Heterogeneity in the Polarity of Nra Regulatory Effects on Streptococcal Pilus Gene Transcription and Virulence

Abstract

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.Pilus surface structures were recently identified as potentially important virulence factors for several species of pathogenic streptococci and closely related organisms, such as en-

Increased Pilus Production Conferred by a Naturally Occurring Mutation Alters Host-Pathogen Interaction in Favor of Carriage in Streptococcus pyogenes

“…Pilus gene regulation may occur through a number of transcriptional regulators and appears to be M protein serotype and FCT type dependent (25)(26)(27)(28). Serotype M3 GAS (FCT type 3) strains may regulate pilus gene expression through regulators that reside within the FCT chromosomal region, including Nra (SpyM3_0097) (26) and MsmR (SpyM3_0103) (28). Additionally, transcriptome analysis following the deletion of the stand-alone regulator Mga suggests that Mga is an activator of pilus in serotype M1 GAS strains (37).…”

“…Studies suggest that the presence of pilus on the GAS cell surface may simultaneously promote epithelial cell colonization and reduce virulence (23,24), phenotypes consistent with a carrier state. Regulation of GAS pilus gene expression occurs through stand-alone regulators, including RofA/Nra (25)(26)(27) and MsmR (28), and varies by serotype but may also involve GAS TCS. Studies in S. pneumoniae (29) and GBS (30) suggest that the LiaFSR three-component system may directly or indirectly regulate pilus gene expression.…”

Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus

“…Several genes that lie within AGR-2 and AGR-21 of Alab49 and display strong LD with emm pattern A-C versus D strains (for the data set, see Table S2 in the supplemental material) also play a critical role in virulence at the skin when GAS strains with targeted gene deletions are tested in a humanized mouse model for impetigo (12,43,45,46,62). Essential virulence factors include regulators of transcription (Mga, Nra) and extracellular proteins (M53/PAM, Ska, Cpa, PrtF2).…”

Streptococcus pyogenesCovRS Mediates Growth in Iron Starvation and in the Presence of the Human Cationic Antimicrobial Peptide LL-37

“…Characterization has begun for several regulators specific for one or a few promoters (e.g., Nra and RofA, etc.) (6,29,33,36), as well as more general ones, including the activator Mga (multiple gene regulator of GAS) (28). Among the 13 two-component signal-transducing systems (TCS) encoded in GAS genomes, the TCS CovRS (CsrRS) seems to play a central role in growth and pathogenesis (41,43).…”