Variation in the Group BStreptococcusCsrRS Regulon and Effects on Pathogenicity

Abstract

CsrRS (or CovRS) is a two-component regulatory system that controls expression of multiple virulence factors in the important human pathogen group B Streptococcus (GBS). We now report global gene expression studies in GBS strains 2603V/R and 515 and their isogenic csrR and csrS mutants. Together with data reported previously for strain NEM316, the results reveal a conserved 39-gene CsrRS regulon. In vitro phosphorylationdependent binding of recombinant CsrR to promoter regions of both positively and negatively regulated genes suggests that direct binding of CsrR can mediate activation as well as repression of target gene expression. Distinct patterns of gene regulation in csrR versus csrS mutants in strain 2603V/R compared to 515 were associated with different hierarchies of relative virulence of wild-type, csrR, and csrS mutants in murine models of systemic infection and septic arthritis. We conclude that CsrRS regulates a core group of genes including important virulence factors in diverse strains of GBS but also displays marked variability in the repertoire of regulated genes and in the relative effects of CsrS signaling on CsrR-mediated gene regulation. Such variation is likely to play an important role in strain-specific adaptation of GBS to particular host environments and pathogenic potential in susceptible hosts.

CsrRS Regulates Group BStreptococcusVirulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine Development

“…An orthologue of the CsrRS system has been identified in GBS (27,31). Expression profiling studies suggest that as many as 7% of GBS genes are regulated by CsrRS (28,31). The CsrRS regulon includes genes that encode secreted or surface components and transport systems for various small molecules, including peptides, amino acids, sugars, and metals.…”

CovR Alleviates Transcriptional Silencing by a Nucleoid-Associated Histone-Like Protein in Streptococcus mutans

“…While CovR generally appears to act as a repressor in GAS, GBS, and S. mutans, there are a few reports in which CovR functions as an activator (36,42). The GAS dppA promoter (PdppA) is one such example, the expression of which is stimulated about 4-fold by CovR (36).…”

“…Similarly, in the case of GBS, CovR has been shown to stimulate the expression of two genes: cfb, which encodes the CAMP factor; and SAG-2042, which encodes a rhodanase-like protein (42). In vitro binding of CovR was demonstrated for the promoter of the cfb gene (Pcfb) (42), but, unlike GAS PdppA, the exact location of CovR binding to Pcfb has not been mapped, and it is not known whether CovR requires any additional factors for stimulation of transcription.…”

Serine/Threonine Phosphatase Stp1 Mediates Post-transcriptional Regulation of Hemolysin, Autolysis, and Virulence of Group B Streptococcus

“…These studies indicated that transcription of the cylE gene in the ⌬stp1 mutant was not significantly different when compared with the isogenic WT (-fold difference compared with WT ϭ 0.92 Ϯ 0.1; Table 3). In GBS, the two-component regulator CovR binds to the promoter of hemolysin (P cylX ) and represses transcription of the cyl operon, including cylE (37,47,49,78). Because Stk1 regulates cylE transcription through phosphorylation of CovR (37), it was of interest to examine whether Stp1 regulation of ␤-H/C required the hemolysin repressor, CovR.…”