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A high-throughput cytotoxicity screening platform reveals -independent mutations in bacteraemia-associated that promote intracellular persistence.

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Author
Cho, Ellie
 Hachani, Abderrahman
 Giulieri, Stefano
 Guerillot, Romain
 Walsh, Calum
 HERISSE, Marion
 Soe, Ye Mon
 Baines, Sarah
 Thomas, David
 Doris Cheung, Shane
 Hayes, Ashleigh
 Newton, Hayley J
 Pidot, Sacha
 Massey, Ruth
 Howden, Benjamin
 Stinear, Timothy
Advisors
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Other Contributors
Departments
Date
08/06/2023
Date Submitted
Keywords
CYTOTOXICITY
GENETICS
genomics
infectious disease
intracellular
Microbiology
bacterial population genomics
evolutionary convergence analysis
GWAS
Staphylococcus aureus
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Start Date
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Principal Investigators
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elife-84778.pdf
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URI
https://hdl.handle.net/10147/637884
Abstract
Staphylococcus aureus infections are associated with high mortality rates. Often considered an extracellular pathogen, S. aureus can persist and replicate within host cells, evading immune responses, and causing host cell death. Classical methods for assessing S. aureus cytotoxicity are limited by testing culture supernatants and endpoint measurements that do not capture the phenotypic diversity of intracellular bacteria. Using a well-established epithelial cell line model, we have developed a platform called InToxSa (intracellular toxicity of S. aureus) to quantify intracellular cytotoxic S. aureus phenotypes. Studying a panel of 387 S. aureus bacteraemia isolates, and combined with comparative, statistical, and functional genomics, our platform identified mutations in S. aureus clinical isolates that reduced bacterial cytotoxicity and promoted intracellular persistence. In addition to numerous convergent mutations in the Agr quorum sensing system, our approach detected mutations in other loci that also impacted cytotoxicity and intracellular persistence. We discovered that clinical mutations in ausA, encoding the aureusimine non-ribosomal peptide synthetase, reduced S. aureus cytotoxicity, and increased intracellular persistence. InToxSa is a versatile, high-throughput cell-based phenomics platform and we showcase its utility by identifying clinically relevant S. aureus pathoadaptive mutations that promote intracellular residency.
Language
en
Citation
ISSN
eISSN
2050-084X
ISBN
DOI
10.7554/eLife.84778
PMID
37289634
PMCID
PMC10259494
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