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 2

RNA-seq analysis of GAS serotype M1 pre-epidemic and epidemic strains.

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RNA-seq analysis of GAS serotype M1 pre-epidemic and epidemic strains. (...
(A) Phylogenetic tree showing genetic relationships among strains used in the RNA-seq experiments. (B) Growth curves of strains used for RNA-seq experiments. The RNA-seq analyses were done in triplicate, and growth curves for the strains are similar. Cells were harvested at OD600 values of 1.0 and 1.8. MGAS strain collection strain designations are given above the growth curves in blue for pre-epidemic strains and in red for epidemic strains. (C) RNA-seq transcriptome data principal component analysis plot. Plotted are expression relationships among the strains based on principal component 1 (PC1) and principal component 2 (PC2), which account for the two largest unrelated variances in the data, 57.4% and 7.3% respectively. The pre-epidemic and epidemic strains are closely clustered, consistent with very limited transcriptome variance between them at both growth points. (D) Schematic showing the 5 genes markedly differentially expressed between pre-epidemic and epidemic stains at both OD600 of 1.0 (green dots) and 1.8 (purple triangles). All 5 differentially expressed genes are located in the 36-kb region of recombinational replacement. Differences in expression are plotted as the fold change of mean normalized transcript levels of 3 biological replicates for the 3 epidemic strains relative to the 4 pre-epidemic strains assessed. Transcript levels for nga, ifs, and slo are all increased by 1.5-fold or greater for the epidemic strains relative to the pre-epidemic strains at both stages of growth. Inferred transcriptional terminators downstream of nusG and slo are indicated as T1 and T2, respectively (17).