D-108. Variation in the Group B Streptococcus CsrRS Regulon and Effects on Pathogenicity

S-M. Jiang1,2, N. Ishmael3, J. D. Hotopp3, M. Puliti4, L. Tissi4, N. Kumar3, M. J. Cieslewicz1,2, H. Tettelin3, M. R. Wessels1,2;
1Children's Hosp., Boston, MA, 2Harvard Med. Sch., Boston, MA, 3The J. Craig Venter Inst., Rockville, MD, 4Univ. of Perugia, Perugia, ITALY.

CsrRS (or CovRS) is a two-component regulatory system (TCS) that controls expression of multiple virulence factors in the important human pathogen, group B Streptococcus (GBS). To understand its global regulatory function, we used genomic microarrays to perform transcriptional profiling of csrR and csrS mutants in the background of strains 2603 and 515. We compared the repertoire of CsrRS-regulated genes in these strains with that described previously for strain NEM316 to determine the extent of conservation and diversity of the CsrRS regulon among GBS strains. The results reveal a conserved 39-gene CsrRS regulon as well as a large repertoire of genes whose regulation varies among GBS isolates. In vitro phosphorylation-dependent 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. The microarray analysis also showed divergence in the relative effects on gene regulation of mutating csrR or csrS in the background of strain 2603 compared to that in 515. To investigate whether such differential effects might be reflected in the relative pathogenic potential of the mutant strains, we tested the virulence of GBS strains in a murine model of systemic infection and septic arthritis. The results suggested the 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 conclusion, 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.