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The M3 Serotype of Group A Streptococcus (GAS) is one of the three most frequent serotypes associated with severe invasive GAS infections, such as necrotizing fasciitis, in the United States and other industrialized countries. The basis for this association and hypervirulence of invasive serotype M3 GAS is not fully understood. In this study, the sequenced serotype M3 strain, MGAS315, and serotype M28 strain, MGAS6180, were characterized in parallel to determine whether contemporary M3 GAS has a higher capacity to invade soft tissues than M28 GAS. In subcutaneous infection, MGAS315 invaded almost the whole skin, inhibited neutrophil recruitment and TNF-α production, and was lethal in subcutaneous infection of mice, whereas MGAS6180 did not invade skin, induced robust neutrophil infiltration and TNF-α production, and failed to kill mice. In contrast to MGAS6180, MGAS315 had  covS  G1370T mutation. Either replacement of the  covS   1370T  gene with wild-type  covS  in MGAS315 chromosome or  in trans  expression of wild-type  covS  in MGAS315 reduced expression of CovRS-controlled virulence genes  hasA ,  spyCEP , and  sse  by >10 fold. MGAS315  covS   wt  lost the capacity to extensively invade skin and to inhibit neutrophil recruitment and had attenuated virulence, indicating that the  covS  G1370T mutation critically contribute to the hypervirulence of MGAS315. Under the background of functional CovRS, MGAS315  covS   wt  still caused greater lesions than MGAS6180, and, consistently under the background of  covS  deletion, MGAS6180 Δ covS  caused smaller lesions than MGAS315 Δ covS . Thus, contemporary invasive M3 GAS has a higher capacity to evade neutrophil and TNF-α responses and to invade soft tissue than M28 GAS and that this skin-invading capacity of M3 GAS is maximized by natural CovRS mutations. These findings enhance our understanding of the basis for the frequent association of M3 GAS with necrotizing fasciitis.

Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-α Responses and to Invade Soft Tissues