TrxR, a new CovR-repressed response regulator that activates the Mga virulence regulon in group A Streptococcus.
Coordinate regulation of virulence factors by the group A streptococcus (GAS) Streptococcus pyogenes is important in this pathogen's ability to cause disease. To further elucidate the regulatory network in this human pathogen, the CovR-repressed two-component system (TCS) trxSR was chosen for further analysis based on its homology to a virulence-related TCS in Streptococcus pneumoniae. In a murine skin infection model, an insertion mutation in the response regulator gene, trxR, led to a significant reduction in lesion size, lesion severity, and lethality. Curing the trxR mutation restored virulence comparable to the wild-type strain. The trxSR operon was defined in vivo, and CovR was found to directly repress its promoter in vitro. DNA microarray analysis established that TrxR activates transcription of Mga-regulated virulence genes, which may explain the virulence attenuation of the trxR mutant. This regulation appears to occur by activation of the mga promoter, Pmga, as demonstrated by analysis of a luciferase reporter fusion. Complementation of the trxR mutant with trxR on a plasmid restored expression of Mga regulon genes and restored virulence in the mouse model to wild-type levels. TrxR is the first TCS shown to regulate Mga expression. Because it is CovR repressed, TrxR defines a new pathway by which CovR can influence Mga to affect pathogenesis in the GAS.
Leday
Temekka V
TV
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Gold
Kathryn M
KM
Kinkel
Traci L
TL
Roberts
Samantha A
SA
Scott
June R
JR
McIver
Kevin S
KS
D000818:Animals; D019677:Artificial Gene Fusion; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016254:Mutagenesis, Insertional; D020411:Oligonucleotide Array Sequence Analysis; D018085:Regulon; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017192:Skin Diseases, Bacterial / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000472:pathogenicity*; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis*
D001426:Bacterial Proteins; C432143:CsrR protein, Streptococcus pyogenes; D012097:Repressor Proteins; D014157:Transcription Factors; D037521:Virulence Factors; C068267:mry protein, Streptococcus pyogenes; D008156:Luciferases