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.pathogenesis | phylogeography | mobile genetic element | flesh-eating disease | molecular clock

Sequence type 1 group B Streptococcus , an emerging cause of invasive disease in adults, evolves by small genetic changes

“…Thus, in conjunction with our Alp findings, these data provide a new platform for investigating why ST-1 GBS strains have emerged as a major cause of invasive disease in nonpregnant adults, such as analysis of the previously unstudied TCS encoded by rdf_0314-0315. Interestingly, although the exact genes under positive selection are distinct between GBS and GAS, the GBS findings are thematically similar to those previously reported for GAS in terms of the high prevalence of nonsynonymous polymorphisms predicted to alter the bacterial cell surface through variation in regulatory proteins controlling cell-surface composition or through changes in cell-surface proteins themselves (4,5,36).…”

“…The increasing feasibility of whole-genome sequencing of large cohorts of clinical bacterial isolates is beginning to elucidate mechanisms of pathogen evolution, which, in turn, is providing key insights into a broad range of medically important issues such as occurrence of epidemics and transmission of drug-resistant pathogens (2,4,6). Most studies that involve high density genomic sequencing of bacterial pathogens investigated bacteria that have been prevalent causes of human disease for centuries (1,4,6).…”

“…Most studies that involve high density genomic sequencing of bacterial pathogens investigated bacteria that have been prevalent causes of human disease for centuries (1,4,6). In contrast, GBS has only recently emerged as a significant cause of human infection, perhaps as a result of the proliferation of tetracycline-resistant clones during an era of widespread tetracycline use, as suggested by Da Cunha et al (10,15,16,18).…”

“…A major outcome of the rapid expansion of available bacterial genomes has been the appreciation of the marked intraspecies genetic variability present in a wide variety of human bacterial pathogens (3,4). This genetic variation can have profound impact on host-pathogen interaction by affecting transmissibility, infection severity, and antimicrobial resistance (2,5,6).…”

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

“…Strain MGAS2221 is genetically representative of contemporary epidemic M1 strains. 17,18 Four isogenic mutant strains were derived from MGAS2221. SPN mutant strains Dnga and Dnga-ifs and SLO mutant strain Dslo were generated for the current study.…”