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

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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.

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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.

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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.

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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.).

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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.

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Correspondence to Michael Otto.

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

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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

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