title: Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences.
abstract: 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 from a 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.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Waleed
authors.initials: W
authors.lastname: Nasser
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beres
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Dean
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Rice
authors.forename: S Wesley
authors.initials: SW
authors.lastname: Long
authors.forename: Karl G
authors.initials: KG
authors.lastname: Kristinsson
authors.forename: Magnus
authors.initials: M
authors.lastname: Gottfredsson
authors.forename: Jaana
authors.initials: J
authors.lastname: Vuopio
authors.forename: Kati
authors.initials: K
authors.lastname: Raisanen
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Caugant
authors.forename: Martin
authors.initials: M
authors.lastname: Steinbakk
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: Allison
authors.initials: A
authors.lastname: McGeer
authors.forename: Jessica
authors.initials: J
authors.lastname: Darenberg
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
authors.forename: Chris A
authors.initials: CA
authors.lastname: Van Beneden
authors.forename: Steen
authors.initials: S
authors.lastname: Hoffmann
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D058872:Epidemics; D019143:Evolution, Molecular; D019115:Fasciitis, Necrotizing / Q000453:epidemiology / Q000235:genetics / Q000382:microbiology; D005387:Finland / Q000453:epidemiology; D005798:Genes, Bacterial / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics*; D023281:Genomics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D010612:Pharyngitis / Q000453:epidemiology / Q000235:genetics / Q000382:microbiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011323:Primates / Q000382:microbiology; D012641:Selection, Genetic; D012703:Serotyping; D013290:Streptococcal Infections / Q000453:epidemiology* / Q000235:genetics* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D013997:Time Factors; D014774:Virulence / Q000235:genetics
keywords: flesh-eating disease; mobile genetic element; molecular clock; pathogenesis; phylogeography
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