A spectrum of CodY activities drives metabolic reorganization and virulence gene expression in Staphylococcus aureus

Summary The global regulator CodY controls the expression of dozens of metabolism and virulence genes in the opportunistic pathogen Staphylococcus aureus in response to the availability of isoleucine, leucine and valine (ILV), and GTP. Using RNA‐Seq transcriptional profiling and partial activity variants, we reveal that S. aureus CodY activity grades metabolic and virulence gene expression as a function of ILV availability, mediating metabolic reorganization and controlling virulence factor production in vitro. Strains lacking CodY regulatory activity produce a PIA‐dependent biofilm, but development is restricted under conditions that confer partial CodY activity. CodY regulates the expression of thermonuclease (nuc) via the Sae two‐component system, revealing cascading virulence regulation and factor production as CodY activity is reduced. Proteins that mediate the host‐pathogen interaction and subvert the immune response are shut off at intermediate levels of CodY activity, while genes coding for enzymes and proteins that extract nutrients from tissue, that kill host cells, and that synthesize amino acids are among the last genes to be derepressed. We conclude that S. aureus uses CodY to limit host damage to only the most severe starvation conditions, providing insight into one potential mechanism by which S. aureus transitions from a commensal bacterium to an invasive pathogen. By analyzing transcriptome profiles and assessing in vitro phenotypes of S. aureus strains producing variants of CodY with variable activity, we shed light on an important link between metabolism and virulence. We show that nutrient acquisition and synthesis, as well as biofilm formation and nuclease production are under graded CodY control. We infer that CodY plays a crucial role in orchestrating responses to environmental nutrient stress, including responses that can be detrimental to the host.