The Covr Regulatory Network Drives The Evolution Of Group B Streptococcus Virulence

Virulence of the neonatal pathogen Group B Streptococcus is under the control of the master regulator CovR. Inactivation of CovR is associated with large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, transcriptome analyses suggested a plasticity of the CovR signaling pathway in clinical isolates leading to phenotypic heterogeneity in the bacterial population. In this study, we characterized the CovR regulatory network in a strain representative of the CC-17 hypervirulent lineage responsible of the majority of neonatal meningitis. Transcriptome and genome-wide binding analysis reveal the architecture of the CovR network characterized by the direct repression of a large array of virulence-associated genes and the extent of co-regulation at specific loci. Comparative functional analysis of the signaling network links strain-specificities to the regulation of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, to mutations in CovR-regulated promoters, and to variability in CovR activation by phosphorylation. This regulatory adaptation occurs at the level of genes, promoters, and of CovR itself, and allows to globally reshape the expression of virulence genes. Overall, our results reveal the direct, coordinated, and strain-specific regulation of virulence genes by the master regulator CovR and suggest that the intra-species evolution of the signaling network is as important as the expression of specific virulence factors in the emergence of clone associated with specific diseases.Author summary Streptococcus agalactiae, commonly known as the Group B Streptococcus (GBS), is a commensal bacterium of the intestinal and vaginal tracts found in approximately 30% of healthy adults. However, GBS is also an opportunistic pathogen and the leading cause of neonatal invasive infections. Epidemiologic data have identified a particular GBS clone, designated the CC-17 hypervirulent clonal complex, as responsible for the overwhelming majority of neonatal meningitis. The hypervirulence of CC-17 has been linked to the expression of two specific surface proteins increasing their abilities to cross epithelial and endothelial barriers. In this study, we characterized the role of the major regulator of virulence gene expression, the CovR response regulator, in a representative hypervirulent strain. Transcriptome and genome-wide binding analysis reveal the architecture of the CovR signaling network characterized by the direct repression of a large array of virulence-associated genes, including the specific hypervirulent adhesins. Comparative analysis in a non-CC-17 wild type strain demonstrates a high level of plasticity of the regulatory network, allowing to globally reshape pathogen-host interaction. Overall, our results suggest that the intra-species evolution of the regulatory network is an important factor in the emergence of GBS clones associated with specific pathologies.