Background. Virulence of Group B Streptococcus (GBS) is under the control of the master regulator CovR. However, important variation in the CovR regulon was observed early on among different wild-type strains.
Methods. We characterized the CovR regulatory network by transcriptome and genome-wide binding analysis in a strain representative of the CC-17 clonal complex, responsible for the majority of neonatal meningitis, and in a non-CC-17 strain. In addition, transcriptomes analysis of activated two-component systems were done to decipher links between signalling pathways.
Results. The CovR signaling network coordinates the direct repression of virulence genes, including the specific hypervirulent adhesins. Comparative analysis between strains reveals a high level of plasticity of the regulatory network, supported by mechanisms acting locally on CovR-regulated genes and promoters and globally at the level of CovR activation by phosphorylation. In addition, the CovR network is connected to response regulators involved in the control of the cell cycle, of specific adhesin, and of the cell-wall damage response to integrate virulence gene expression with the physiological state of the bacteria.
Conclusions. The CovR regulatory network is the direct repressor of virulence. Due to its central role, the network is subject to selective pressures leading to phenotypic heterogeneity at the species level. This intra-species evolution reshapes the host-pathogen interaction and could contribute to the emergence of GBS clones associated with specific hosts or pathologies.