Heterogeneity in the polarity of Nra regulatory effects on streptococcal pilus gene transcription and virulence.

Transcription of several key virulence factors of Streptococcus pyogenes is under the control of Mga and Nra/RofA. In an M serotype 49 (M49) strain, Nra is a negative regulator of pilus gene transcription; also, Nra represses mga expression, leading to downregulation of the M protein surface fibril and secreted cysteine protease SpeB. In this report, the role of Nra in the virulence of an M53 classical skin strain was investigated. In contrast to the case for the M49 strain, Nra functions as a positive regulator of pilus gene transcription in the M53 strain, and inactivation of nra leads to loss of virulence in a humanized mouse model of superficial skin infection. Furthermore, Nra has no measurable effect on mga transcription in the M53 strain; this finding is further supported by a lack of detectable Nra effects on M protein- and SpeB-dependent phenotypes. Whereas MsmR is reported to activate nra and pilus gene transcription in the M49 strain, in the M53 strain it acts as a repressor of these genes. In both strains, MsmR and Nra form a feed-forward loop network motif for pilus gene transcription, but their effects have opposite signs. The findings demonstrate key strain-specific differences in the transcriptional circuitry governing virulence gene expression in S. pyogenes and its impact on pathogenesis.