The agr locus regulates virulence and colonization genes in clostridium difficile 027

Journal of Bacteriology

Volumn 195, Issue 16, 2013, Pages 3672-3681

  Martin, Melissa J ^a   Clare, Simon ^b   Goulding, David ^b   Faulds Pain, Alexandra ^a   Barquist, Lars ^b,c   Browne, Hilary P ^b   Pettit, Laura ^b   Dougan, Gordon ^b   Lawley, Trevor D ^b   Wren, Brendan W ^a  

^a LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE   (United Kingdom)

^b WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^c EUROPEAN BIOINFORMATICS INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIAL TOXIN; CYCLIC GMP;

AGR GENE LOCUS; ARTICLE; BACTERIAL COLONIZATION; BACTERIAL GENE; BACTERIAL GROWTH; BACTERIAL VIRULENCE; BIOSYNTHESIS; CLOSTRIDIUM DIFFICILE; CONTROLLED STUDY; GENE CONTROL; GENE LOCUS; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; RNA SEQUENCE;

AMINO ACID SEQUENCE; BACTERIAL PROTEINS; CHROMOSOME MAPPING; CHROMOSOMES, BACTERIAL; CLOSTRIDIUM DIFFICILE; GENE EXPRESSION REGULATION, BACTERIAL; GENOME, BACTERIAL; MOLECULAR SEQUENCE DATA; MUTAGENESIS, INSERTIONAL; REGULON; RNA, BACTERIAL; VIRULENCE;

EID: 84881238786     PISSN: 00219193     EISSN: 10985530     Source Type: Journal    
DOI: 10.1128/JB.00473-13     Document Type: Article

References (73)

1. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R, Adams V, Vedantam G, Johnson S, Gerding DN, Rood JI. 2009. Toxin B is essential for virulence of Clostridium difficile. Nature 458:1176-1179.
2. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP. 2010. The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711-713.
3. Shen A. 2012. Clostridium difficile toxins: mediators of inflammation. J. Innate Immun. 4:149-158.
4. Johnson S, Gerding DN. 1998. Clostridium difficile-associated diarrhea. Clin. Infect. Dis. 26:1027-1034.
5. Kelly CP, LaMont JT. 2008. Clostridium difficile-more difficult than ever. N. Engl. J. Med. 359:1932-1940.
6. McDonald LC, Killgore GE, Thompson A, Owens RC, Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN. 2005. An epidemic, toxin genevariant strain of Clostridium difficile. N. Engl. J. Med. 353:2433-2441.
7. Hubert B, Loo VG, Bourgault AM, Poirier L, Dascal A, Fortin E, Dionne M, Lorange M. 2007. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin. Infect. Dis. 44:238-244.
8. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, Rene P, Monczak Y, Dascal A. 2005. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N. Engl. J. Med. 353:2442-2449.
9. Redelings MD, Sorvillo F, Mascola L. 2007. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg. Infect. Dis. 13:1417-1419.
10. Goorhuis A, Van der Kooi T, Vaessen N, Dekker FW, Van den Berg R, Harmanus C, van den Hof S, Notermans DW, Kuijper EJ. 2007. Spread and epidemiology of Clostridium difficile polymerase chain reaction ribotype 027/toxinotype III in The Netherlands. Clin. Infect. Dis. 45:695-703.
11. Kuijper EJ, van Dissel JT, Wilcox MH. 2007. Clostridium difficile: changing epidemiology and new treatment options. Curr. Opin. Infect. Dis. 20:376-383.
12. Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, Frost E, McDonald LC. 2005. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366:1079-1084.
13. He M, Miyajima F, Roberts P, Ellison L, Pickard DJ, Martin MJ, Connor TR, Harris SR, Fairley D, Bamford KB, D'Arc S, Brazier J, Brown D, Coia JE, Douce G, Gerding D, Kim HJ, Koh TH, Kato H, Senoh M, Louie T, Michell S, Butt E, Peacock SJ, Brown NM, Riley T, Songer G, Wilcox M, Pirmohamed M, Kuijper E, Hawkey P, Wren BW, Dougan G, Parkhill J, Lawley TD. 2012. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat. Genet. 45:109-113.
14. Stabler RA, He M, Dawson L, Martin M, Valiente E, Corton C, Lawley TD, Sebaihia M, Quail MA, Rose G, Gerding DN, Gibert M, PopoffMR, Parkhill J, Dougan G, Wren BW. 2009. Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol. 10:R102. doi:10.1186/gb-2011-12-10-r102.
15. Healthcare Commission. 2007. Investigation into outbreaks of Clostridium difficile at Maidstone and Tunbridge Wells NHS Trust. Commission for Healthcare Audit and Inspection, London, United Kingdom.
16. Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeno-Tarraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbin-owitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B, Parkhill J. 2006. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat. Genet. 38:779-786.
17. Dapa T, Leuzzi R, Ng YK, Baban ST, Adamo R, Kuehne SA, Scarselli M, Minton NP, Serruto D, Unnikrishnan M. 2013. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile. J. Bacteriol. 195:545-555.
18. Lee AS, Song KP. 2005. LuxS/autoinducer-2 quorum sensing molecule regulates transcriptional virulence gene expression in Clostridium difficile. Biochem. Biophys. Res. Commun. 335:659-666.
19. Antunes A, Martin-Verstraete I, Dupuy B. 2011. CcpA-mediated repression of Clostridium difficile toxin gene expression. Mol. Microbiol. 79:882-899.
20. Dineen SS, Villapakkam AC, Nordman JT, Sonenshein AL. 2007. Repression of Clostridium difficile toxin gene expression by CodY. Mol. Microbiol. 66:206-219.
21. Saujet L, Monot M, Dupuy B, Soutourina O, Martin-Verstraete I. 2011. The key sigma factor of transition phase, SigH, controls sporulation, metabolism, and virulence factor expression in Clostridium difficile. J. Bacteriol. 193:3186-3196.
22. Rosenbusch KE, Bakker D, Kuijper EJ, Smits WK. 2012. C. difficile 630Deltaerm Spo0A regulates sporulation, but does not contribute to toxin production, by direct high-affinity binding to target DNA. PLoS One 7:e48608. doi:10.1371/journal.pone.0048608.
23. Deakin LJ, Clare S, Fagan RP, Dawson LF, Pickard DJ, West MR, Wren BW, Fairweather NF, Dougan G, Lawley TD. 2012. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect. Immun. 80:2704-2711.
24. Underwood S, Guan S, Vijayasubhash V, Baines SD, Graham L, Lewis RJ, Wilcox MH, Stephenson K. 2009. Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. J. Bacteriol. 191:7296-7305.
25. Aubry A, Hussack G, Chen W, KuoLee R, Twine SM, Fulton KM, Foote S, Carrillo CD, Tanha J, Logan SM. 2012. Modulation of toxin production by the flagellar regulon in Clostridium difficile. Infect. Immun. 80: 3521-3532.
26. Tasteyre A, Barc MC, Collignon A, Boureau H, Karjalainen T. 2001. Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization. Infect. Immun. 69:7937-7940.
27. Recsei P, Kreiswirth B, O'Reilly M, Schlievert P, Gruss A, Novick RP. 1986. Regulation of exoprotein gene expression in Staphylococcus aureus by agar. Mol. Gen. Genet. 202:58-61.
28. Novick RP, Ross HF, Projan SJ, Kornblum J, Kreiswirth B, Moghazeh S. 1993. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J. 12:3967-3975.
29. Tegmark K, Morfeldt E, Arvidson S. 1998. Regulation of agr-dependent virulence genes in Staphylococcus aureus by RNAIII from coagulasenegative staphylococci. J. Bacteriol. 180:3181-3186.
30. Koenig RL, Ray JL, Maleki SJ, Smeltzer MS, Hurlburt BK. 2004. Staphylococcus aureus AgrA binding to the RNAIII-agr regulatory region. J. Bacteriol. 186:7549-7555.
31. Leonard PG, Bezar IF, Sidote DJ, Stock AM. 2012. Identification of a hydrophobic cleft in the LytTR domain of AgrA as a locus for small molecule interactions that inhibit DNA binding. Biochemistry 51:10035-10043.
32. Marsden GL, Davis IJ, Wright VJ, Sebaihia M, Kuijper EJ, Minton NP. 2010. Array comparative hybridisation reveals a high degree of similarity between UK and European clinical isolates of hypervirulent Clostridium difficile. BMC Genomics 11:389. doi:10.1186/1471-2164-11-389.
33. Wilson KH. 1983. Efficiency of various bile salt preparations for stimulation of Clostridium difficile spore germination. J. Clin. Microbiol. 18: 1017-1019.
34. Wren BW, Tabaqchali S. 1987. Restriction endonuclease DNA analysis of Clostridium difficile. J. Clin. Microbiol. 25:2402-2404.
35. Harris SR, Feil EJ, Holden MT, Quail MA, Nickerson EK, Chantratita N, Gardete S, Tavares A, Day N, Lindsay JA, Edgeworth JD, de Lencastre H, Parkhill J, Peacock SJ, Bentley SD. 2010. Evolution of MRSA during hospital transmission and intercontinental spread. Science 327: 469-474.
36. Li H, Durbin R. 2009. Fast and accurate short read alignment with Burrows- Wheeler transform. Bioinformatics 25:1754-1760.
37. Heap JT, Kuehne SA, Ehsaan M, Cartman ST, Cooksley CM, Scott JC, Minton NP. 2010. The ClosTron: mutagenesis in Clostridium refined and streamlined. J. Microbiol. Methods 80:49-55.
38. Heap JT, Pennington OJ, Cartman ST, Carter GP, Minton NP. 2007. The ClosTron: a universal gene knock-out system for the genus Clostridium. J. Microbiol. Methods 70:452-464.
39. Perutka J, Wang W, Goerlitz D, Lambowitz AM. 2004. Use of computerdesigned group II introns to disrupt Escherichia coli DExH/D-box protein and DNA helicase genes. J. Mol. Biol. 336:421-439.
40. Purdy D, O'Keeffe TA, Elmore M, Herbert M, McLeod A, Bokori-Brown M, Ostrowski A, Minton NP. 2002. Conjugative transfer of clostridial shuttle vectors from Escherichia coli to Clostridium difficile through circumvention of the restriction barrier. Mol. Microbiol. 46:439-452.
41. Williams DR, Young DI, Young M. 1990. Conjugative plasmid transfer from Escherichia coli to Clostridium acetobutylicum. J. Gen. Microbiol. 136:819-826.
42. Heap JT, Pennington OJ, Cartman ST, Minton NP. 2009. A modular system for Clostridium shuttle plasmids. J. Microbiol. Methods 78:79-85.
43. Perocchi F, Xu Z, Clauder-Munster S, Steinmetz LM. 2007. Antisense artifacts in transcriptome microarray experiments are resolved by actinomycin D. Nucleic Acids Res. 35:e128.
44. Anders S, Huber W. 2010. Differential expression analysis for sequence count data. Genome Biol. 11:R106. doi:10.1186/gb-2010-11-10-r106.
45. Schmittgen TD, Livak KJ. 2008. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc. 3:1101-1108.
46. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG. 2007. Clustal W and Clustal X version 2.0. Bioinformatics 23:2947-2948.
47. Goujon M, McWilliam H, Li W, Valentin F, Squizzato S, Paern J, Lopez R. 2010. A new bioinformatics analysis tools framework at EMBL-EBI. Nucleic Acids Res. 38:W695-W699.
48. He M, Sebaihia M, Lawley TD, Stabler RA, Dawson LF, Martin MJ, Holt KE, Seth-Smith HM, Quail MA, Rance R, Brooks K, Churcher C, Harris D, Bentley SD, Burrows C, Clark L, Corton C, Murray V, Rose G, Thurston S, van Tonder A, Walker D, Wren BW, Dougan G, Parkhill J. 2010. Evolutionary dynamics of Clostridium difficile over short and long time scales. Proc. Natl. Acad. Sci. U. S. A. 107:7527-7532.
49. Ji G, Beavis R, Novick RP. 1997. Bacterial interference caused by autoinducing peptide variants. Science 276:2027-2030.
50. Cartman ST, Heap JT, Kuehne SA, Cockayne A, Minton NP. 2010. The emergence of "hypervirulence" in Clostridium difficile. Int. J. Med. Microbiol. 300:387-395.
51. Chen Y, Indurthi DC, Jones SW, Papoutsakis ET. 2011. Small RNAs in the genus Clostridium. mBio 2:e00340-00310. doi:10.1128/mBio.00340-10.
52. Burge SW, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki EP, Eddy SR, Gardner PP, Bateman A. 2013. Rfam 11.0 10 years of RNA families. Nucleic Acids Res. 41:D226-D232.
53. Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR. 2008. Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science 321:411-413.
54. Lawley TD, Clare S, Walker AW, Goulding D, Stabler RA, Croucher N, Mastroeni P, Scott P, Raisen C, Mottram L, Fairweather NF, Wren BW, Parkhill J, Dougan G. 2009. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77: 3661-3669.
55. Chen X, Katchar K, Goldsmith JD, Nanthakumar N, Cheknis A, Gerding DN, Kelly CP. 2008. A mouse model of Clostridium difficile-associated disease. Gastroenterology 135:1984-1992.
56. Lawley TD, Clare S, Walker AW, Stares MD, Connor TR, Raisen C, Goulding D, Rad R, Schreiber F, Brandt C, Deakin LJ, Pickard DJ, Duncan SH, Flint HJ, Clark TG, Parkhill J, Dougan G. 2012. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8:e1002995. doi:10.1371/journal.ppat.1002995.
57. Qin X, Singh KV, Weinstock GM, Murray BE. 2000. Effects of Enterococcus faecalis fsr genes on production of gelatinase and a serine protease and virulence. Infect. Immun. 68:2579-2586.
58. Wuster A, Babu MM. 2008. Conservation and evolutionary dynamics of the agr cell-to-cell communication system across firmicutes. J. Bacteriol. 190:743-746.
59. Bourgogne A, Hilsenbeck SG, Dunny GM, Murray BE. 2006. Compar-ison of OG1RF and an isogenic fsrB deletion mutant by transcriptional analysis: the Fsr system of Enterococcus faecalis is more than the activator of gelatinase and serine protease. J. Bacteriol. 188:2875-2884.
60. Dingle TC, Mulvey GL, Armstrong GD. 2011. Mutagenic analysis of the Clostridium difficile flagellar proteins, FliC and FliD, and their contribution to virulence in hamsters. Infect. Immun. 79:4061-4067.
61. Simm R, Morr M, Kader A, Nimtz M, Romling U. 2004. GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol. Microbiol. 53:1123-1134.
62. Bordeleau E, Fortier LC, Malouin F, Burrus V. 2011. c-di-GMP turnover in Clostridium difficile is controlled by a plethora of diguanylate cyclases and phosphodiesterases. PLoS Genet. 7:e1002039. doi:10.1371/journal.pgen.1002039.
63. Srivastava D, Waters CM. 2012. A tangled web: regulatory connections between quorum sensing and cyclic Di-GMP. J. Bacteriol. 194:4485-4493.
64. Purcell EB, McKee RW, McBride SM, Waters CM, Tamayo R. 2012. Cyclic diguanylate inversely regulates motility and aggregation in Clostridium difficile. J. Bacteriol. 194:3307-3316.
65. Garcia B, Latasa C, Solano C, Garcia-del Portillo F, Gamazo C, Lasa I. 2004. Role of the GGDEF protein family in Salmonella cellulose biosynthesis and biofilm formation. Mol. Microbiol. 54:264-277.
66. Zogaj X, Nimtz M, Rohde M, Bokranz W, Romling U. 2001. The multicellular morphotypes of Salmonella typhimurium and Escherichia coli produce cellulose as the second component of the extracellular matrix. Mol. Microbiol. 39:1452-1463.
67. Autret N, Raynaud C, Dubail I, Berche P, Charbit A. 2003. Identification of the agr locus of Listeria monocytogenes: role in bacterial virulence. Infect. Immun. 71:4463-4471.
68. Engelbert M, Mylonakis E, Ausubel FM, Calderwood SB, Gilmore MS. 2004. Contribution of gelatinase, serine protease, and fsr to the pathogenesis of Enterococcus faecalis endophthalmitis. Infect. Immun. 72:3628-3633.
69. Mylonakis E, Engelbert M, Qin X, Sifri CD, Murray BE, Ausubel FM, Gilmore MS, Calderwood SB. 2002. The Enterococcus faecalis fsrB gene, a key component of the fsr quorum-sensing system, is associated with virulence in the rabbit endophthalmitis model. Infect. Immun. 70:4678-4681.
70. Sifri CD, Mylonakis E, Singh KV, Qin X, Garsin DA, Murray BE, Ausubel FM, Calderwood SB. 2002. Virulence effect of Enterococcus faecalis protease genes and the quorum-sensing locus fsr in Caenorhabditis elegans and mice. Infect. Immun. 70:5647-5650.
71. Steiner E, Scott J, Minton NP, Winzer K. 2012. An agr quorum sensing system that regulates granulose formation and sporulation in Clostridium acetobutylicum. Appl. Environ. Microbiol. 78:1113-1122.
72. Sidote DJ, Barbieri CM, Wu T, Stock AM. 2008. Structure of the Staphylococcus aureus AgrA LytTR domain bound to DNA reveals a beta fold with an unusual mode of binding. Structure 16:727-735.
73. Carver T, Thomson N, Bleasby A, Berriman M, Parkhill J. 2009. DNAPlotter: circular and linear interactive genome visualization. Bioinformatics 25:119-120.