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A molecular trigger for intercontinental epidemics of group A Streptococcus
Luchang Zhu, … , Frank R. DeLeo, James M. Musser
Luchang Zhu, … , Frank R. DeLeo, James M. Musser
Published August 10, 2015
Citation Information: J Clin Invest. 2015;125(9):3545-3559. https://doi.org/10.1172/JCI82478.
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Research Article Infectious disease

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.

Authors

Luchang Zhu, Randall J. Olsen, Waleed Nasser, Stephen B. Beres, Jaana Vuopio, Karl G. Kristinsson, Magnus Gottfredsson, Adeline R. Porter, Frank R. DeLeo, James M. Musser

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Figure 7

An analogous molecular event has triggered an intercontinental epidemic of infections caused by serotype M89 GAS.

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An analogous molecular event has triggered an intercontinental epidemic ...
(A) Epidemic curve showing increase in frequency of infections caused by progeny of a new clone (variant 3) of serotype M89 strains. Data are from comprehensive population-based studies in the US, Finland, and Iceland. (B) Three nga promoter variants in the M89 strains. The genetically representative strains used (C) have variant 1 (MGAS11027), variant 2 (MGAS23530), and variant 3 (MGAS26844) patterns. (C) TaqMan qRT-PCR analysis of in vivo nga and slo transcript levels in the 3 strains. Transcript levels are displayed relative to the strain MGAS26844 (with variant 3) transcript level. Cultures were analyzed in triplicate on 3 separate occasions. NADase and SLO activity data for wild-type strain MGAS26844 (variant 3) and isogenic mutant strains with variant 2 (26844-V2) and variant 1 (26844-V1) nga promoter. Transcript data and NADase and SLO activity data are shown as mean ± SD (n = 3). Statistical significance was determined by 2-tailed Student’s t test. (D) Mouse survival data. Shown are Kaplan-Meier survival curves. Mice (n = 15 per strain) were inoculated in the hind limb with epidemic parental wild-type strain MGAS26844 or isoallelic mutant strains. P values were determined using the log-rank test.