Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA

Nature Medicine volume 13, pages 1510–1514 (2007)Cite this article

This article has been updated

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings1,2. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room3. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PSMs in S. aureus.
Figure 2: Mouse models of S. aureus infection.
Figure 3: Interaction of PSMs with human neutrophils.
Figure 4: PSM-induced lysis of human neutrophils.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

  • 27 November 2007

    In the version of this article initially published online, the PSMα peptide presented as a helical wheel in Figure 4e is PSMα4, not PSMα3 as stated in the figure and in the legend. The error has been corrected for all versions of the article.

References

  1. Miller, L.G. et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N. Engl. J. Med. 352, 1445–1453 (2005).

    Article  CAS  Google Scholar 

  2. Chambers, H.F. Community-associated MRSA–resistance and virulence converge. N. Engl. J. Med. 352, 1485–1487 (2005).

    Article  CAS  Google Scholar 

  3. Moran, G.J. et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N. Engl. J. Med. 355, 666–674 (2006).

    Article  CAS  Google Scholar 

  4. Baba, T. et al. Genome and virulence determinants of high virulence community-acquired MRSA. Lancet 359, 1819–1827 (2002).

    Article  CAS  Google Scholar 

  5. Diep, B.A. et al. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet 367, 731–739 (2006).

    Article  CAS  Google Scholar 

  6. Vandenesch, F. et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg. Infect. Dis. 9, 978–984 (2003).

    Article  Google Scholar 

  7. Gillet, Y. et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359, 753–759 (2002).

    Article  CAS  Google Scholar 

  8. Grojec, P.L. & Jeljaszewicz, J. Effect of staphylococcal leukocidin on mouse leukocyte system. Zentralbl. Bakteriol. Mikrobiol. Hyg. [A] 250, 446–455 (1981).

    CAS  Google Scholar 

  9. Cribier, B. et al. Staphylococcus aureus leukocidin: a new virulence factor in cutaneous infections? An epidemiological and experimental study. Dermatology 185, 175–180 (1992).

    Article  CAS  Google Scholar 

  10. Labandeira-Rey, M. et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science 315, 1130–1133 (2007).

    Article  CAS  Google Scholar 

  11. Fridkin, S.K. et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N. Engl. J. Med. 352, 1436–1444 (2005).

    Article  CAS  Google Scholar 

  12. Voyich, J.M. et al. Is Panton-Valentineleukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J. Infect. Dis. 194, 1761–1770 (2006).

    Article  CAS  Google Scholar 

  13. Mehlin, C., Headley, C.M. & Klebanoff, S.J. An inflammatory polypeptide complex from Staphylococcus epidermidis: isolation and characterization. J. Exp. Med. 189, 907–918 (1999).

    Article  CAS  Google Scholar 

  14. Voyich, J.M. et al. Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. J. Immunol. 175, 3907–3919 (2005).

    Article  CAS  Google Scholar 

  15. Adem, P.V. et al. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. N. Engl. J. Med. 353, 1245–1251 (2005).

    Article  CAS  Google Scholar 

  16. Kravitz, G.R., Dries, D.J., Peterson, M.L. & Schlievert, P.M. Purpura fulminans due to Staphylococcus aureus. Clin. Infect. Dis. 40, 941–947 (2005).

    Article  Google Scholar 

  17. Mellor, I.R., Thomas, D.H. & Sansom, M.S. Properties of ion channels formed by Staphylococcus aureus delta-toxin. Biochim. Biophys. Acta 942, 280–294 (1988).

    Article  CAS  Google Scholar 

  18. Kong, K.F., Vuong, C. & Otto, M. Staphylococcus quorum sensing in biofilm formation and infection. Int. J. Med. Microbiol. 296, 133–139 (2006).

    Article  CAS  Google Scholar 

  19. Redfield, R.J. Is quorum sensing a side effect of diffusion sensing? Trends Microbiol. 10, 365–370 (2002).

    Article  CAS  Google Scholar 

  20. Holden, M.T. et al. Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc. Natl. Acad. Sci. USA 101, 9786–9791 (2004).

    Article  CAS  Google Scholar 

  21. Gill, S.R. et al. Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain. J. Bacteriol. 187, 2426–2438 (2005).

    Article  CAS  Google Scholar 

  22. Kuroda, M. et al. Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet 357, 1225–1240 (2001).

    Article  CAS  Google Scholar 

  23. Diep, B.A., Carleton, H.A., Chang, R.F., Sensabaugh, G.F. & Perdreau-Remington, F. Roles of 34 virulence genes in the evolution of hospital- and community-associated strains of methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 193, 1495–1503 (2006).

    Article  CAS  Google Scholar 

  24. Vuong, C., Gotz, F. & Otto, M. Construction and characterization of an agr deletion mutant of Staphylococcus epidermidis. Infect. Immun. 68, 1048–1053 (2000).

    Article  CAS  Google Scholar 

  25. Bae, T. & Schneewind, O. Allelic replacement in Staphylococcus aureus with inducible counter-selection. Plasmid 55, 58–63 (2006).

    Article  CAS  Google Scholar 

  26. Novick, R.P. et al. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J. 12, 3967–3975 (1993).

    Article  CAS  Google Scholar 

  27. Peschel, A., Ottenwalder, B. & Gotz, F. Inducible production and cellular location of the epidermin biosynthetic enzyme EpiB using an improved staphylococcal expression system. FEMS Microbiol. Lett. 137, 279–284 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Diep and H. Chambers (University of California, San Francisco, USA) for S. aureus strains, T. Bae and O. Schneewind for plasmid pKOR1 (University of Chicago, Chicago, USA) and M. Teintze for help with circular dichroism measurements. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (to M.O. and F.R.D.) and the German Research Council (SFB 685) and the German Ministry of Education and Research (to A.P.).

Author information

Authors and Affiliations

  1. Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, 903 South 4th Street, Hamilton, 59840, Montana, USA

    Rong Wang, Kevin R Braughton, Thanh-Huy L Bach, Shu Y Queck, Min Li, Adam D Kennedy, Frank R DeLeo & Michael Otto

  2. Medical Microbiology and Hygiene Department, Cellular and Molecular Microbiology Unit, University of Tübingen, Elfriede-Auhorn-Str. 6, 72076, Tübingen, Germany

    Dorothee Kretschmer & Andreas Peschel

  3. Microscopy Unit, Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, 903 South 4th Street, Hamilton, 59840, Montana, USA

    David W Dorward

  4. Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, 98195, Washington, USA

    Seymour J Klebanoff

Authors
  1. Rong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin R Braughton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dorothee Kretschmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thanh-Huy L Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu Y Queck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adam D Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David W Dorward
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Seymour J Klebanoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andreas Peschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frank R DeLeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.O. isolated and identified the PSM peptides and performed HPLC/MS, D.K. performed chemotaxis experiments, R.W. and K.R.B. performed neutrophil lysis experiments, T.-H.L.B. performed bacterial growth curves, R.W., S.Y.Q. and M.L. performed animal experiments, R.W. and S.Y.Q. performed circular dichroism experiments, R.W. and A.D.K. performed flow cytometry, D.W.D. performed electron microscopy, and R.W. performed all other experiments. S.J.K., A.P., F.R.D. and M.O. supervised the experiments and M.O. prepared the manuscript.

Corresponding author

Correspondence to Michael Otto.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6 and Supplementary Methods (PDF 10335 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, R., Braughton, K., Kretschmer, D. et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med 13, 1510–1514 (2007). https://doi.org/10.1038/nm1656

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1656

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing