1887

Abstract

EDIN-B (epidermal cell differentiation inhibitor-B; also termed C3Stau) is an exotoxin of which ADP-ribosylates and inactivates Rho GTP binding proteins. The EDIN-B gene () and the gene for exfoliative toxin D () make up the central part of a recently described pathogenicity island. Here we evaluated the prevalence and genetic organization of the pathogenicity island in invasive isolates, and characterized transcription and EDIN-B production using artificial constructs transduced in strains RN6390 and Newman. We found that eight out of121 (7 %) blood culture isolates harbour , which is organized in three novel variants of the original pathogenicity island. In the serum of patients infected with -positive , significant titres of anti-EDIN-B antibodies could be detected. Regulation of transcription depended on the but not on the regulatory system. Furthermore, retrieval of EDIN-B protein secreted by RN6390 required the presence of 2-macroglobulin to inhibit the activity of extracellular proteases. These data suggest that the EDIN-B toxin is produced during human infection, is part of a highly variable pathogenicity island and can be controlled by the gene regulon and secreted bacterial proteases.

Keyword(s): CC, clonal complex
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2010-03-01
2020-11-23
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References

  1. Aepfelbacher M., Essler M., Huber E., Sugai M., Weber P. C. 1997; Bacterial toxins block endothelial wound repair. Evidence that Rho GTPases control cytoskeletal rearrangements in migrating endothelial cells. Arterioscler Thromb Vasc Biol 17:1623–1629
    [Google Scholar]
  2. Aepfelbacher M., Trasak C., Ruckdeschel K. 2007; Effector functions of pathogenic Yersinia species. Thromb Haemost 98:521–529
    [Google Scholar]
  3. Aktories K., Barbieri J. T. 2005; Bacterial cytotoxins: targeting eukaryotic switches. Nat Rev Microbiol 3:397–410
    [Google Scholar]
  4. Arvidson S., Tegmark K. 2001; Regulation of virulence determinants in Staphylococcus aureus. Int J Med Microbiol 291:159–170
    [Google Scholar]
  5. Augustin J., Gotz F. 1990; Transformation of Staphylococcus epidermidis and other staphylococcal species with plasmid DNA by electroporation. FEMS Microbiol Lett 54:203–207
    [Google Scholar]
  6. Ben Nejma M., Mastouri M., Bel Hadj Jrad B., Nour M. 2008; Characterization of ST80 Panton–Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus clone in Tunisia. Diagn Microbiol Infect Dis in press
    [Google Scholar]
  7. Bischoff M., Dunman P., Kormanec J., Macapagal D., Murphy E., Mounts W., Berger-Bachi B., Projan S. 2004; Microarray-based analysis of the Staphylococcus aureus σB regulon. J Bacteriol 186:4085–4099
    [Google Scholar]
  8. Blevins J. S., Beenken K. E., Elasri M. O., Hurlburt B. K., Smeltzer M. S. 2002; Strain-dependent differences in the regulatory roles of sarA and agr in Staphylococcus aureus. Infect Immun 70:470–480
    [Google Scholar]
  9. Bokoch G. M. 2005; Regulation of innate immunity by Rho GTPases. Trends Cell Biol 15:163–171
    [Google Scholar]
  10. Boyer L., Doye A., Rolando M., Flatau G., Munro P., Gounon P., Clément R., Pulcini C., Popoff M. R. other authors 2006; Induction of transient macroapertures in endothelial cells through RhoA inhibition by Staphylococcus aureus factors. J Cell Biol 173:809–819
    [Google Scholar]
  11. Bronner S., Monteil H., Prevost G. 2004; Regulation of virulence determinants in Staphylococcus aureus: complexity and applications. FEMS Microbiol Rev 28:183–200
    [Google Scholar]
  12. Bruckner R. 1992; A series of shuttle vectors for Bacillus subtilis and Escherichia coli. Gene 122:187–192
    [Google Scholar]
  13. Cassat J., Dunman P. M., Murphy E., Projan S. J., Beenken K. E., Palm K. J., Yang S. J., Rice K. C., Bayles K. W., Smeltzer M. S. 2006; Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390. Microbiology 152:3075–3090
    [Google Scholar]
  14. Chan P. F., Foster S. J. 1998; Role of SarA in virulence determinant production and environmental signal transduction in Staphylococcus aureus. J Bacteriol 180:6232–6241
    [Google Scholar]
  15. Cheung A. L., Eberhardt K., Heinrichs J. H. 1997; Regulation of protein A synthesis by the sar and agr loci of Staphylococcus aureus. Infect Immun 65:2243–2249
    [Google Scholar]
  16. Cheung A. L., Bayer A. S., Zhang G., Gresham H., Xiong Y. Q. 2004; Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol Med Microbiol 40:1–9
    [Google Scholar]
  17. Cheung A. L., Nishina K. A., Trotonda M. P., Tamber S. 2008; The SarA protein family of Staphylococcus aureus. Int J Biochem Cell Biol 40:355–361
    [Google Scholar]
  18. Chien Y., Manna A. C., Projan S. J., Cheung A. L. 1999; SarA, a global regulator of virulence determinants in Staphylococcus aureus, binds to a conserved motif essential for sar-dependent gene regulation. J Biol Chem 274:37169–37176
    [Google Scholar]
  19. Chongtrakool P., Ito T., Ma X. X., Kondo Y., Trakulsomboon S., Tiensasitorn C., Jamklang M., Chavalit T., Song J. H., Hiramatsu K. 2006; Staphylococcal cassette chromosome mec (SCC mec) typing of methicillin-resistant Staphylococcus aureus strains isolated in 11 Asian countries: a proposal for a new nomenclature for SCC mec elements. Antimicrob Agents Chemother 50:1001–1012
    [Google Scholar]
  20. Clarke S. R., Brummell K. J., Horsburgh M. J., McDowell P. W., Mohamad S. A., Stapleton M. R., Acevedo J., Read R. C., Day N. P. other authors 2006; Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J Infect Dis 193:1098–1108
    [Google Scholar]
  21. Czech A., Yamaguchi T., Bader L., Linder S., Kaminski K., Sugai M., Aepfelbacher M. 2001; Prevalence of Rho-inactivating epidermal cell differentiation inhibitor toxins in clinical Staphylococcus aureus isolates. J Infect Dis 184:785–788
    [Google Scholar]
  22. Deurenberg R. H., Stobberingh E. E. 2008; The evolution of Staphylococcus aureus. Infect Genet Evol 8:747–763
    [Google Scholar]
  23. Deurenberg R. H., Vink C., Kalenic S., Friedrich A. W., Bruggeman C. A., Stobberingh E. E. 2007; The molecular evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 13:222–235
    [Google Scholar]
  24. Dunman P. M., Murphy E., Haney S., Palacios D., Tucker-Kellogg G., Wu S., Brown E. L., Zagursky R. J., Shlaes D., Projan S. J. 2001; Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol 183:7341–7353
    [Google Scholar]
  25. Duthie E. S., Lorenz L. L. 1952; Staphylococcal coagulase; mode of action and antigenicity. J Gen Microbiol 6:95–107
    [Google Scholar]
  26. Fitzgerald J. R., Reid S. D., Ruotsalainen E., Tripp T. J., Liu M., Cole R., Kuusela P., Schlievert P. M., Järvinen A., Musser J. M. 2003; Genome diversification in Staphylococcus aureus: molecular evolution of a highly variable chromosomal region encoding the staphylococcal exotoxin-like family of proteins. Infect Immun 71:2827–2838
    [Google Scholar]
  27. Genth H., Dreger S. C., Huelsenbeck J., Just I. 2008; Clostridium difficile toxins: more than mere inhibitors of Rho proteins. Int J Biochem Cell Biol 40:592–597
    [Google Scholar]
  28. Giachino P., Engelmann S., Bischoff M. 2001; σB activity depends on RsbU in Staphylococcus aureus. J Bacteriol 183:1843–1852
    [Google Scholar]
  29. Goerke C., Wolz C. 2004; Regulatory and genomic plasticity of Staphylococcus aureus during persistent colonization and infection. Int J Med Microbiol 294:195–202
    [Google Scholar]
  30. Goerke C., Fluckiger U., Steinhuber A., Zimmerli W., Wolz C. 2001; Impact of the regulatory loci agr, sarA and sae of Staphylococcus aureus on the induction of α-toxin during device-related infection resolved by direct quantitative transcript analysis. Mol Microbiol 40:1439–1447
    [Google Scholar]
  31. Gordon J. J., Towsey M. W., Hogan J. M., Mathews S. A., Timms P. 2006; Improved prediction of bacterial transcription start sites. Bioinformatics 22:142–148
    [Google Scholar]
  32. Hacker J., Kaper J. B. 2000; Pathogenicity islands and the evolution of microbes. Annu Rev Microbiol 54:641–679
    [Google Scholar]
  33. Harmsen D., Claus H., Witte W., Rothganger J., Turnwald D., Vogel U. 2003; Typing of methicillin-resistant Staphylococcus aureus in a university hospital setting by using novel software for spa repeat determination and database management. J Clin Microbiol 41:5442–5448
    [Google Scholar]
  34. Harraghy N., Kormanec J., Wolz C., Homerova D., Goerke C., Ohlsen K., Qazi S., Hill P., Herrmann M. 2005; sae is essential for expression of the staphylococcal adhesins Eap and Emp. Microbiology 151:1789–1800
    [Google Scholar]
  35. Holmes A., Ganner M., McGuane S., Pitt T. L., Cookson B. D., Kearns A. M. 2005; Staphylococcus aureus isolates carrying Panton–Valentine leucocidin genes in England and Wales: frequency, characterization, and association with clinical disease. J Clin Microbiol 43:2384–2390
    [Google Scholar]
  36. Holtfreter S., Grumann D., Schmudde M., Nguyen H. T., Eichler P., Strommenger B., Kopron K., Kolata J., Giedrys-Kalemba S. other authors 2007; Clonal distribution of superantigen genes in clinical Staphylococcus aureus isolates. J Clin Microbiol 45:2669–2680
    [Google Scholar]
  37. Horsburgh M. J., Aish J. L., White I. J., Shaw L., Lithgow J. K., Foster S. J. 2002; σB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4. J Bacteriol 184:5457–5467
    [Google Scholar]
  38. Jaffe A. B., Hall A. 2005; Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269
    [Google Scholar]
  39. Karlsson A., Arvidson S. 2002; Variation in extracellular protease production among clinical isolates of Staphylococcus aureus due to different levels of expression of the protease repressor sarA. Infect Immun 70:4239–4246
    [Google Scholar]
  40. Knobloch J. K., Jager S., Horstkotte M. A., Rohde H., Mack D. 2004; RsbU-dependent regulation of Staphylococcus epidermidis biofilm formation is mediated via the alternative sigma factor σB by repression of the negative regulator gene icaR. Infect Immun 72:3838–3848
    [Google Scholar]
  41. Ladhani S., Joannou C. L., Lochrie D. P., Evans R. W., Poston S. M. 1999; Clinical, microbial, and biochemical aspects of the exfoliative toxins causing staphylococcal scalded-skin syndrome. Clin Microbiol Rev 12:224–242
    [Google Scholar]
  42. Laemmli U. K. 1970; Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685
    [Google Scholar]
  43. Lindsay J. A., Foster S. J. 1999; Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus. Mol Gen Genet 262:323–331
    [Google Scholar]
  44. Lindsay J. A., Holden M. T. 2006; Understanding the rise of the superbug: investigation of the evolution and genomic variation of Staphylococcus aureus. Funct Integr Genomics 6:186–201
    [Google Scholar]
  45. Livak K. J., Schmittgen T. D. 2001; Analysis of relative gene expression data using real-time quantitative PCR and the method. Methods 25:402–408
    [Google Scholar]
  46. Lowy F. D. 1998; Staphylococcus aureus infections. N Engl J Med 339:520–532
    [Google Scholar]
  47. Mack D., Bartscht K., Fischer C., Rohde H., de Grahl C., Dobinsky S., Horstkotte M. A., Kiel K., Knobloch J. K. 2001; Genetic and biochemical analysis of Staphylococcus epidermidis biofilm accumulation. Methods Enzymol 336:215–239
    [Google Scholar]
  48. McAleese F. M., Walsh E. J., Sieprawska M., Potempa J., Foster T. J. 2001; Loss of clumping factor B fibrinogen binding activity by Staphylococcus aureus involves cessation of transcription, shedding and cleavage by metalloprotease. J Biol Chem 276:29969–29978
    [Google Scholar]
  49. Mellmann A., Weniger T., Berssenbrugge C., Rothganger J., Sammeth M., Stoye J., Harmsen D. 2007; Based Upon Repeat Pattern (BURP): an algorithm to characterize the long-term evolution of Staphylococcus aureus populations based on spa polymorphisms. BMC Microbiol 7:98
    [Google Scholar]
  50. Monecke S., Slickers P., Hotzel H., Richter-Huhn G., Pohle M., Weber S., Witte W., Ehricht R. 2006; Microarray-based characterisation of a Panton–Valentine leukocidin-positive community-acquired strain of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 12:718–728
    [Google Scholar]
  51. Morfeldt E., Janzon L., Arvidson S., Lofdahl S. 1988; Cloning of a chromosomal locus ( exp) which regulates the expression of several exoprotein genes in Staphylococcus aureus. Mol Gen Genet 211:435–440
    [Google Scholar]
  52. Murchan S., Kaufmann M. E., Deplano A., de Ryck R., Struelens M., Zinn C. E., Fussing V., Salmenlinna S., Vuopio-Varkila J. other authors 2003; Harmonization of pulsed-field gel electrophoresis protocols for epidemiological typing of strains of methicillin-resistant Staphylococcus aureus: a single approach developed by consensus in 10 European laboratories and its application for tracing the spread of related strains. J Clin Microbiol 41:1574–1585
    [Google Scholar]
  53. Novick R. P. 1991; Genetic systems in staphylococci. Methods Enzymol 204:587–636
    [Google Scholar]
  54. Novick R. P. 2003; Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 48:1429–1449
    [Google Scholar]
  55. Novick R. P., Ross H. F., Projan S. J., Kornblum J., Kreiswirth B., Moghazeh S. 1993; Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J 12:3967–3975
    [Google Scholar]
  56. Oscarsson J., Kanth A., Tegmark-Wisell K., Arvidson S. 2006a; SarA is a repressor of hla ( α-hemolysin) transcription in Staphylococcus aureus: its apparent role as an activator of hla in the prototype strain NCTC 8325 depends on reduced expression of sarS. J Bacteriol 188:8526–8533
    [Google Scholar]
  57. Oscarsson J., Tegmark-Wisell K., Arvidson S. 2006b; Coordinated and differential control of aureolysin ( aur) and serine protease ( sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII. Int J Med Microbiol 296:365–380
    [Google Scholar]
  58. Peacock S. J., Moore C. E., Justice A., Kantzanou M., Story L., Mackie K., O'Neill G., Day N. P. 2002; Virulent combinations of adhesin and toxin genes in natural populations of Staphylococcus aureus. Infect Immun 70:4987–4996
    [Google Scholar]
  59. Peng H. L., Novick R. P., Kreiswirth B., Kornblum J., Schlievert P. 1988; Cloning, characterization, and sequencing of an accessory gene regulator ( agr) in Staphylococcus aureus. J Bacteriol 170:4365–4372
    [Google Scholar]
  60. Recsei P., Kreiswirth B., O'Reilly M., Schlievert P., Gruss A., Novick R. P. 1986; Regulation of exoprotein gene expression in Staphylococcus aureus by agr. Mol Gen Genet 202:58–61
    [Google Scholar]
  61. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: a Laboratory Manual, 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
  62. Shaw L., Golonka E., Potempa J., Foster S. J. 2004; The role and regulation of the extracellular proteases of Staphylococcus aureus. Microbiology 150:217–228
    [Google Scholar]
  63. Sugai M., Enomoto T., Hashimoto K., Matsumoto K., Matsuo Y., Ohgai H., Hong Y. M., Inoue S., Yoshikawa K., Suginaka H. 1990; A novel epidermal cell differentiation inhibitor (EDIN): purification and characterization from Staphylococcus aureus. Biochem Biophys Res Commun 173:92–98
    [Google Scholar]
  64. Sugai M., Hashimoto K., Kikuchi A., Inoue S., Okumura H., Matsumoto K., Goto Y., Ohgai H., Moriishi K. other authors 1992; Epidermal cell differentiation inhibitor ADP-ribosylates small GTP-binding proteins and induces hyperplasia of epidermis. J Biol Chem 267:2600–2604
    [Google Scholar]
  65. Sung J. M., Lloyd D. H., Lindsay J. A. 2008; Staphylococcus aureus host specificity: comparative genomics of human versus animal isolates by multi-strain microarray. Microbiology 154:1949–1959
    [Google Scholar]
  66. Tenover F. C., Arbeit R. D., Goering R. V., Mickelsen P. A., Murray B. E., Persing D. H., Swaminathan B. 1995; Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol 33:2233–2239
    [Google Scholar]
  67. Vandenesch F., Naimi T., Enright M. C., Lina G., Nimmo G. R., Heffernan H., Liassine N., Bes M., Greenland T. other authors 2003; Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton–Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 9:978–984
    [Google Scholar]
  68. Wilde C., Chhatwal G. S., Schmalzing G., Aktories K., Just I. 2001; A novel C3-like ADP-ribosyltransferase from Staphylococcus aureus modifying RhoE and Rnd3. J Biol Chem 276:9537–9542
    [Google Scholar]
  69. Witte W., Strommenger B., Cuny C., Heuck D., Nuebel U. 2007; Methicillin-resistant Staphylococcus aureus containing the Panton–Valentine leucocidin gene in Germany in 2005 and 2006. J Antimicrob Chemother 60:1258–1263
    [Google Scholar]
  70. Wolz C., McDevitt D., Foster T. J., Cheung A. L. 1996; Influence of agr on fibrinogen binding in Staphylococcus aureus Newman. Infect Immun 64:3142–3147
    [Google Scholar]
  71. Wolz C., Pohlmann-Dietze P., Steinhuber A., Chien Y. T., Manna A., van Wamel W., Cheung A. 2000; agr-independent regulation of fibronectin-binding protein(s) by the regulatory locus sar in Staphylococcus aureus. Mol Microbiol 36:230–243
    [Google Scholar]
  72. Yamaguchi T., Hayashi T., Takami H., Ohnishi M., Murata T., Nakayama K., Asakawa K., Ohara M., Komatsuzawa H., Sugai M. 2001; Complete nucleotide sequence of a Staphylococcus aureus exfoliative toxin B plasmid and identification of a novel ADP-ribosyltransferase, EDIN-C. Infect Immun 69:7760–7771
    [Google Scholar]
  73. Yamaguchi T., Nishifuji K., Sasaki M., Fudaba Y., Aepfelbacher M., Takata T., Ohara M., Komatsuzawa H., Amagai M., Sugai M. 2002a; Identification of the Staphylococcus aureus etd pathogenicity island which encodes a novel exfoliative toxin, ETD, and EDIN-B. Infect Immun 70:5835–5845
    [Google Scholar]
  74. Yamaguchi T., Yokota Y., Terajima J., Hayashi T., Aepfelbacher M., Ohara M., Komatsuzawa H., Watanabe H., Sugai M. 2002b; Clonal association of Staphylococcus aureus causing bullous impetigo and the emergence of new methicillin-resistant clonal groups in Kansai district in Japan. J Infect Dis 185:1511–1516
    [Google Scholar]
  75. Yamasaki O., Tristan A., Yamaguchi T., Sugai M., Lina G., Bes M., Vandenesch F., Etienne J. 2006; Distribution of the exfoliative toxin D gene in clinical Staphylococcus aureus isolates in France. Clin Microbiol Infect 12:585–588
    [Google Scholar]
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