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

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Abstract
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 ΔcsrRS 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 × 106 to 4 × 106 CFU of either acapsular or SLS− strains into hairless mice resulted in lesions ∼70% smaller than those of the ΔcsrRS 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.

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