Contribution of CsrR-Regulated Virulence Factors to the Progress and Outcome of Murine Skin Infections byStreptococcus pyogenes

Streptococcus pyogenes with null mutations in the csrRS regulatory locus are highly virulent in mice due to derepression of hyaluronic acid capsule synthesis and exotoxins, e.g., streptolysin S (SLS) and pyrogenic exotoxin B (SpeB). We generated derivatives of a DeltacsrRS strain that also carry deletions in hasAB (leading to an acapsular phenotype) or in sagA (phenotypically SLS-) or an interruption of speB (SpeB-) to test the relative contributions of these factors to the development of necrotic skin lesions. Inoculation of 2 x 10(6) to 4 x 10(6) CFU of either acapsular or SLS- strains into hairless mice resulted in lesions approximately 70% smaller than those of the DeltacsrRS parent strain. Elimination of SLS also reduced lethality from 100% to 0% at this inoculum (P < 10(-7); Fisher exact test). In contrast, SLS+ SpeB- mutants yielded lesions that were only 41% smaller than the parent strain (t = 2.2; P = 0.04), but only 3 the 17 lesions had dermal sloughing (P = 10(-5)). The nonulcerative lesions associated with SpeB- strains appeared pale with surrounding erythema. We conclude that capsule and SLS contribute to the subcutaneous spread of S. pyogenes and to a fatal outcome of infection. SpeB facilitates early dermal ulceration but has minor influence on lesion size and mortality. Large ulcerative lesions are observed only when both toxins are present.