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 8

Summary of molecular events underpinning serotype M1 and M89 GAS virulent clone emergence and epidemics of bacterial pathogens.

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Summary of molecular events underpinning serotype M1 and M89 GAS virulen...
The key molecular event for both M1 and M89 epidemics was recombinational replacement of a segment of chromosomal DNA with SNPs that cause upregulation and increased production of two potent secreted toxins. The asterisk above the nga gene denotes that the recombined segment in the new epidemic M1 clone contains a nonsynonymous SNP that results in production of enzymatically active extracellular NADase. All serotype M89 strains produce enzymatically active NADase. The two asterisks upstream of the nga gene denote SNPs in the promoter space region that result in significant upregulation of transcription of this operon in M1 and M89 epidemic strains. The blue arrows in the histopathology panel identify the small lesion observed in muscle infected with the SPN/SLO-deficient pre-epidemic emm1 strain SF370 (left) compared with the much larger lesion with extensive tissue destruction caused by the epidemic emm1 strain MGAS2221 (right). Original magnification, ×4.