We present the following findings: I) In contrast with MGAS6180, MGAS315 has an extremely high capacity to invade soft tissue, evade neutrophil responses, disseminate and kill mice in subcutaneous infection; II) MGAS315 suppresses TNF-α production at skin infection sites; III) the covS G1370T mutation in MGAS315 critically contributes to its hypervirulent phenotype; and IV) M3 GAS has significantly higher soft tissue-invading capacity than M28 GAS with or without functional CovRS. This evidence concerns the gene TNF and infection.