1887

Abstract

is a major human pathogen and a common cause of nosocomial infections. This facultative pathogen produces a large arsenal of virulence factors, including the haemolysins, which allow the bacterium to lyse erythrocytes and thereby release large amounts of the haem-containing haemoglobin. The released haem is thought to be the main iron source of this organism during the course of infection, and is considered to be crucial for bacterial proliferation . High concentrations of haem and its degradation products, on the other hand, are known to be toxic for , making it essential for the pathogen to tightly control haem release from red blood cells. Here we show that responds to haemin by downregulating the expression of haemolysins. Subinhibitory concentrations of haemin were found to significantly reduce transcription of the haemolysin genes (encoding β-haemolysin) and (encoding the S-class component of γ-haemolysin), while (encoding α-haemolysin) and RNAIII (encoding δ-haemolysin) transcription did not appear to be affected. The presence of haemin also reduced the haemolytic potential of the supernatants of LS1 cultures. Inactivation of the locus in LS1 abolished the haemin effect on the transcription of haemolysin genes, indicating that the two-component regulatory system is required for this regulatory effect. Iron limitation, on the other hand, was found to induce the expression of haemolysins, and this effect was again abolished in the mutant, indicating that modulates its haemolysin production in response to iron and haem availability in an Sae-dependent manner.

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2012-10-01
2024-03-28
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References

  1. Adhikari R. P., Novick R. P. ( 2008). Regulatory organization of the staphylococcal sae locus. Microbiology 154:949–959 [View Article][PubMed]
    [Google Scholar]
  2. Beasley F. C., Vinés E. D., Grigg J. C., Zheng Q., Liu S., Lajoie G. A., Murphy M. E., Heinrichs D. E. ( 2009). Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus. . Mol Microbiol 72:947–963 [View Article][PubMed]
    [Google Scholar]
  3. Bischoff M., Dunman P., Kormanec J., Macapagal D., Murphy E., Mounts W., Berger-Bächi B., Projan S. ( 2004). Microarray-based analysis of the Staphylococcus aureus sigmaB regulon. J Bacteriol 186:4085–4099[PubMed] [CrossRef]
    [Google Scholar]
  4. Bremell T., Abdelnour A., Tarkowski A. ( 1992). Histopathological and serological progression of experimental Staphylococcus aureus arthritis. Infect Immun 60:2976–2985[PubMed]
    [Google Scholar]
  5. Bronner S., Monteil H., Prévost G. ( 2004). Regulation of virulence determinants in Staphylococcus aureus: complexity and applications. FEMS Microbiol Rev 28:183–200[PubMed] [CrossRef]
    [Google Scholar]
  6. Chatterjee I., Becker P., Grundmeier M., Bischoff M., Somerville G. A., Peters G., Sinha B., Harraghy N., Proctor R. A., Herrmann M. ( 2005). Staphylococcus aureus ClpC is required for stress resistance, aconitase activity, growth recovery, and death. J Bacteriol 187:4488–4496 [View Article][PubMed]
    [Google Scholar]
  7. Cheung A. L., Chien Y. T., Bayer A. S. ( 1999). Hyperproduction of alpha-hemolysin in a sigB mutant is associated with elevated SarA expression in Staphylococcus aureus. . Infect Immun 67:1331–1337[PubMed]
    [Google Scholar]
  8. CLSI( 2009).Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically
  9. Diekema D. J., Pfaller M. A., Schmitz F. J., Smayevsky J., Bell J., Jones R. N., Beach M. SENTRY Partcipants Group ( 2001). Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 32:Suppl 2S114–S132 [View Article][PubMed]
    [Google Scholar]
  10. Dryla A., Gelbmann D., von Gabain A., Nagy E. ( 2003). Identification of a novel iron regulated staphylococcal surface protein with haptoglobin-haemoglobin binding activity. Mol Microbiol 49:37–53 [View Article][PubMed]
    [Google Scholar]
  11. Duthie E. S. ( 1952). Variation in the antigenic composition of staphylococcal coagulase. J Gen Microbiol 7:320–326 [View Article][PubMed]
    [Google Scholar]
  12. Dyke K. G., Jevons M. P., Parker M. T. ( 1966). Penicillinase production and intrinsic resistance to penicillins in Staphylococcus aureus . Lancet 287:835–838 [View Article]
    [Google Scholar]
  13. Entenza J. M., Vouillamoz J., Glauser M. P., Moreillon P. ( 1997). Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus. . Antimicrob Agents Chemother 41:1662–1667[PubMed]
    [Google Scholar]
  14. Everse J., Hsia N. ( 1997). The toxicities of native and modified hemoglobins. Free Radic Biol Med 22:1075–1099 [View Article][PubMed]
    [Google Scholar]
  15. Fenwick B., Rider M., Liang J., Brightman A. ( 1996). Iron repressible outer membrane proteins of Moraxella bovis and demonstration of siderophore-like activity. Vet Microbiol 48:315–324 [View Article][PubMed]
    [Google Scholar]
  16. Geiger T., Goerke C., Mainiero M., Kraus D., Wolz C. ( 2008). The virulence regulator Sae of Staphylococcus aureus: promoter activities and response to phagocytosis-related signals. J Bacteriol 190:3419–3428 [View Article][PubMed]
    [Google Scholar]
  17. Giraudo A. T., Cheung A. L., Nagel R. ( 1997). The sae locus of Staphylococcus aureus controls exoprotein synthesis at the transcriptional level. Arch Microbiol 168:53–58 [View Article][PubMed]
    [Google Scholar]
  18. Giraudo A. T., Mansilla C., Chan A., Raspanti C., Nagel R. ( 2003). Studies on the expression of regulatory locus sae in Staphylococcus aureus. . Curr Microbiol 46:246–250[PubMed] [CrossRef]
    [Google Scholar]
  19. 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 alpha-toxin during device-related infection resolved by direct quantitative transcript analysis. Mol Microbiol 40:1439–1447 [View Article][PubMed]
    [Google Scholar]
  20. Goerke C., Fluckiger U., Steinhuber A., Bisanzio V., Ulrich M., Bischoff M., Patti J. M., Wolz C. ( 2005). Role of Staphylococcus aureus global regulators sae and sigmaB in virulence gene expression during device-related infection. Infect Immun 73:3415–3421 [View Article][PubMed]
    [Google Scholar]
  21. 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 [View Article][PubMed]
    [Google Scholar]
  22. Horsburgh M. J., Ingham E., Foster S. J. ( 2001). In Staphylococcus aureus, fur is an interactive regulator with PerR, contributes to virulence, and Is necessary for oxidative stress resistance through positive regulation of catalase and iron homeostasis. J Bacteriol 183:468–475 [View Article][PubMed]
    [Google Scholar]
  23. Horsburgh M. J., Aish J. L., White I. J., Shaw L., Lithgow J. K., Foster S. J. ( 2002). sigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4. J Bacteriol 184:5457–5467 [View Article][PubMed]
    [Google Scholar]
  24. Johnson M., Sengupta M., Purves J., Tarrant E., Williams P. H., Cockayne A., Muthaiyan A., Stephenson R., Ledala N. & other authors ( 2011). Fur is required for the activation of virulence gene expression through the induction of the sae regulatory system in Staphylococcus aureus. . Int J Med Microbiol 301:44–52 [View Article][PubMed]
    [Google Scholar]
  25. Kuroda M., Ohta T., Uchiyama I., Baba T., Yuzawa H., Kobayashi I., Cui L., Oguchi A., Aoki K. & other authors ( 2001). Whole genome sequencing of meticillin-resistant Staphylococcus aureus. . Lancet 357:1225–1240 [View Article][PubMed]
    [Google Scholar]
  26. Lee W. C., Reniere M. L., Skaar E. P., Murphy M. E. P. ( 2008). Ruffling of metalloporphyrins bound to IsdG and IsdI, two heme-degrading enzymes in Staphylococcus aureus. . J Biol Chem 283:30957–30963[PubMed] [CrossRef]
    [Google Scholar]
  27. Li D., Cheung A. ( 2008). Repression of hla by rot is dependent on sae in Staphylococcus aureus. . Infect Immun 76:1068–1075 [View Article][PubMed]
    [Google Scholar]
  28. Liang X., Zheng L., Landwehr C., Lunsford D., Holmes D., Ji Y. ( 2005). Global regulation of gene expression by ArlRS, a two-component signal transduction regulatory system of Staphylococcus aureus. . J Bacteriol 187:5486–5492 [View Article][PubMed]
    [Google Scholar]
  29. 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 [View Article][PubMed]
    [Google Scholar]
  30. Lowy F. D. ( 1998). Staphylococcus aureus infections. N Engl J Med 339:520–532 [View Article][PubMed]
    [Google Scholar]
  31. Luong T. T., Sau K., Roux C., Sau S., Dunman P. M., Lee C. Y. ( 2011). Staphylococcus aureus ClpC divergently regulates capsule via sae and codY in strain newman but activates capsule via codY in strain UAMS-1 and in strain Newman with repaired saeS. . J Bacteriol 193:686–694 [View Article][PubMed]
    [Google Scholar]
  32. Mainiero M., Goerke C., Geiger T., Gonser C., Herbert S., Wolz C. ( 2010). Differential target gene activation by the Staphylococcus aureus two-component system saeRS. . J Bacteriol 192:613–623 [View Article][PubMed]
    [Google Scholar]
  33. Maresso A. W., Schneewind O. ( 2006). Iron acquisition and transport in Staphylococcus aureus. . Biometals 19:193–203[PubMed] [CrossRef]
    [Google Scholar]
  34. Mason W. J., Skaar E. P. ( 2009). Assessing the contribution of heme-iron acquisition to Staphylococcus aureus pneumonia using computed tomography. PLoS ONE 4:e6668[PubMed] [CrossRef]
    [Google Scholar]
  35. Mazmanian S. K., Skaar E. P., Gaspar A. H., Humayun M., Gornicki P., Jelenska J., Joachmiak A., Missiakas D. M., Schneewind O. ( 2003). Passage of heme-iron across the envelope of Staphylococcus aureus. . Science 299:906–909 [View Article][PubMed]
    [Google Scholar]
  36. Morfeldt E., Taylor D., von Gabain A., Arvidson S. ( 1995). Activation of alpha-toxin translation in Staphylococcus aureus by the trans-encoded antisense RNA, RNAIII. EMBO J 14:4569–4577[PubMed]
    [Google Scholar]
  37. Nilsson I. M., Hartford O., Foster T., Tarkowski A. ( 1999). Alpha-toxin and gamma-toxin jointly promote Staphylococcus aureus virulence in murine septic arthritis. Infect Immun 67:1045–1049[PubMed]
    [Google Scholar]
  38. Novick R. P. ( 1967). Properties of a cryptic high-frequency transducing phage in Staphylococcus aureus. . Virology 33:155–166 [View Article][PubMed]
    [Google Scholar]
  39. Novick R. P., Jiang D. ( 2003). The staphylococcal saeRS system coordinates environmental signals with agr quorum sensing. Microbiology 149:2709–2717[PubMed] [CrossRef]
    [Google Scholar]
  40. Nygaard T. K., Pallister K. B., Ruzevich P., Griffith S., Vuong C., Voyich J. M. ( 2010). SaeR binds a consensus sequence within virulence gene promoters to advance USA300 pathogenesis. J Infect Dis 201:241–254[PubMed] [CrossRef]
    [Google Scholar]
  41. O’Reilly M., de Azavedo J. C. S., Kennedy S., Foster T. J. ( 1986). Inactivation of the alpha-haemolysin gene of Staphylococcus aureus 8325-4 by site-directed mutagenesis and studies on the expression of its haemolysins. Microb Pathog 1:125–138 [View Article][PubMed]
    [Google Scholar]
  42. Qazi S. N., Counil E., Morrissey J., Rees C. E., Cockayne A., Winzer K., Chan W. C., Williams P., Hill P. J. ( 2001). agr expression precedes escape of internalized Staphylococcus aureus from the host endosome. Infect Immun 69:7074–7082 [View Article][PubMed]
    [Google Scholar]
  43. Ray B., Ballal A., Manna A. C. ( 2009). Transcriptional variation of regulatory and virulence genes due to different media in Staphylococcus aureus. . Microb Pathog 47:94–100 [View Article][PubMed]
    [Google Scholar]
  44. Rayner M. H., Sadler P. J. ( 1990). Precipitation of cadmium in a bacterial culture medium: Luria-Bertani broth. FEMS Microbiol Lett 71:253–257 [View Article]
    [Google Scholar]
  45. Reniere M. L., Torres V. J., Skaar E. P. ( 2007). Intracellular metalloporphyrin metabolism in Staphylococcus aureus. . Biometals 20:333–345 [View Article][PubMed]
    [Google Scholar]
  46. Rogasch K., Rühmling V., Pané-Farré J., Höper D., Weinberg C., Fuchs S., Schmudde M., Bröker B. M., Wolz C. & other authors ( 2006). Influence of the two-component system SaeRS on global gene expression in two different Staphylococcus aureus strains. J Bacteriol 188:7742–7758 [View Article][PubMed]
    [Google Scholar]
  47. Rouault T. A. ( 2004). Microbiology. Pathogenic bacteria prefer heme. Science 305:1577–1578 [View Article][PubMed]
    [Google Scholar]
  48. Schäfer D., Lâm T. T., Geiger T., Mainiero M., Engelmann S., Hussain M., Bosserhoff A., Frosch M., Bischoff M. & other authors ( 2009). A point mutation in the sensor histidine kinase SaeS of Staphylococcus aureus strain Newman alters the response to biocide exposure. J Bacteriol 191:7306–7314 [View Article][PubMed]
    [Google Scholar]
  49. Skaar E. P., Gaspar A. H., Schneewind O. ( 2004). IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus. . J Biol Chem 279:436–443 [View Article][PubMed]
    [Google Scholar]
  50. Sobke A. C., Selimovic D., Orlova V., Hassan M., Chavakis T., Athanasopoulos A. N., Schubert U., Hussain M., Thiel G. & other authors ( 2006). The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation. FASEB J 20:2621–2623 [View Article][PubMed]
    [Google Scholar]
  51. Somerville G. A., Proctor R. A. ( 2009). At the crossroads of bacterial metabolism and virulence factor synthesis in Staphylococci. Microbiol Mol Biol Rev 73:233–248 [View Article][PubMed]
    [Google Scholar]
  52. Stojiljkovic I., Perkins-Balding D. ( 2002). Processing of heme and heme-containing proteins by bacteria. DNA Cell Biol 21:281–295 [View Article][PubMed]
    [Google Scholar]
  53. Sun F., Li C., Jeong D., Sohn C., He C., Bae T. ( 2010). In the Staphylococcus aureus two-component system sae, the response regulator SaeR binds to a direct repeat sequence and DNA binding requires phosphorylation by the sensor kinase SaeS. J Bacteriol 192:2111–2127 [View Article][PubMed]
    [Google Scholar]
  54. Thöny-Meyer L. ( 1997). Biogenesis of respiratory cytochromes in bacteria. Microbiol Mol Biol Rev 61:337–376[PubMed]
    [Google Scholar]
  55. Torres V. J., Pishchany G., Humayun M., Schneewind O., Skaar E. P. ( 2006). Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization. J Bacteriol 188:8421–8429 [View Article][PubMed]
    [Google Scholar]
  56. Torres V. J., Stauff D. L., Pishchany G., Bezbradica J. S., Gordy L. E., Iturregui J., Anderson K. L., Dunman P. M., Joyce S., Skaar E. P. ( 2007). A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence. Cell Host Microbe 1:109–119 [View Article][PubMed]
    [Google Scholar]
  57. Torres V. J., Attia A. S., Mason W. J., Hood M. I., Corbin B. D., Beasley F. C., Anderson K. L., Stauff D. L., McDonald W. H. & other authors ( 2010). Staphylococcus aureus fur regulates the expression of virulence factors that contribute to the pathogenesis of pneumonia. Infect Immun 78:1618–1628 [View Article][PubMed]
    [Google Scholar]
  58. Touati D. ( 2000). Iron and oxidative stress in bacteria. Arch Biochem Biophys 373:1–6 [View Article][PubMed]
    [Google Scholar]
  59. Xiong Y. Q., Willard J., Yeaman M. R., Cheung A. L., Bayer A. S. ( 2006). Regulation of Staphylococcus aureus α-toxin gene (hla) expression by agr, sarA, and sae in vitro and in experimental infective endocarditis. J Infect Dis 194:1267–1275 [View Article][PubMed]
    [Google Scholar]
  60. Yamazaki K., Kato F., Kamio Y., Kaneko J. ( 2006). Expression of γ-hemolysin regulated by sae in Staphylococcus aureus strain Smith 5R. FEMS Microbiol Lett 259:174–180 [View Article][PubMed]
    [Google Scholar]
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