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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 4

Genes encoding proven or putative transporters are an abundant portion of fitness genes that are required during necrotizing myositis in NHPs.

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Genes encoding proven or putative transporters are an abundant portion o...
(A) M1 GAS fitness genes (n = 32, 25.4%) and M28 GAS fitness genes (n = 32, 27.6%) that encode proven or putative transporters. (B) Venn diagram showing the relationship between M1 and M28 transporter genes required during NHP skeletal muscle infections; 26 genes are required in both M1 and M28 GAS strains. (C) Schematic showing the proven or putative transporters encoded by the shared transporter genes and their inferred functions. Inferred substrate-binding lipoproteins (Spy0271, Spy0596, MtsA, and Spy1728) are positioned outside of the bacterial cell. Elements that are positioned on the membrane and in the bacterial cell are putative transmembrane proteins and cytosolic proteins, respectively. The locus tag numbers refer to the annotation for serotype M1 GAS strain MGAS5005. PTS: phosphotransferase system; QS: quorum sensing.

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

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