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A molecular trigger for intercontinental epidemics of group A Streptococcus.

ABSTRACT: The identification of the molecular events responsible for strain emergence, enhanced virulence, and epidemicity has been a long-pursued goal in infectious diseases research. A recent analysis of 3,615 genomes of serotype M1 group A Streptococcus strains (the so-called "flesh-eating" bacterium) identified a recombination event that coincides with the global M1 pandemic beginning in the early 1980s. Here, we have shown that the allelic variation that results from this recombination event, which replaces the chromosomal region encoding secreted NADase and streptolysin O, is the key driver of increased toxin production and enhanced infection severity of the M1 pandemic strains. Using isoallelic mutant strains, we found that 3 polymorphisms in this toxin gene region increase resistance to killing by human polymorphonuclear leukocytes, increase bacterial proliferation, and increase virulence in animal models of pharyngitis and necrotizing fasciitis. Genome sequencing of an additional 1,125 streptococcal strains and virulence studies revealed that a highly similar recombinational replacement event underlies an ongoing intercontinental epidemic of serotype M89 group A Streptococcus infections. By identifying the molecular changes that enhance upper respiratory tract fitness, increased resistance to innate immunity, and increased tissue destruction, we describe a mechanism that underpins epidemic streptococcal infections, which have affected many millions of people.

SUBMITTER: Zhu L

PROVIDER: S-EPMC4588293 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A molecular trigger for intercontinental epidemics of group A Streptococcus.

Zhu Luchang L Olsen Randall J RJ Nasser Waleed W Beres Stephen B SB Vuopio Jaana J Kristinsson Karl G KG Gottfredsson Magnus M Porter Adeline R AR DeLeo Frank R FR Musser James M JM

The Journal of clinical investigation 20150810 9

The identification of the molecular events responsible for strain emergence, enhanced virulence, and epidemicity has been a long-pursued goal in infectious diseases research. A recent analysis of 3,615 genomes of serotype M1 group A Streptococcus strains (the so-called "flesh-eating" bacterium) identified a recombination event that coincides with the global M1 pandemic beginning in the early 1980s. Here, we have shown that the allelic variation that results from this recombination event, which r ...[more]

PMID: 26258415

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Project description:The characteristic recurrent epidemics of human respiratory syncytial virus (RSV) within communities may result from the genetic variability of the virus and associated evolutionary adaptation, reducing the efficiency of preexisting immune responses. We analyzed the molecular evolutionary changes in the attachment (G) glycoprotein of RSV-A viruses collected over 13 epidemic seasons (2000 to 2012) in Kilifi (n = 649), Kenya, and contemporaneous sequences (n = 1,131) collected elsewhere within Kenya and 28 other countries. Genetic diversity in the G gene in Kilifi was dynamic both within and between epidemics, characterized by frequent new variant introductions and limited variant persistence between consecutive epidemics. Four RSV-A genotypes were detected in Kilifi: ON1 (11.9%), GA2 (75.5%), GA5 (12.3%), and GA3 (0.3%), with predominant genotype replacement of GA5 by GA2 and then GA2 by ON1. Within these genotypes, there was considerable variation in potential N-glycosylation sites, with GA2 and ON1 viruses showing up to 15 different patterns involving eight possible sites. Further, we identified 15 positively selected and 34 genotype-distinguishing codon sites, with six of these sites exhibiting both characteristics. The mean substitution rate of the G ectodomain for the Kilifi data set was estimated at 3.58 × 10(-3) (95% highest posterior density interval = 3.04 to 4.16) nucleotide substitutions/site/year. Kilifi viruses were interspersed in the global phylogenetic tree, clustering mostly with Kenyan and European sequences. Our findings highlight ongoing genetic evolution and high diversity of circulating RSV-A strains, locally and globally, with potential antigenic differences. Taken together, these provide a possible explanation on the nature of recurrent local RSV epidemics.The mechanisms underlying recurrent epidemics of RSV are poorly understood. We observe high genetic diversity in circulating strains within and between epidemics in both local and global settings. On longer time scales (?7 years) there is sequential replacement of genotypes, whereas on shorter time scales (one epidemic to the next or within epidemics) there is a high turnover of variants within genotypes. Further, this genetic diversity is predicted to be associated with variation in antigenic profiles. These observations provide an explanation for recurrent RSV epidemics and have potential implications on the long-term effectiveness of vaccines.

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A molecular trigger for intercontinental epidemics of group A Streptococcus.

Publications

A molecular trigger for intercontinental epidemics of group A Streptococcus.

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