Integration of metabolism and virulence in Clostridium difficile

Research in Microbiology

Volumn 166, Issue 4, 2015, Pages 375-383

  Bouillaut, Laurent ^a   Dubois, Thomas ^b   Sonenshein, Abraham L ^a   Dupuy, Bruno ^b  

^a TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b INSTITUT PASTEUR   (France)

Author keywords

Clostridium difficile; Metabolic regulation; Redox state; Stickland metabolism; Toxinogenesis

Indexed keywords

BIOTIN; BRANCHED CHAIN AMINO ACID; BUTANOL; BUTYRIC ACID; CYSTEINE; GLUCOSE; NICOTINAMIDE ADENINE DINUCLEOTIDE; PROLINE; REGULATOR PROTEIN; RNA POLYMERASE; SIGMA FACTOR; AMINO ACID; BACTERIAL TOXIN; BUTYRIC ACID DERIVATIVE; FATTY ACID;

ARTICLE; BACTERIAL GENE; BACTERIAL GENOME; BACTERIAL METABOLISM; BACTERIAL VIRULENCE; BACTERIOPHAGE; CARBON SOURCE; CATABOLITE REPRESSION; CLOSTRIDIUM DIFFICILE INFECTION; FRAMESHIFT MUTATION; GENE DELETION; GENE EXPRESSION; GENE INSERTION; GENE LOCUS; GENETIC TRANSCRIPTION; HUMAN; METABOLIC REGULATION; NONHUMAN; NUTRIENT LIMITATION; OXIDATION REDUCTION STATE; PATHOGENESIS; PATHOGENICITY; PATHOGENICITY LOCUS; PEPTOCLOSTRIDIUM DIFFICILE; POINT MUTATION; PRDR GENE; PRIORITY JOURNAL; PROTEIN SYNTHESIS; REGULATOR GENE; REX GENE; SIGH GENE; SPO0A GENE; SPOROGENESIS; START CODON; TCDA GENE; TCDB GENE; TCDR GENE; TOXIN SYNTHESIS; TRANSCRIPTION INITIATION SITE; BIOSYNTHESIS; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENETICS; GROWTH, DEVELOPMENT AND AGING; METABOLISM; VIRULENCE;

BACTERIA (MICROORGANISMS); CLOSTRIDIUM DIFFICILE;

AMINO ACIDS; BACTERIAL TOXINS; BUTYRATES; CLOSTRIDIUM DIFFICILE; FATTY ACIDS; GENE EXPRESSION REGULATION, BACTERIAL; GENE REGULATORY NETWORKS; GLUCOSE; METABOLIC NETWORKS AND PATHWAYS; SIGMA FACTOR; VIRULENCE;

EID: 84928581959     PISSN: 09232508     EISSN: 17697123     Source Type: Journal    
DOI: 10.1016/j.resmic.2014.10.002     Document Type: Article

References (86)

1. 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.
2. 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.
3. Karlsson S., Dupuy B., Mukherjee K., Norin E., Burman L.G., Akerlund T. Expression of Clostridium difficile toxins A and B and their sigma factor TcdD is controlled by temperature. Infect Immun 2003, 71:1784-1793.
4. Yamakawa K., Karasawa T., Ikoma S., Nakamura S. Enhancement of Clostridium difficile toxin production in biotin-limited conditions. J Med Microbiol 1996, 44:111-114.
5. Onderdonk A.B., Lowe B.R., Bartlett J.G. Effect of environmental stress on Clostridium difficile toxin levels during continuous cultivation. Appl Environ Microbiol 1979, 38:637-641.
6. Dupuy B., Sonenshein A.L. Regulated transcription of Clostridium difficile toxin genes. Mol Microbiol 1998, 27:107-120.
7. 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/FEBS 1997, 244:735-742.
8. Karlsson S., Lindberg A., Norin E., Burman L.G., Akerlund T. Toxins, butyric acid, and other short-chain fatty acids are coordinately expressed and down-regulated by cysteine in Clostridium difficile. Infect Immun 2000, 68:5881-5888.
9. Karasawa T., Maegawa T., Nojiri T., Yamakawa K., Nakamura S. Effect of arginine on toxin production by Clostridium difficile in defined medium. Microbiol Immunol 1997, 41:581-585.
10. Karlsson S., Burman L.G., Akerlund T. Suppression of toxin production in Clostridium difficile VPI 10463 by amino acids. Microbiology 1999, 145(Pt. 7):1683-1693.
11. Antunes A., Martin-Verstraete I., Dupuy B. CcpA-mediated repression of Clostridium difficile toxin gene expression. Mol Microbiol 2011, 79:882-899.
12. Underwood S., Guan S., Vijayasubhash V., Baines S.D., Graham L., Lewis R.J., et al. Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. J Bacteriol 2009, 191:7296-7305.
13. 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.
14. Dineen S.S., Villapakkam A.C., Nordman J.T., Sonenshein A.L. Repression of Clostridium difficile toxin gene expression by CodY. Mol Microbiol 2007, 66:206-219.
15. Braun V., Hundsberger T., Leukel P., Sauerborn M., von Eichel-Streiber C. Definition of the single integration site of the pathogenicity locus in Clostridium difficile. Gene 1996, 181:29-38.
16. 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.
17. Matamouros S., England P., Dupuy B. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol Microbiol 2007, 64:1274-1288.
18. Govind R., Dupuy B. Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS pathog 2012, 8:e1002727.
19. 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.
20. Rupnik M. Heterogeneity of large clostridial toxins: importance of Clostridium difficile toxinotypes. FEMS Microbiol Rev 2008, 32:541-555.
21. Hammond G.A., Lyerly D.M., Johnson J.L. Transcriptional analysis of the toxigenic element of Clostridium difficile. Microb Pathog 1997, 22:143-154.
22. Moncrief J.S., Barroso L.A., Wilkins T.D. Positive regulation of Clostridium difficile toxins. Infect Immun 1997, 65:1105-1108.
23. Mani N., Lyras D., Barroso L., Howarth P., Wilkins T., Rood J.I., et al. Environmental response and autoregulation of Clostridium difficile TxeR, a sigma factor for toxin gene expression. J Bacteriol 2002, 184:5971-5978.
24. El Meouche I., Peltier J., Monot M., Soutourina O., Pestel-Caron M., Dupuy B., 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.
25. Raffestin S., Dupuy B., Marvaud J.C., Popoff M.R. BotR/A and TetR are alternative RNA polymerase sigma factors controlling the expression of the neurotoxin and associated protein genes in Clostridium botulinum type A and Clostridium tetani. Mol Microbiol 2005, 55:235-249.
26. Sirigi Reddy A.R., Girinathan B.P., Zapotocny R., Govind R. Identification and characterization of Clostridium sordellii toxin gene regulator. J Bacteriol 2013, 195:4246-4254.
27. Carter G.P., Larcombe S., Li L., Jayawardena D., Awad M.M., Songer J.G., et al. Expression of the large clostridial toxins is controlled by conserved regulatory mechanisms. Int J Med Microbiol 2014 Aug 18, pii: S1438-4221(14)00107-6 [Epub ahead of print]. 10.1016/j.ijmm.2014.08.008.
28. Finn C.W., Silver R.P., Habig W.H., Hardegree M.C., Zon G., Garon C.F. The structural gene for tetanus neurotoxin is on a plasmid. Science 1984, 224:881-884.
29. Garnier T., Cole S.T. Characterization of a bacteriocinogenic plasmid from Clostridium perfringens and molecular genetic analysis of the bacteriocin-encoding gene. J Bacteriol 1986, 168:1189-1196.
30. Eklund M.W., Poysky F.T., Reed S.M., Smith C.A. Bacteriophage and the toxigenicity of Clostridium botulinum type C. Science 1971, 172:480-482.
31. Dupuy B., Matamouros S. Regulation of toxin and bacteriocin synthesis in Clostridium species by a new subgroup of RNA polymerase sigma-factors. Res Microbiol 2006, 157:201-205.
32. Curry S.R., Marsh J.W., Muto C.A., O'Leary M.M., Pasculle A.W., Harrison L.H. tcdC genotypes associated with severe TcdC truncation in an epidemic clone and other strains of Clostridium difficile. J Clin Microbiol 2007, 45:215-221.
33. 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.
34. Govind R., Vediyappan G., Rolfe R.D., Fralick J.A. Evidence that Clostridium difficile TcdC is a membrane-associated protein. J Bacteriol 2006, 188:3716-3720.
35. 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.
36. 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.
37. 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.
38. Bakker D., Smits W.K., Kuijper E.J., Corver J. TcdC does not significantly repress toxin expression in Clostridium difficile 630DeltaErm. PLoS One 2012, 7:e43247.
39. Stickland L.H. Studies in the metabolism of the strict anaerobes (genus Clostridium): the oxidation of alanine by Cl. sporogenes. IV. The reduction of glycine by Cl. sporogenes. Biochem J 1935, 29:889-898.
40. Stickland L.H. Studies in the metabolism of the strict anaerobes (Genus Clostridium): the reduction of proline by Cl. sporogenes. Biochem J 1935, 29:288-290.
41. Woods D.D. Studies in the metabolism of the strict anaerobes (genus Clostridium): further experiments on the coupled reactions between pairs of amino-acids induced by Cl. sporogenes. Biochem J 1936, 30:1934-1946.
42. Pagels M., Fuchs S., Pane-Farre J., Kohler C., Menschner L., Hecker M., et al. Redox sensing by a Rex-family repressor is involved in the regulation of anaerobic gene expression in Staphylococcus aureus. Mol Microbiol 2010, 76:1142-1161.
43. Jackson S., Calos M., Myers A., Self W.T. Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. J Bacteriol 2006, 188:8487-8495.
44. Haslam S.C., Ketley J.M., Mitchell T.J., Stephen J., Burdon D.W., Candy D.C. Growth of Clostridium difficile and production of toxins A and B in complex and defined media. J Med Microbiol 1986, 21:293-297.
45. Karasawa T., Ikoma S., Yamakawa K., Nakamura S. A defined growth medium for Clostridium difficile. Microbiology 1995, 141(Pt. 2):371-375.
46. Osgood D.P., Wood N.P., Sperry J.F. Nutritional aspects of cytotoxin production by Clostridium difficile. Appl Environ Microbiol 1993, 59:3985-3988.
47. Bouillaut L., Self W.T., Sonenshein A.L. Proline-dependent regulation of Clostridium difficile Stickland metabolism. J Bacteriol 2013, 195:844-854.
48. Janoir C., Deneve C., Bouttier S., Barbut F., Hoys S., Caleechum L., et al. Adaptive strategies and pathogenesis of Clostridium difficile from invivo transcriptomics. Infect Immun 2013, 81:3757-3769.
49. Wietzke M., Bahl H. The redox-sensing protein Rex, a transcriptional regulator of solventogenesis in Clostridium acetobutylicum. Appl Microbiol Biotechnol 2012, 96:749-761.
50. Brekasis D., Paget M.S. A novel sensor of NADH/NAD+ redox poise in Streptomyces coelicolor A3(2). EMBO J 2003, 22:4856-4865.
51. Sickmier E.A., Brekasis D., Paranawithana S., Bonanno J.B., Paget M.S., Burley S.K., et al. X-ray structure of a Rex-family repressor/NADH complex insights into the mechanism of redox sensing. Structure 2005, 13:43-54.
52. Gyan S., Shiohira Y., Sato I., Takeuchi M., Sato T. Regulatory loop between redox sensing of the NADH/NAD(+) ratio by Rex (YdiH) and oxidation of NADH by NADH dehydrogenase Ndh in Bacillus subtilis. J Bacteriol 2006, 188:7062-7071.
53. Schau M., Chen Y., Hulett F.M. Bacillus subtilis YdiH is a direct negative regulator of the cydABCD operon. J Bacteriol 2004, 186:4585-4595.
54. Ravcheev D.A., Li X., Latif H., Zengler K., Leyn S.A., Korostelev Y.D., et al. Transcriptional regulation of central carbon and energy metabolism in bacteria by redox-responsive repressor Rex. J Bacteriol 2012, 194:1145-1157.
55. Fujita Y. Carbon catabolite control of the metabolic network in Bacillus subtilis. Biosci Biotechnol Biochem 2009, 73:245-259.
56. Deutscher J., Francke C., Postma P.W. How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. Microbiol Mol Biol Rev 2006, 70:939-1031.
57. Antunes A., Camiade E., Monot M., Courtois E., Barbut F., Sernova N.V., et al. Global transcriptional control by glucose and carbon regulator CcpA in Clostridium difficile. Nucleic Acids Res 2012, 40:10701-10718.
58. Dineen S.S., McBride S.M., Sonenshein A.L. Integration of metabolism and virulence by Clostridium difficile CodY. J Bacteriol 2010, 192:5350-5362.
59. Sonenshein A.L. CodY, a global regulator of stationary phase and virulence in Gram-positive bacteria. Curr Opin Microbiol 2005, 8:203-207.
60. Slack F.J., Serror P., Joyce E., Sonenshein A.L. A gene required for nutritional repression of the Bacillus subtilis dipeptide permease operon. Mol Microbiol 1995, 15:689-702.
61. Molle V., Nakaura Y., Shivers R.P., Yamaguchi H., Losick R., Fujita Y., et al. Additional targets of the Bacillus subtilis global regulator CodY identified by chromatin immunoprecipitation and genome-wide transcript analysis. J Bacteriol 2003, 185:1911-1922.
62. den Hengst C.D., van Hijum S.A., Geurts J.M., Nauta A., Kok J., Kuipers O.P. The Lactococcus lactis CodY regulon: identification of a conserved cis-regulatory element. J Biol Chem 2005, 280:34332-34342.
63. Bennett H.J., Pearce D.M., Glenn S., Taylor C.M., Kuhn M., Sonenshein A.L., et al. Characterization of relA and codY mutants of Listeria monocytogenes: identification of the CodY regulon and its role in virulence. Mol Microbiol 2007, 63:1453-1467.
64. Hendriksen W.T., Bootsma H.J., Estevao S., Hoogenboezem T., de Jong A., de Groot R., et al. CodY of Streptococcus pneumoniae: link between nutritional gene regulation and colonization. J Bacteriol 2008, 190:590-601.
65. Malke H., Ferretti J.J. CodY-affected transcriptional gene expression of Streptococcus pyogenes during growth in human blood. J Med Microbiol 2007, 56:707-714.
66. Hsueh Y.H., Somers E.B., Wong A.C. Characterization of the codY gene and its influence on biofilm formation in Bacillus cereus. Arch Microbiol 2008, 189:557-568.
67. van Schaik W., Chateau A., Dillies M.A., Coppee J.Y., Sonenshein A.L., Fouet A. The global regulator CodY regulates toxin gene expression in Bacillus anthracis and is required for full virulence. Infect Immun 2009, 77:4437-4445.
68. Pohl K., Francois P., Stenz L., Schlink F., Geiger T., Herbert S., et al. CodY in Staphylococcus aureus: a regulatory link between metabolism and virulence gene expression. J Bacteriol 2009, 191:2953-2963.
69. Majerczyk C.D., Sadykov M.R., Luong T.T., Lee C., Somerville G.A., Sonenshein A.L. Staphylococcus aureus CodY negatively regulates virulence gene expression. J Bacteriol 2008, 190:2257-2265.
70. Levdikov V.M., Blagova E., Colledge V.L., Lebedev A.A., Williamson D.C., Sonenshein A.L., et al. Structural rearrangement accompanying ligand binding in the GAF domain of CodY from Bacillus subtilis. J Mol Biol 2009, 390:1007-1018.
71. Villapakkam A.C., Handke L.D., Belitsky B.R., Levdikov V.M., Wilkinson A.J., Sonenshein A.L. Genetic and biochemical analysis of the interaction of Bacillus subtilis CodY with branched-chain amino acids. J Bacteriol 2009, 191:6865-6876.
72. Shivers R.P., Sonenshein A.L. Activation of the Bacillus subtilis global regulator CodY by direct interaction with branched-chain amino acids. Mol Microbiol 2004, 53:599-611.
73. Ratnayake-Lecamwasam M., Serror P., Wong K.W., Sonenshein A.L. Bacillus subtilis CodY represses early-stationary-phase genes by sensing GTP levels. Genes Dev 2001, 15:1093-1103.
74. Handke L.D., Shivers R.P., Sonenshein A.L. Interaction of Bacillus subtilis CodY with GTP. J Bacteriol 2008, 190:798-806.
75. Guedon E., Sperandio B., Pons N., Ehrlich S.D., Renault P. Overall control of nitrogen metabolism in Lactococcus lactis by CodY, and possible models for CodY regulation in Firmicutes. Microbiology 2005, 151:3895-3909.
76. Belitsky B.R., Sonenshein A.L. Genetic and biochemical analysis of CodY-binding sites in Bacillus subtilis. J Bacteriol 2008, 190:1224-1236.
77. Lopez J.M., Dromerick A., Freese E. Response of guanosine 5'-triphosphate concentration to nutritional changes and its significance for Bacillus subtilis sporulation. J Bacteriol 1981, 146:605-613.
78. Morohashi M., Ohashi Y., Tani S., Ishii K., Itaya M., Nanamiya H., et al. Model-based definition of population heterogeneity and its effects on metabolism in sporulating Bacillus subtilis. J Biochem 2007, 142:183-191.
79. Ikeda D., Karasawa T., Yamakawa K., Tanaka R., Namiki M., Nakamura S. Effect of isoleucine on toxin production by Clostridium difficile in a defined medium. Zentralbl Bakteriol 1998, 287:375-386.
80. Ochi K., Kandala J., Freese E. Evidence that Bacillus subtilis sporulation induced by the stringent response is caused by the decrease in GTP or GDP. J Bacteriol 1982, 151:1062-1065.
81. Piggot P.J., Hilbert D.W. Sporulation of Bacillus subtilis. Curr Opin Microbiol 2004, 7:579-586.
82. Paredes-Sabja D., Shen A., Sorg J.A. Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. Trends Microbiol 2014, 22:406-416.
83. Pettit L.J., Browne H.P., Yu L., Smits W.K., Fagan R.P., Barquist L., et al. Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism. BMC Genomics 2014, 15:160.
84. Deakin L.J., Clare S., Fagan R.P., Dawson L.F., Pickard D.J., West M.R., et al. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect Immun 2012, 80:2704-2711.
85. Mackin K.E., Carter G.P., Howarth P., Rood J.I., Lyras D. Spo0A differentially regulates toxin production in evolutionarily diverse strains of Clostridium difficile. PLoS One 2013, 8:e79666.
86. Rosenbusch K.E., Bakker D., Kuijper E.J., Smits W.K. C. difficile 630Deltaerm Spo0A regulates sporulation, but does not contribute to toxin production, by direct high-affinity binding to target DNA. PLoS One 2012, 7:e48608.