Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

Waleed Nasser, Stephen B. Beres, Randall J. Olsen, Melissa A. Dean, Kelsey A. Rice, S. Wesley Long, Karl G. Kristinsson, Magnus Gottfredsson, Jaana Vuopio, Kati Raisanen, Dominique A. Caugant, Martin Steinbakk, Donald E. Low, Allison McGeer, Jessica Darenberg, Birgitta Henriques-Normark, Chris A. Van Beneden, Steen Hoffmann, James M. Musser

Research output: Contribution to journalArticlepeer-review

175 Scopus citations


We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion froma precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD+-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population- based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.

Original languageEnglish (US)
Pages (from-to)E1768-E1776
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 29 2014


  • Flesh-eating disease
  • Mobile genetic element
  • Molecular clock
  • Pathogenesis
  • Phylogeography

ASJC Scopus subject areas

  • General


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