A two-component regulatory system, CsrR-CsrS, represses expression of three Streptococcus pyogenes virulence factors, hyaluronic acid capsule, streptolysin S, and pyrogenic exotoxin B

Certain Tn916 insertions in the chromosome of an M1-type, nonmucoid Strepto coccus pyogenes isolate (MGAS166) were previously shown to result in stable mucoidy with increased expression of the capsular synthetic genes. The tra nsposon insertions in these strains are directly upstream of an apparent op eron encoding a two-component regulatory system, designated csrR-csrS. Comp ared with MGAS166, these mucoid mutants are more hemolytic and cause signif icantly more tissue damage in a murine model of skin infection. To extend t hese observations, we constructed an in-frame deletion in the gene encoding the response regulator, csrR, and we evaluated the expression of other kno wn S. pyogenes virulence factors. We discovered that csrR mutants have enha nced transcription of sagA, a gene associated with streptolysin S (SLS) and speB, the gene encoding pyrogenic exotoxin B (SpeB). The mutants also expr ess substantially higher SLS activity and SpeB antigen in late-exponential- phase cultures. There is no change in expression of emm, scpA, sic, or cpa (genes encoding other S. pyogenes virulence factors). CsrR(-) strains but n ot the wild-type parental strain produce necrotizing lesions in a mouse mod el of subcutaneous infection. A double mutant with deletions in both csrR a nd the capsular synthesis genes caused fewer and smaller necrotic skin lesi ons than the csrR mutants. However, this nonmucoid csrR strain was more lik ely than the wild type to yield necrotic lesions, suggesting that mucoidy c ontributes to virulence in this model of infection but that there are other csrR-regulated factors involved in the production of necrotic lesions.