Abstract
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 ΔcovS caused smaller lesions than MGAS315 ΔcovS. 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.
Highlights
Group A Streptococcus (GAS) is a major human pathogen that commonly causes pharyngitis and superficial skin infections [1]
While the number of severe invasive GAS infections declined in the majority of the 20th century, cases of streptococcal necrotizing fasciitis, toxic shock syndrome, and bacteremia have significantly increased in industrialized countries since the 1980s
According to the GAS genome databases [10,41,46], the CovS protein has G457V and E226G replacements in MGAS315 and MGAS6180, respectively, and the RopB/Rgg protein in MGAS315 and MGAS6180 has S103P and R11K mutations, respectively, compared with the CovS and RopB proteins of the M1 GAS strain SF370 [46]. Both MGAS315 and MGAS6180 had no detectable SpeB activity in the supernatants of their overnight culture, and in trans complementation with the MGAS2221 ropB/rgg gene, but not the MGAS2221 covS gene, restored SpeB production in both MGAS315 and MGAS6180 (Fig 1). These data indicate that the RopB mutations, but not the CovS mutations, were the basis for the SpeB activity-negative phenotype (SpeBA-) of MGAS315 and MGAS6180
Summary
Group A Streptococcus (GAS) is a major human pathogen that commonly causes pharyngitis and superficial skin infections [1]. GAS caused severe and frequent epidemics of invasive and often fatal illnesses in the 19th century [2]. While the number of severe invasive GAS infections declined in the majority of the 20th century, cases of streptococcal necrotizing fasciitis, toxic shock syndrome, and bacteremia have significantly increased in industrialized countries since the 1980s. Contemporary severe invasive GAS infections are caused disproportionately by serotype M1, M3, and M12 GAS [3,4,5,6]. Pharyngitis and invasive groups of M3 GAS show distinct patterns of diversifying selection and have more polymorphisms in the hyaluronic acid capsule synthesis operon and in the covS gene of the two-component regulatory system CovRS ( known as CsrRS), respectively [12]. Whether the frequent covS polymorphisms among invasive M3 GAS isolates critically contribute to their hypervirulence has not been experimentally demonstrated, and the basis for the hypervirulence of invasive M3 GAS is not fully understood
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