regulation in Clostridioides difficile: novel systems linked to hypervirulence. PLoS Pathog 2021; 17:1–20 [View Article]
    [Google Scholar]
  219. Tao L, Tian S, Zhang J, Liu Z, Robinson-McCarthy L et al. Sulfated glycosaminoglycans and low-density lipoprotein receptor contribute to Clostridium difficile toxin A entry into cells. Nat Microbiol 2019; 4:1760–1769 [View Article]
    [Google Scholar]
  220. Chen P, Tao L, Wang T, Zhang J, He A et al. Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B. Science 2018; 360:664–669 [View Article]
    [Google Scholar]
  221. Yuan P, Zhang H, Cai C, Zhu S, Zhou Y et al. Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. Cell Res 2015; 25:157–168 [View Article]
    [Google Scholar]
  222. Hirota SA, Fines K, Ng J, Traboulsi D, Lee J et al. Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. Gastroenterology 2010; 139:259–269 [View Article]
    [Google Scholar]
  223. Mileto SJ, Jardé T, Childress KO, Jensen JL, Rogers AP et al. Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease. Proc Natl Acad Sci 2020; 117:8064–8073 [View Article]
    [Google Scholar]
  224. Knippel RJ, Zackular JP, Moore JL, Celis AI, Weiss A et al. Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection. PLoS Pathog 2018; 14:e1007486 [View Article]
    [Google Scholar]
  225. Knippel RJ, Wexler AG, Miller JM, Beavers WN, Weiss A et al. Clostridioides difficile senses and hijacks host heme for incorporation into an oxidative stress defense system. Cell Host Microbe 2020; 28:411–421 [View Article]
    [Google Scholar]
  226. Zackular JP, Knippel RJ, Lopez CA, Beavers WN, Maxwell CN et al. ZupT facilitates Clostridioides difficile resistance to host-mediated nutritional immunity. mSphere 2020; 5:1–9 [View Article]
    [Google Scholar]
  227. Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, Noto MJ et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat Med 2016; 22:1330–1334 [View Article]
    [Google Scholar]
  228. Engevik MA, Yacyshyn MB, Engevik KA, Wang J, Darien B et al. Human Clostridium difficile infection: altered mucus production and composition. Am J Physiol Gastrointest Liver Physiol 2015; 308:G510–24 [View Article]
    [Google Scholar]
  229. Engevik MA, Engevik AC, Engevik KA, Auchtung JM, Chang-Graham AL et al. Mucin-degrading microbes release monosaccharides that chemoattract Clostridioides difficile and facilitate colonization of the human intestinal mucus layer. ACS Infect Dis 2021; 7:1126–1142 [View Article]
    [Google Scholar]
  230. Pereira FC, Wasmund K, Cobankovic I, Jehmlich N, Herbold CW et al. Rational design of a microbial consortium of mucosal sugar utilizers reduces Clostridiodes difficile colonization. Nat Commun 2020; 11: [View Article]
    [Google Scholar]
  231. Keel MK, Songer JG. The comparative pathology of Clostridium difficile -associated disease. Vet Pathol 2006; 43:225–240 [View Article]
    [Google Scholar]
  232. Sun X, Hirota SA. 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 [View Article]
    [Google Scholar]
  233. Mahida YR, Makh S, Hyde S, Gray T, Borriello SP. Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut 1996; 38:337–347 [View Article]
    [Google Scholar]
  234. Castagliuolo I, Keates AC, Wang CC, Pasha A, Valenick L et al. Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol 1998; 160:6039–6045
    [Google Scholar]
  235. Kim JM, Kim JS, Jung HC, Oh Y, Song IS et al. Differential expression and polarized secretion of CXC and CC chemokines by human intestinal epithelial cancer cell lines in response to Clostridium difficile toxin A. Microbiol Immunol 2002; 46:333–342 [View Article]
    [Google Scholar]
  236. Ng EK, Panesar N, Longo WE, Shapiro MJ, Kaminski DL et al. Human intestinal epithelial and smooth muscle cells are potent producers of IL-6. Mediators Inflamm 2003; 12:3–8 [View Article]
    [Google Scholar]
  237. Yeh C-Y, Lin C-N, Chang C-F, Lin C-H, Lien H-T et al. C-terminal repeats of Clostridium difficile toxin A induce production of chemokine and adhesion molecules in endothelial cells and promote migration of leukocytes. Infect Immun 2008; 76:1170–1178 [View Article]
    [Google Scholar]
  238. Hansen A, Alston L, Tulk SE, Schenck LP, Grassie ME et al. The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction. PLoS One 2013; 8:e81491 [View Article]
    [Google Scholar]
  239. Jarchum I, Liu M, Shi C, Equinda M, Pamer EG et al. Critical role for MyD88-mediated neutrophil recruitment during Clostridium difficile colitis. Infect Immun 2012; 80:2989–2996 [View Article]
    [Google Scholar]
  240. Hasegawa M, Yamazaki T, Kamada N, Tawaratsumida K, Kim Y-G et al. Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. J Immunol 2011; 186:4872–4880 [View Article]
    [Google Scholar]
  241. Huang AM, Marini BL, Frame D, Aronoff DM, Nagel JL. Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2014; 16:744–750 [View Article]
    [Google Scholar]
  242. Bauer MP, Hensgens MPM, Miller MA, Gerding DN, Wilcox MH et al. Renal failure and leukocytosis are predictors of a complicated course of Clostridium difficile infection if measured on day of diagnosis. Clin Infect Dis 2012; 55:S149–S153 [View Article]
    [Google Scholar]
  243. Solomon K. The host immune response to Clostridium difficile infection. Ther Adv Infect Dis 2013; 1:19–35 [View Article]
    [Google Scholar]
  244. Kelly CP, Becker S, Linevsky JK, Joshi MA, O’Keane JC et al. Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest 1994; 93:1257–1265 [View Article]
    [Google Scholar]
  245. Buonomo EL, Madan R, Pramoonjago P, Li L, Okusa MD et al. Role of interleukin 23 signaling in Clostridium difficile colitis. J Infect Dis 2013; 208:917–920 [View Article]
    [Google Scholar]
  246. McDermott AJ, Falkowski NR, McDonald RA, Pandit CR, Young VB et al. Interleukin-23 (IL-23), independent of IL-17 and IL-22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice. Immunology 2016; 147:114–124 [View Article]
    [Google Scholar]
  247. Cowardin CA, Buonomo EL, Saleh MM, Wilson MG, Burgess SL et al. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol 2016; 1:16108 [View Article]
    [Google Scholar]
  248. Batah J, Kobeissy H, Bui Pham PT, Denève-Larrazet C, Kuehne S et al. Clostridium difficile flagella induce a pro-inflammatory response in intestinal epithelium of mice in cooperation with toxins. Sci Rep 2017; 7:3256 [View Article]
    [Google Scholar]
  249. Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K, Yanagimoto 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 [View Article]
    [Google Scholar]
  250. Ghose C, Eugenis I, Sun X, Edwards AN, McBride SM et al. Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC. Emerg Microbes Infect 2016; 5:1–10 [View Article]
    [Google Scholar]
  251. Jafari NV, Songane M, Stabler RA, Elawad M, Wren BW et al. Host immunity to Clostridium difficile PCR ribotype 017 strains. Infect Immun 2014; 82:4989–4996 [View Article]
    [Google Scholar]
  252. Simpson M, Frisbee A, Kumar P, Schwan C, Aktories K et al. Clostridioides difficile binary toxin is recognized by the toll-like receptor 2/6 heterodimer to induce a nuclear factor-κB response. J Infect Dis 2022; 225:1296–1300 [View Article]
    [Google Scholar]
  253. Chen X, Yang X, de Anda J, Huang J, Li D et al. Clostridioides difficile toxin A remodels membranes and mediates DNA entry into cells to activate toll-like receptor 9 signaling. Gastroenterology 2020; 159:2181–2192 [View Article]
    [Google Scholar]
  254. Siffert JC, Baldacini O, Kuhry JG, Wachsmann D, Benabdelmoumene S et al. Effects of Clostridium difficile toxin B on human monocytes and macrophages: possible relationship with cytoskeletal rearrangement. Infect Immun 1993; 61:1082–1090 [View Article]
    [Google Scholar]
  255. Flegel WA, Müller F, Däubener W, Fischer HG, Hadding U et al. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun 1991; 59:3659–3666 [View Article]
    [Google Scholar]
  256. McGhee JR, Mahida YR, Galvin A, Makh S, Hyde S et al. Effect of Clostridium difficile toxin A on human colonic lamina propria cells: early loss of macrophages followed by T-cell apoptosis. Infect Immun 1998; 66:5462–5469 [View Article]
    [Google Scholar]
  257. Rocha MF, Maia ME, Bezerra LR, Lyerly DM, Guerrant RL et al. Clostridium difficile toxin A induces the release of neutrophil chemotactic factors from rat peritoneal macrophages: role of interleukin-1beta, tumor necrosis factor alpha, and leukotrienes. Infect Immun 1997; 65:2740–2746 [View Article]
    [Google Scholar]
  258. Castagliuolo I, Keates AC, Qiu B, Kelly CP, Nikulasson S et al. Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci 1997; 94:4788–4793 [View Article]
    [Google Scholar]
  259. Vohra P, Poxton IR. Induction of cytokines in a macrophage cell line by proteins of Clostridium difficile. FEMS Immunol Med Microbiol 2012; 65:96–104 [View Article]
    [Google Scholar]
  260. Lynch M, Walsh TA, Marszalowska I, Webb AE, Mac Aogain M et al. Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response. BMC Evol Biol 2017; 17:90 [View Article]
    [Google Scholar]
  261. Artis D, Spits H. The biology of innate lymphoid cells. Nature 2015; 517:293–301 [View Article]
    [Google Scholar]
  262. Saleh MM, Petri WA. Type 3 immunity during Clostridioides difficile infection: too much of a good thing?. Infect Immun 2019; 88:1–14 [View Article]
    [Google Scholar]
  263. Kamizono S, Duncan GS, Seidel MG, Morimoto A, Hamada K et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J Exp Med 2009; 206:2977–2986 [View Article]
    [Google Scholar]
  264. Yu X, Wang Y, Deng M, Li Y, Ruhn KA et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife 2014; 3:1–20
    [Google Scholar]
  265. Geiger TL, Abt MC, Gasteiger G, Firth MA, O’Connor MH et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med 2014; 211:1723–1731 [View Article]
    [Google Scholar]
  266. Abt MC, Lewis BB, Caballero S, Xiong H, Carter RA et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host Microbe 2015; 18:27–37 [View Article]
    [Google Scholar]
  267. Frisbee AL, Saleh MM, Young MK, Leslie JL, Simpson ME et al. IL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection. Nat Commun 2019; 10:1–13 [View Article]
    [Google Scholar]
  268. Nagao-Kitamoto H, Leslie JL, Kitamoto S, Jin C, Thomsson KA et al. Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota. Nat Med 2020; 26:608–617 [View Article]
    [Google Scholar]
  269. Johal SS, Lambert CP, Hammond J, James PD, Borriello SP et al. Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrent Clostridium difficile associated diarrhoea. J Clin Pathol 2004; 57:973–979 [View Article]
    [Google Scholar]
  270. Littman DR, Pamer EG. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 2011; 10:311–323 [View Article]
    [Google Scholar]
  271. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 2009; 30:626–635 [View Article]
    [Google Scholar]
  272. Yacyshyn MB, Reddy TN, Plageman LR, Wu J, Hollar AR et al. Clostridium difficile recurrence is characterized by pro-inflammatory peripheral blood mononuclear cell (PBMC) phenotype. J Med Microbiol 2014; 63:1260–1273 [View Article]
    [Google Scholar]
  273. Saleh MM, Frisbee AL, Leslie JL, Buonomo EL, Cowardin CA et al. Colitis-induced Th17 cells increase the risk for severe subsequent Clostridium difficile infection. Cell Host Microbe 2019; 25:756–765 [View Article]
    [Google Scholar]
  274. Johnston PF, Gerding DN, Knight KL, Morrison RP. Protection from Clostridium difficile infection in CD4 T cell- and polymeric immunoglobulin receptor-deficient mice. Infect Immun 2014; 82:522–531 [View Article]
    [Google Scholar]
  275. Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL et al. Nonsteroidal anti-inflammatory drugs alter the microbiota and exacerbate Clostridium difficile colitis while dysregulating the inflammatory response. mBio 2019; 10:1–18 [View Article]
    [Google Scholar]
  276. Monaghan TM, Robins A, Knox A, Sewell HF, Mahida YR et al. Circulating antibody and memory B-cell responses to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea, inflammatory bowel disease and cystic fibrosis. PLoS One 2013; 8:e74452 [View Article]
    [Google Scholar]
  277. Devera TS, Lang GA, Lanis JM, Rampuria P, Gilmore CL et al. Memory B cells encode neutralizing antibody specific for toxin B from the Clostridium difficile strains VPI 10463 and NAP1/BI/027 but with superior neutralization of VPI 10463 Toxin B. Infect Immun 2016; 84:194–204 [View Article]
    [Google Scholar]
  278. Amadou Amani S, Shadid T, Ballard JD, Lang ML, Torres VJ. Clostridioides difficile infection induces an inferior IgG response to that induced by immunization and is associated with a lack of T follicular helper cell and memory B cell expansion. Infect Immun 2020; 88:1–13 [View Article]
    [Google Scholar]
  279. Shah HB, Smith K, Scott EJ, Larabee JL, James JA et al. Human C. difficile toxin–specific memory B cell repertoires encode poorly neutralizing antibodies. JCI Insight 2020; 5:1–18 [View Article]
    [Google Scholar]
  280. Warny M, Vaerman JP, Avesani V, Delmée M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62:384–389 [View Article]
    [Google Scholar]
  281. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001; 357:189–193 [View Article]
    [Google Scholar]
  282. Leav BA, Blair B, Leney M, Knauber M, Reilly C et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine 2010; 28:965–969 [View Article]
    [Google Scholar]
  283. Wullt M, Norén T, Ljungh Å, Åkerlund T. IgG antibody response to toxins A and B in patients with Clostridium difficile infection. Clin Vaccine Immunol 2012; 19:1552–1554 [View Article]
    [Google Scholar]
  284. Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med 2017; 376:305–317 [View Article]
    [Google Scholar]
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