Highly Frequent Mutations in Negative Regulators of Multiple Virulence Genes in Group A Streptococcal Toxic Shock Syndrome Isolates

• Published in: PLoS pathogens Vol. 6; no. 4; p. e1000832
• Main Authors: Ikebe, Tadayoshi, Ato, Manabu, Matsumura, Takayuki, Hasegawa, Hideki, Sata, Tetsutaro, Kobayashi, Kazuo, Watanabe, Haruo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2010; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Amino acids; Animals; Bacterial Proteins - genetics; Bacteriology; Blotting, Western; Child; Child, Preschool; Comparative Genomic Hybridization; Gene Expression; Gene Expression Regulation, Viral; Gene mutations; Genes; Genetic aspects; Genetic research; Genetics and Genomics/Disease Models; Genetics and Genomics/Genetics of Disease; Health aspects; Humans; Infant; Infant, Newborn; Infectious Diseases/Bacterial Infections; Male; Mice; Mice, Nude; Microbiology/Medical Microbiology; Middle Aged; Mortality; Mutation; Protein Kinases - genetics; Proteins; Repressor Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Shock, Septic - genetics; Streptococcal Infections - genetics; Streptococcus pyogenes - genetics; Streptococcus pyogenes - pathogenicity; Studies; Toxic shock syndrome; Trans-Activators - genetics; Virulence; Virulence Factors - biosynthesis; Virulence Factors - genetics; Young Adult; Japan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• 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.