Staphylococcus aureus CodY Negatively Regulates Virulence Gene Expression

Tufts University Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA, University of Nebraska, Lincoln, NE 68583, USA, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, and Tufts University School of Medicine, Boston, MA 02111, USA

^* To whom correspondence should be addressed. Email: linc.sonenshein{at}tufts.edu.

	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. Introduction of a codY null mutation into two S. aureus clinical isolates, SA564 and UAMS-1, through allelic replacement, resulted in 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 -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.