Transcriptional regulation of the sil locus by the SilCR signalling peptide and its implications on group A streptococcus virulence

Abstract

SummaryIn the last two decades an increasing number of local outbreaks of invasive group A streptococcus (GAS) infections including necrotizing fasciitis (NF) have been reported. We identified the streptococcal invasion locus (sil) which is essential for virulence of the M14 strain JS95 isolated from an NF patient. This locus contains six genes: silA/B and silD/E encoding two-component system (TCS) and ABC transporter, respectively, homologous to the corresponding entities in the regulon of Streptococcus pneumoniae involved in genetic competence. Situated between these two units are silC and silCR, which highly overlap and are transcribed from the complementing strand at opposite directions. SilCR is a putative competence stimulating peptide, but in the M14 strain it has a start codon mutation. Deletion of silC or addition of synthetic SilCR attenuates virulence of the M14 strain. Here we found that silC and silCR form a novel regulatory circuit that controls the sil locus transcription. Under non-inducing conditions silC represses the silCR promoter. Externally added SilCR peptide activates the TCS, which in turn stimulates silCR transcription. Ongoing silCR transcription mediates the repression of the converging and overlapping silC transcript. Transcription of bacteriocinlike peptide (blp) operon mirrors the inverse relationships between the silC and silCR transcripts. It is upregulated by either addition of SilCR or deletion of silC. Moreover, expression of silC from a plasmid in a silC deleted-mutant significantly represses blp transcription. Finally, we show that 18% of clinically relevant GAS isolates possess sil and produce SilCR. Based on these results we propose a working model for regulation gene expression and virulence in GAS by the SilCR signalling peptide.

Molecular Epidemiology of the sil Streptococcal Invasive Locus in Group A Streptococci Causing Invasive Infections in French Children

“…The disruption of the silD ORF could thus prevent the correct expression and functionality of the SilCR signaling and promote silC-mediated virulence in M4 strains. In this latter study the sil locus was present in 28% of the strains, a higher rate of presence probably reflecting the difference in serotype prevalence between France and Israel (16), but SilCR was not always produced in these strains (7).…”

Molecular Epidemiology of sil Locus in Clinical Streptococcus pyogenes Strains

“…PCR detection of the sil locus was performed as previously described, using two sets of primers, SD-sil-f1 and SD-sil-r1 or SD-sil-f2 and SD-sil-r2 ( Fig. 1 and Table 2), amplifying, respectively, a fragment of 638 bp or 1,562 bp, encompassing silB and silD (14).…”

“…Upon reaching a threshold concentration, the mature SilCR binds to the TCS. This in turn activates the transcription of silCR (autoregulation) and silD and silE and represses that of silC (14). The silC gene product is linked to GAS virulence in the mouse model of human NF (13,15).…”

StreptococcusAdherence and Colonization

“…The CSP-like peptide is encoded by SilCR, whereas SilC encodes a signaling peptide. Together, SilC and SilCR form a novel regulatory circuit that controls the transcription of the sil locus (151). The deletion of silC drastically reduces biofilm accumulation by GAS (341).…”