Staphylococcus aureusCodY Negatively Regulates Virulence Gene Expression

Abstract

CodY is a global regulatory protein that was first discovered in Bacillus subtilis, where it couples gene expression to changes in the pools of critical metabolites through its activation by GTP and branched-chain amino acids. Homologs of CodY can be found encoded in the genomes of nearly all low-G؉C gram-positive bacteria, including Staphylococcus aureus. The introduction of a codY-null mutation into two S. aureus clinical isolates, SA564 and UAMS-1, through allelic replacement, resulted in the overexpression of several virulence genes. The mutant strains had higher levels of hemolytic activity toward rabbit erythrocytes in their culture fluid, produced more polysaccharide intercellular adhesin (PIA), and formed more robust biofilms than did their isogenic parent strains. These phenotypes were associated with derepressed levels of RNA for the hemolytic alpha-toxin (hla), the accessory gene regulator (agr) (RNAII and RNAIII/hld), and the operon responsible for the production of PIA (icaADBC). These data suggest that CodY represses, either directly or indirectly, the synthesis of a number of virulence factors of S. aureus.

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

“…One interesting effect of CodY is its differential effect on bacterial growth in a biofilm. Streptococcus mutans and B. cereus codY mutant strains have reduced capacities to form biofilms (99,132); however, S. aureus codY mutants have an increased capacity to form biofilms (147). Although further research is needed to understand these differences in biofilm growth, one possible explanation may be due to differences in the relative importance of exopolysaccharides versus proteins for facilitating adherence to the substratum.…”

“…This hypothesis has proven to be correct for Bacillus cereus, Clostridium difficile, Listeria monocytogenes, S. aureus, Streptococcus pneumoniae, and Streptococcus pyogenes (14,51,87,132,147,149). Similar to CodY in B. subtilis, CodY in pathogenic bacteria represses genes involved in amino acid transport, catabolism, and biosynthesis.…”

“…The inactivation of codY in L. monocytogenes affects motility and chemotaxis but has only a slight effect on virulence in a murine listeriosis model (14). The genetic inactivation of codY in two clinical isolates of S. aureus derepresses the synthesis of the agr loci, polysaccharide intercellular adhesin (PIA), and alpha-toxin (hla) (147). In addition, S. aureus CodY coordinately represses the expression of cysteine protease, serine protease, V8 protease, peptide and amino acid transporters, and amino acid catabolic genes (C. Majerczyk et al, unpublished observations).…”

The formation ofStaphylococcus aureusenterotoxin in food environments and advances in risk assessment

“…CodY is a transcriptional regulator, whose DNA binding ability is controlled by the cellular GTP pool, thus sensing nutrient availability. [77][78][79][80] SarA, another member of the Sar family of homologs, positively affects agr transcription and its DNA-binding activity to P2 is dependent on cellular redox conditions and pH and has been demonstrated to positively control seb and sec. 76,81,82 In accordance with the above observations, dissolved oxygen level, nutrient availability and pH have been shown to influence the formation of agr-regulated enterotoxins ( Table 1).…”

Hierarchical expression of genes controlled by theBacillus subtilisglobal regulatory protein CodY

“…First identified in Bacillus subtilis as a factor that represses stationary phase genes during exponential growth in rich medium (11), CodY is now known to provide a critical regulatory link between metabolism and pathogenesis in bacteria important for human health (5,6,(12)(13)(14)(15)(16). CodY is activated as a DNA-binding protein in vitro by at least two classes of metabolites: the branched-chain amino acids [BCAAs; i.e., isoleucine, leucine, and valine (ILV)] and GTP (17)(18)(19)(20)(21).…”