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Proc Natl Acad Sci U S A. 2016 May 31;113(22):E3101-10. doi: 10.1073/pnas.1520255113. Epub 2016 May 16.

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation.

Author information

  • 1Biocenter, Chair of Microbiology, University of Würzburg, D-97074 Wuerzburg, Germany;
  • 2Jenner Institute, Centre for Molecular and Cellular Physiology, Oxford OX3 7BN, United Kingdom;
  • 3Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
  • 4Institute of Molecular Infection Biology, University of Würzburg, D-97080 Wuerzburg, Germany;
  • 5Max Planck Genome Centre, D-50829 Cologne, Germany;
  • 6Oxford Vaccine Group, University of Oxford, Oxford, United Kingdom;
  • 7Biocenter, Chair of Bioinformatics, University of Würzburg, D-97074 Wuerzburg, Germany;
  • 8Biocenter, Chair of Bioinformatics, University of Würzburg, D-97074 Wuerzburg, Germany; Institute of Human Genetics, University of Würzburg, D-97074 Wuerzburg, Germany;
  • 9Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom;
  • 10Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom thomas.rudel@biozentrum.uni-wuerzburg.de daniel.wilson@ndm.ox.ac.uk.
  • 11Biocenter, Chair of Microbiology, University of Würzburg, D-97074 Wuerzburg, Germany; thomas.rudel@biozentrum.uni-wuerzburg.de daniel.wilson@ndm.ox.ac.uk.

Abstract

Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.

KEYWORDS:

SSR42; Staphylococcus aureus; bloodstream infection; rsp; toxicity regulator

PMID:
27185949
PMCID:
PMC4896717
DOI:
10.1073/pnas.1520255113
[PubMed - indexed for MEDLINE]
Free PMC Article
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