The CodY pleiotropic repressor controls virulence in gram-positive pathogens.

CodY is involved in the adaptive response to starvation in at least 30 different low G+C gram-positive bacteria. After dimerization and activation by cofactor binding, CodY binds to a consensus palindromic DNA sequence, leading to the repression of approximately 5% of the genome. CodY represses the transcription of target genes when bound to DNA by competition with the RNA polymerase for promoter binding, or by interference with transcriptional elongation as a roadblock. CodY displays enhanced affinity for its DNA target when bound to GTP and/or branched chain amino acids (BCAA). When nutrients become limiting in the postexponential growth phase, a decrease of intracellular levels of GTP and BCAA causes a deactivation of CodY and decreases its affinity for DNA, leading to the induction of its regulon. CodY-regulated genes trigger adaptation of the bacteria to starvation by highly diverse mechanisms, such as secretion of proteases coupled to expression of amino acid transporters, and promotion of survival strategies like sporulation or biofilm formation. Additionally, in pathogenic bacteria, several virulence factors are regulated by CodY. As a function of their access to nutrients, pathogenic gram-positive bacteria express virulence factors in a codY-dependant manner. This is true for the anthrax toxins of Bacillus anthracis and the haemolysins of Staphylococcus aureus. The purpose of this review is to illustrate CodY-regulated mechanisms on virulence in major gram-positive pathogens.