The global transcriptional regulator CodY is essential for in vivo virulence of Group B Streptococcus (#126)

In low-G+C Gram-positive bacteria, CodY is a highly conserved global regulator linking nutrient availability and metabolism to pathogenesis. To investigate the signals and mechanisms controlling the ability of Group B Streptococcus (GBS) to adapt to different host niches and to switch from a commensal to a pathogen responsible for invasive neonatal infections, we assessed the role of CodY in in this bacterium. To check the in vivo impact of CodY on the ability of GBS to sustain infection, a ∆codY derivative of a hypervirulent strain responsible for neonatal meningitis was prepared and its virulence properties were assessed in murine neonatal and adult models of infection. Transcriptomic analysis combined with qRT-PCR and transcriptional fusions experiments allowed determining the CodY regulon and the mechanism of CodY-mediated regulation of gene expression. The ∆codY strain showed a reduced in vivo lethality, not associated with an altered cytokine response in the host but related to pleiotropic effects on virulence traits of the bacterium, including a reduced adhesion to human epithelial cells and an increased ability to form biofilm, a characteristic which is generally associated to GBS strains able to asymptomatically colonize the host. Transcriptomic analysis highlighted the role of CodY as a branched-chain amino acids-dependent global regulator of metabolism, with genes involved in the uptake of amino acids and oligopeptides subjected to the highest level of repression. The obtained results provide new insights on the signals and regulatory mechanisms governing GBS pathogenesis and set the basis for future research aimed at designing targeted therapeutic strategies to prevent GBS pathogenesis.