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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 Article has an altmetric score of 17

A molecular trigger for intercontinental epidemics of group A Streptococcus

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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 5

An isoallelic mutant GAS strain that overexpresses NADase and SLO is significantly more virulent than MGAS2221 in a mouse model of necrotizing fasciitis.

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An isoallelic mutant GAS strain that overexpresses NADase and SLO is sig...
(A) Transcript levels of nga and slo in MGAS2221, 2-SNP mutant nga(G-22T/T-18C), Nga/Slo-OE (overexpressing), and Nga/Slo-DE (2-nucleotide deletion) as determined by TaqMan qRT-PCR (n = 3 per strain). Data are expressed as the mean ± SD. *P < 0.05 vs. MGAS2221, Student’s t test. (B) Western immunoblot analysis of NADase and SLO present in the culture supernatant of each strain. (C) Kaplan-Meier survival curves of mice (n = 15 per strain) infected with strain MGAS2221, nga(G-22T/T-18C), Nga/Slo-OE (overexpression), or Nga/Slo-DE (2-nucleotide deletion mutant). P values were determined using the log-rank test. (D) Bacterial load in mice infected with each strain. Shown are CFUs of GAS per gram of infected hind limb tissue at 96 hours after infection. Data are shown as mean ± SEM (n = 20 per strain). P values were calculated using the Mann-Whitney test. (E) Histopathology scores of mouse limbs infected with each strain (n = 3 per strain). Data are shown as mean ± SEM. P values were calculated using the Mann-Whitney test. (F) Percentage GAS survival after treatment with purified human PMNs. At 3 hours, the isoallelic mutant strain overexpressing SPN and SLO exhibited significantly greater survival than wild-type parental strain MGAS2221. Results are presented as the mean ± SEM for GAS survival using 13 separate human PMN donors. P values were determined by paired 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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