Nutritional Regulation of the Sae Two-Component System by CodY in Staphylococcus aureus

J Bacteriol. 2018 Mar 26;200(8):e00012-18. doi: 10.1128/JB.00012-18. Print 2018 Apr 15.


Staphylococcus aureus subverts innate defenses during infection in part by killing host immune cells to exacerbate disease. This human pathogen intercepts host cues and activates a transcriptional response via the S. aureus exoprotein expression (SaeR/SaeS [SaeR/S]) two-component system to secrete virulence factors critical for pathogenesis. We recently showed that the transcriptional repressor CodY adjusts nuclease (nuc) gene expression via SaeR/S, but the mechanism remained unknown. Here, we identified two CodY binding motifs upstream of the sae P1 promoter, which suggested direct regulation by this global regulator. We show that CodY shares a binding site with the positive activator SaeR and that alleviating direct CodY repression at this site is sufficient to abrogate stochastic expression, suggesting that CodY represses sae expression by blocking SaeR binding. Epistasis experiments support a model that CodY also controls sae indirectly through Agr and Rot-mediated repression of the sae P1 promoter. We also demonstrate that CodY repression of sae restrains production of secreted cytotoxins that kill human neutrophils. We conclude that CodY plays a previously unrecognized role in controlling virulence gene expression via SaeR/S and suggest a mechanism by which CodY acts as a master regulator of pathogenesis by tying nutrient availability to virulence gene expression.IMPORTANCE Bacterial mechanisms that mediate the switch from a commensal to pathogenic lifestyle are among the biggest unanswered questions in infectious disease research. Since the expression of most virulence genes is often correlated with nutrient depletion, this implies that virulence is a response to the lack of nourishment in host tissues and that pathogens like S. aureus produce virulence factors in order to gain access to nutrients in the host. Here, we show that specific nutrient depletion signals appear to be funneled to the SaeR/S system through the global regulator CodY. Our findings reveal a strategy by which S. aureus delays the production of immune evasion and immune-cell-killing proteins until key nutrients are depleted.

Keywords: CodY; Sae; Sae TCS; Staphylococcus aureus; branched-chain amino acids; gene regulation; two-component system; virulence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cells, Cultured
  • Culture Media / chemistry
  • Gene Expression Regulation, Bacterial
  • Humans
  • Leukocidins / metabolism
  • Neutrophils / microbiology
  • Nutrients*
  • Promoter Regions, Genetic
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Virulence
  • Virulence Factors / genetics
  • Virulence Factors / metabolism


  • Bacterial Proteins
  • CodY protein, Staphylococcus aureus
  • Culture Media
  • Leukocidins
  • Recombinant Proteins
  • Repressor Proteins
  • SaeR protein, Staphylococcus aureus
  • Transcription Factors
  • Virulence Factors
  • Protein Kinases
  • SaeS protein, Staphylococcus aureus