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J Clin Invest. 2019 Feb 1;129(2):887-901. doi: 10.1172/JCI124994. Epub 2019 Jan 22.

Gene fitness landscape of group A streptococcus during necrotizing myositis.

Author information

1
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
2
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York, USA.
3
Department of Comparative Medicine, Houston Methodist Research Institute, Houston, Texas, USA.
4
Animal Health Trust, Newmarket, Suffolk, United Kingdom.
5
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

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.

KEYWORDS:

Bacterial infections; Infectious disease; Microbiology

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