The global transcriptional regulator CodY controls virulence in Group B Streptococcus

CodY is a highly conserved global transcriptional regulator of metabolism in low-G+C Gram-positive bacteria. As its activity is dependent on its interaction with branched-chain amino acids (BCAAs) and GTP (except for Lactococcus and Streptococcus species), this regulator controls gene expression in response to the nutritional status of the cell. In pathogens, CodY links nutrient availability with the concerted regulation of metabolism and virulence. In this study, we investigated the role of CodY in Streptococcus agalactiae, a harmless colonizer of the intestinal and urogenital tracts of healthy adults that is responsible of severe, invasive infections in neonates and immunocompromised subjects. Adaptation to the different environments encountered during colonization and infection is essential to the success of S. agalactiae as a commensal and as an opportunistic pathogen. However, to date, there is still a great lack of information on how this bacterium integrates the diverse environmental signals and orchestrates the different regulatory pathways to rapidly adapt to distinct human host niches and control its switch from commensal to pathogen. Here, a codY deletion derivative (codY) of the hypervirulent S. agalactiae strain BM110 was prepared. The mutant strain displayed decreased bacterial virulence in different murine models of infection. The reduced lethality observed in vivo was related to a decreased ability of the codY strain to disseminate in blood and to distant organs of infected mice. In vitro investigation of virulence-related characteristics revealed that several traits linked to the ability to colonize the host were affected in the codY strain, including its ability to adhere to and invade human epithelial cells, bind to plasma and extracellular matrix proteins and form biofilm. A transcriptomic analysis showed that CodY controls about 13% of the S. agalactiae genome, with genes encoding functions related to amino acid transport and metabolism, adhesion, DNA replication, recombination, and repair being subjected to the highest level of regulation. The regulatory activity of CodY was demonstrated to be dependent on the presence of BCAAs, whose intracellular abundance is influenced by CodY-mediated regulation of genes encoding BCAAs transport systems. The list of genes under CodY control includes srr2, encoding a virulence factor known to be negatively regulated by the two-component system CovRS, the master regulator of virulence. We showed that CodY is a direct repressor of srr2 and provided preliminary results suggesting a potential interplay of CodY and CovR in the regulation of srr2. The obtained results show that CodY is a global regulator of metabolism and virulence in S. agalactiae. The activity of this factor appears to be coordinated with the regulatory action of CovRS, highlighting the existence of interlinked regulatory pathways governing S. agalactiae virulence and gene expression. Dissection of the molecular mechanisms governing S. agalactiae transition from harmless to potent pathogen could set the basis for the development of new therapeutic strategies.