The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes

Authors

  • Audrey Brenot,

    1. Department of Molecular Microbiology, Washington University School of Medicine, Box 8230, St. Louis, MO 63110-1093, USA.
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    • These authors contributed equally to this work.

  • Katherine Y. King,

    1. Department of Molecular Microbiology, Washington University School of Medicine, Box 8230, St. Louis, MO 63110-1093, USA.
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    • Present address: Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

    • These authors contributed equally to this work.

  • Michael G. Caparon

    Corresponding author
    1. Department of Molecular Microbiology, Washington University School of Medicine, Box 8230, St. Louis, MO 63110-1093, USA.
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E-mail caparon@borcim.wustl.edu; Tel. (+1) 314 362 1485; Fax (+1) 314 362 3203.

Summary

Prior studies have shown that the catalase-deficient pathogen Streptococcus pyogenes (group A streptococcus) has a robust ability to resist oxidative stress that partially involves the transcriptional regulator PerR. However, the extent of the PerR regulon and the contribution of the members of this regulon to virulence are unknown. In this study, DNase I footprinting revealed that PerR binds specifically to a single site upstream of the promoter for the gene encoding alkyl hydroperoxide reductase (ahpC). However, analyses of transcript abundance revealed that while ahpC is regulated in response to growth phase, its regulation is independent of PerR. Instead, PerR regulates transcription of a divergent gene cluster that encodes a putative cold shock protein. The gene encoding the Dps-like peroxide resistance protein MrgA was repressed by PerR, consistent with the presence of a PerR binding site in its promoter. Phenotypic analyses of PerR, AhpC and MrgA mutants revealed that while AhpC is not essential for resistance to challenge with hydrogen peroxide in vitro, AhpC does contribute to scavenging of endogenous hydrogen peroxide and is required for virulence in a murine model of infection. In contrast, a MrgA mutant was hypersensitive to challenge with peroxide in vitro, but was fully virulent in all animal models tested. Finally, a PerR mutant was hyper-resistant to peroxide, yet was highly attenuated for virulence in all murine models. These data demonstrate that while a mutant's capacity to resist peroxide stress did not directly correlate with its ability to cause disease, the appropriate regulation of the peroxide stress response is critical for virulence.

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