A spectrum of CodY activities drives metabolic reorganization and virulence gene expression in Staphylococcus aureus.
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.
Department of Biology, Georgetown University, Washington, DC, USA.
Nicholas R
NR
Waters
Department of Biology, Georgetown University, Washington, DC, USA.
David J
DJ
Samuels
Department of Biology, Georgetown University, Washington, DC, USA.
Ranjan K
RK
Behera
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jonathan
J
Livny
Department of Medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York, NY, USA.
Kyu Y
KY
Rhee
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
Marat R
MR
Sadykov
Department of Biology, Georgetown University, Washington, DC, USA.
Shaun R
SR
Brinsmade
D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D018441:Biofilms; D054884:Host-Pathogen Interactions / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; C540555:CodY protein, Staphylococcus aureus; D012097:Repressor Proteins; D037521:Virulence Factors