title: Transcriptional regulation of the sil locus by the SilCR signalling peptide and its implications on group A streptococcus virulence.
abstract: In 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 bacteriocin-like 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.
authors.affiliation: Institute of Microbiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yoni
authors.initials: Y
authors.lastname: Eran
authors.forename: Yoav
authors.initials: Y
authors.lastname: Getter
authors.forename: Moshe
authors.initials: M
authors.lastname: Baruch
authors.forename: Ilia
authors.initials: I
authors.lastname: Belotserkovsky
authors.forename: Gilly
authors.initials: G
authors.lastname: Padalon
authors.forename: Inbal
authors.initials: I
authors.lastname: Mishalian
authors.forename: Andreas
authors.initials: A
authors.lastname: Podbielski
authors.forename: Bernd
authors.initials: B
authors.lastname: Kreikemeyer
authors.forename: Emanuel
authors.initials: E
authors.lastname: Hanski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000472:pathogenicity; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014774:Virulence / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D014157:Transcription Factors