Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Stephen B. Beres, Ellen W. Richter, Michal J. Nagiec, Paul Sumby, Stephen F. Porcella, Frank R. DeLeo, James M. Musser

Research output: Contribution to journalArticle

152 Scopus citations

Abstract

In recent years we have studied the relationship between strain genotypes and patient phenotypes in group A Streptococcus (GAS), a model human bacterial pathogen that causes extensive morbidity and mortality worldwide. We have concentrated our efforts on serotype W13 organisms because these strains are common causes of pharyngeal and invasive infections, produce unusually severe invasive infections, and can exhibit epidemic behavior. Our studies have been hindered by the lack of genome-scale phytogenies of multiple GAS strains and whole-genome sequences of multiple serotype M3 strains recovered from individuals with defined clinical phenotypes. To remove some of these impediments, we sequenced to closure the genome of four additional GAS strains and conducted comparative genomic resequencing of 12 contemporary serotype M3 strains representing distinct genotypes and phenotypes. Serotype M3 strains are a single phylogenetic lineage. Strains from asymptomatic throat carriers were significantly less virulent for mice than sterile-site isolates and evolved to a less virulent phenotype by multiple genetic pathways. Strain persistence or extinction between epidemics was strongly associated with presence or absence, respectively, of the prophage encoding streptococcal pyrogenic exotoxin A. A serotype M3 clone significantly underrepresented among necrotizing fasciitis cases has a unique frameshift mutation that truncates MtsR, a transcriptional regulator controlling expression of genes encoding iron-acquisition proteins. Expression microarray analysis of this clone confirmed significant alteration in expression of genes encoding iron metabolism proteins. Our analysis provided unprecedented detail about the molecular anatomy of bacterial strain genotype-patient phenotype relationships.

Original languageEnglish (US)
Pages (from-to)7059-7064
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number18
DOIs
StatePublished - May 2 2006

Keywords

  • Carrier
  • Epidemic
  • Genomic resequencing
  • Phylogeny
  • SNP

ASJC Scopus subject areas

  • Genetics
  • General

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