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

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 t...

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Autores principales: Hachani, Abderrahman, Giulieri, Stefano G, Guérillot, Romain, Walsh, Calum J, Herisse, Marion, Soe, Ye Mon, Baines, Sarah L, Thomas, David R, Cheung, Shane Doris, Hayes, Ashleigh S, Cho, Ellie, Newton, Hayley J, Pidot, Sacha, Massey, Ruth C, Howden, Benjamin P, Stinear, Timothy P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259494/
https://www.ncbi.nlm.nih.gov/pubmed/37289634
http://dx.doi.org/10.7554/eLife.84778
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author Hachani, Abderrahman
Giulieri, Stefano G
Guérillot, Romain
Walsh, Calum J
Herisse, Marion
Soe, Ye Mon
Baines, Sarah L
Thomas, David R
Cheung, Shane Doris
Hayes, Ashleigh S
Cho, Ellie
Newton, Hayley J
Pidot, Sacha
Massey, Ruth C
Howden, Benjamin P
Stinear, Timothy P
author_facet Hachani, Abderrahman
Giulieri, Stefano G
Guérillot, Romain
Walsh, Calum J
Herisse, Marion
Soe, Ye Mon
Baines, Sarah L
Thomas, David R
Cheung, Shane Doris
Hayes, Ashleigh S
Cho, Ellie
Newton, Hayley J
Pidot, Sacha
Massey, Ruth C
Howden, Benjamin P
Stinear, Timothy P
author_sort Hachani, Abderrahman
collection PubMed
description 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.
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spelling pubmed-102594942023-06-13 A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence Hachani, Abderrahman Giulieri, Stefano G Guérillot, Romain Walsh, Calum J Herisse, Marion Soe, Ye Mon Baines, Sarah L Thomas, David R Cheung, Shane Doris Hayes, Ashleigh S Cho, Ellie Newton, Hayley J Pidot, Sacha Massey, Ruth C Howden, Benjamin P Stinear, Timothy P eLife Genetics and Genomics 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. eLife Sciences Publications, Ltd 2023-06-08 /pmc/articles/PMC10259494/ /pubmed/37289634 http://dx.doi.org/10.7554/eLife.84778 Text en © 2023, Hachani, Giulieri, Guérillot et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Hachani, Abderrahman
Giulieri, Stefano G
Guérillot, Romain
Walsh, Calum J
Herisse, Marion
Soe, Ye Mon
Baines, Sarah L
Thomas, David R
Cheung, Shane Doris
Hayes, Ashleigh S
Cho, Ellie
Newton, Hayley J
Pidot, Sacha
Massey, Ruth C
Howden, Benjamin P
Stinear, Timothy P
A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title_full A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title_fullStr A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title_full_unstemmed A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title_short A high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated Staphylococcus aureus that promote intracellular persistence
title_sort high-throughput cytotoxicity screening platform reveals agr-independent mutations in bacteraemia-associated staphylococcus aureus that promote intracellular persistence
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259494/
https://www.ncbi.nlm.nih.gov/pubmed/37289634
http://dx.doi.org/10.7554/eLife.84778
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