The SaeRS two-component system dynamically regulates cellular adhesion and invasion during group B Streptococcus infection

Group B Streptococcus (GBS) is a pathobiont responsible for invasive infections in neonates and in the elderly. The transition from a commensal to an invasive pathogen relies on the timely regulation of a set of virulence factors. In this study, we characterized the role of the SaeRS two-component system in GBS pathogenesis. Loss-of-function mutations in the SaeR response regulator decrease virulence in mouse models of invasive infection . Transcriptome and in vivo analysis reveal a regulatory system specifically activated during infection to control the expression of only two virulence factors: the PbsP adhesin and the BvaP secreted protein. The in vivo surge in SaeRS-regulated genes is complemented by fine-tuning mediated by the repressor of virulence CovRS system to establish a coordinated response. Constitutive activation of the SaeRS regulatory pathway increases adhesion and invasion of epithelial and endothelial barriers, though at the cost of reduced virulence. In conclusion, SaeRS is a specialized and dynamic system that balances the invasion of host barriers with disease progression. To characterize the SaeR-regulated genes, we generated a saeR deletion mutants (∆saeR), a mutant expressing an inactived SaeR variant (SaeR D53A), and a constitutive activated mutant having a specific mutation in SaeS specifically abolishing the phosphatase activity of the histidine kinase (SaeS T133A) in the wild-type strain NEM316 (capsular serotype III, CC-23) We performed RNA-sequencing of the three mutants against the WT strain. RNA are purified from exponentially growing cultures (OD600 = 0.5) in rich media (THY) incubated at 37°C in static condition. Biological triplicate (Replicate 1, 2, and 3) are done on different days to take into account batch effect.