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 6

Epidemic parental strain MGAS2221 is significantly more virulent than a triple-SNP isoallelic mutant strain in a nonhuman primate model of upper respiratory tract infection.

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Epidemic parental strain MGAS2221 is significantly more virulent than a ...
(A) Cynomolgus macaques (n = 4 per strain) were inoculated in the upper respiratory tract with epidemic parental wild-type strain MGAS2221 or triple-SNP isoallelic mutant strain nga(G-22T/T-18C/G989A). P values were assessed by repeated-measures 2-way ANOVA. Mean CFUs recovered from the oropharynx on each day are shown with SEM. (B) Viability of PMNs in throat swab samples of each strain group determined by flow cytometry. Data are shown as average percentage of nonviable PMNs ± SEM (n = 4 per strain). *P < 0.029, Mann-Whitney test. (C) Relative transcript levels of nga and slo in animals infected with strain MGAS2221 or nga(G-22T/T-18C/G989A) during pharyngitis, as determined by TaqMan qRT-PCR. Data are shown as mean ± SD (n = 4 per strain). *P < 0.003, Student’s t test.