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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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 4

Virulence features of GAS M1 reference and isoallelic mutant strains.

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Virulence features of GAS M1 reference and isoallelic mutant strains. (A...
(A) Kaplan-Meier survival curves for mice (n = 10 per strain) inoculated intramuscularly with reference and mutant strains as indicated. P values were determined using the log-rank test. (B) GAS CFUs per gram of infected hind limb at 96 hours after infection (n = 20 per strain) and relative transcript levels (n = 3 per strain) of nga and slo extracted from infected hind limbs at 96 hours after infection. CFU data are expressed as the mean ± SEM. Transcript data are expressed as the mean ± SD. #P < 0.0044, Mann-Whitney test. *P < 0.05, Student’s t test. (C) Tissue damage histology scores derived from microscopic examination by a pathologist blinded to infecting strain. Replicate scores are expressed as mean ± SEM (n = 3 per strain). *P < 0.05, Mann-Whitney test. (D) GAS resistance to the bactericidal activity of purified human PMNs was assessed with a suspension phagocytosis assay using PMNs from 6 donors. Shown are percentages of GAS survival after a 3-hour PMN exposure. Survival data are expressed as the mean ± SEM. *P < 0.05 vs. MGAS2221; #P < 0.05 vs. nga(G-22T); †P < 0.05 vs. nga(G-22T/T-18C), repeated-measures 1-way ANOVA and Tukey’s post test.