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Gene fitness landscape of group A streptococcus during necrotizing myositis
Luchang Zhu, … , Andrew S. Waller, James M. Musser
Luchang Zhu, … , Andrew S. Waller, James M. Musser
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):887-901. https://doi.org/10.1172/JCI124994.
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Research Article Infectious disease Microbiology

Gene fitness landscape of group A streptococcus during necrotizing myositis

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Abstract

Necrotizing fasciitis and myositis are devastating infections characterized by high mortality. Group A streptococcus (GAS) is a common cause of these infections, but the molecular pathogenesis is poorly understood. We report a genome-wide analysis using serotype M1 and M28 strains that identified GAS genes contributing to necrotizing myositis in nonhuman primates (NHP), a clinically relevant model. Using transposon-directed insertion-site sequencing (TraDIS), we identified 126 and 116 GAS genes required for infection by serotype M1 and M28 organisms, respectively. For both M1 and M28 strains, more than 25% of the GAS genes required for necrotizing myositis encode known or putative transporters. Thirteen GAS transporters contributed to both M1 and M28 strain fitness in NHP myositis, including putative importers for amino acids, carbohydrates, and vitamins and exporters for toxins, quorum-sensing peptides, and uncharacterized molecules. Targeted deletion of genes encoding 5 transporters confirmed that each isogenic mutant strain was significantly (P < 0.05) impaired in causing necrotizing myositis in NHPs. Quantitative reverse-transcriptase PCR (qRT-PCR) analysis showed that these 5 genes are expressed in infected NHP and human skeletal muscle. Certain substrate-binding lipoproteins of these transporters, such as Spy0271 and Spy1728, were previously documented to be surface exposed, suggesting that our findings have translational research implications.

Authors

Luchang Zhu, Randall J. Olsen, Stephen B. Beres, Jesus M. Eraso, Matthew Ojeda Saavedra, Samantha L. Kubiak, Concepcion C. Cantu, Leslie Jenkins, Amelia R. L. Charbonneau, Andrew S. Waller, James M. Musser

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Figure 10

Relative transcript level of GAS fitness genes.

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Relative transcript level of GAS fitness genes.
Transcript levels are sh...
Transcript levels are shown in an infected NHP with experimental necrotizing myositis (A) and in an infected human with necrotizing fasciitis (B). In vivo transcript level of GAS genes Spy0014, Spy0271, braB, Spy1726, pptA, and glgP relative to housekeeping gene rpsL. The experiment was performed in triplicate, and mean ± SD are shown.
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