Highly frequent mutations in negative regulators of multiple virulence genes in group A streptococcal toxic shock syndrome isolates

PLoS Pathog. 2010 Apr 1;6(4):e1000832. doi: 10.1371/journal.ppat.1000832.


Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock and multiorgan failure; it has a high mortality rate. Although a number of studies have attempted to determine the crucial factors behind the onset of STSS, the responsible genes in group A Streptococcus have not been clarified. We previously reported that mutations of csrS/csrR genes, a two-component negative regulator system for multiple virulence genes of Streptococcus pyogenes, are found among the isolates from STSS patients. In the present study, mutations of another negative regulator, rgg, were also found in clinical isolates of STSS patients. The rgg mutants from STSS clinical isolates enhanced lethality and impaired various organs in the mouse models, similar to the csrS mutants, and precluded their being killed by human neutrophils, mainly due to an overproduction of SLO. When we assessed the mutation frequency of csrS, csrR, and rgg genes among S. pyogenes isolates from STSS (164 isolates) and non-invasive infections (59 isolates), 57.3% of the STSS isolates had mutations of one or more genes among three genes, while isolates from patients with non-invasive disease had significantly fewer mutations in these genes (1.7%). The results of the present study suggest that mutations in the negative regulators csrS/csrR and rgg of S. pyogenes are crucial factors in the pathogenesis of STSS, as they lead to the overproduction of multiple virulence factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Bacterial Proteins / genetics*
  • Blotting, Western
  • Child
  • Child, Preschool
  • Comparative Genomic Hybridization
  • Gene Expression
  • Gene Expression Regulation, Viral
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Mutation
  • Protein Kinases / genetics*
  • Repressor Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Shock, Septic / genetics*
  • Streptococcal Infections / genetics*
  • Streptococcus pyogenes / genetics
  • Streptococcus pyogenes / pathogenicity
  • Trans-Activators / genetics*
  • Virulence
  • Virulence Factors / biosynthesis
  • Virulence Factors / genetics
  • Young Adult


  • Bacterial Proteins
  • CsrR protein, Streptococcus pyogenes
  • Repressor Proteins
  • Trans-Activators
  • Virulence Factors
  • rgg protein, Streptococcus
  • Protein Kinases
  • CsrS protein, bacteria