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Staphylococcus aureus regulates the expression and production of the staphylococcal superantigen-like secreted proteins in a Rot-dependent manner

Authors

  • Meredith A. Benson,

    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
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  • Sarit Lilo,

    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
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  • Gregory A. Wasserman,

    1. Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, NY 10016, USA.
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  • Matthew Thoendel,

    1. Department of Microbiology, Roy J and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
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  • Amanda Smith,

    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
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  • Alexander R. Horswill,

    1. Department of Microbiology, Roy J and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
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  • John Fraser,

    1. School of Medical Sciences and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
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  • Richard P. Novick,

    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
    2. The Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
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  • Bo Shopsin,

    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
    2. Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, NY 10016, USA.
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  • Victor J. Torres

    Corresponding author
    1. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
      E-mail victor.torres@nyumc.org; Tel. (+1) (212) 263 9232; Fax (+1) (212) 263 9180.
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E-mail victor.torres@nyumc.org; Tel. (+1) (212) 263 9232; Fax (+1) (212) 263 9180.

Summary

Staphylococcus aureus overproduces a subset of immunomodulatory proteins known as the staphylococcal superantigen-like proteins (Ssls) under conditions of pore-mediated membrane stress. In this study we demonstrate that overproduction of Ssls during membrane stress is due to the impaired activation of the two-component module of the quorum-sensing accessory gene regulator (Agr) system. Agr-dependent repression of ssl expression is indirect and mediated by the transcription factor repressor of toxins (Rot). Surprisingly, we observed that Rot directly interacts with and activates the ssl promoters. The role of Agr and Rot as regulators of ssl expression was observed across several clinically relevant strains, suggesting that overproduction of immunomodulatory proteins benefits agr-defective strains. In support of this notion, we demonstrate that Ssls contribute to the residual virulence of S. aureus lacking agr in a murine model of systemic infection. Altogether, these results suggest that S. aureus compensates for the inactivation of Agr by producing immunomodulatory exoproteins that could protect the bacterium from host-mediated clearance.

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