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Modelled-Microgravity Reduces Virulence Factor Production in Staphylococcus aureus through Downregulation of agr-Dependent Quorum Sensing

Green, Macauley J.; Murray, Ewan J.; Williams, Paul; Ghaemmaghami, Amir M.; Aylott, Jonathan W.; Williams, Philip M.

Authors

Macauley J. Green

Ewan J. Murray

PAUL WILLIAMS PAUL.WILLIAMS@NOTTINGHAM.AC.UK
Professor of Molecular Microbiology

PHIL WILLIAMS PHIL.WILLIAMS@NOTTINGHAM.AC.UK
Professor of Biophysics



Abstract

Bacterial contamination during space missions is problematic for human health and damages filters and other vital support systems. Staphylococcus aureus is both a human commensal and an opportunistic pathogen that colonizes human tissues and causes acute and chronic infections. Virulence and colonization factors are positively and negatively regulated, respectively, by bacterial cell-to-cell communication (quorum sensing) via the agr (accessory gene regulator) system. When cultured under low-shear modelled microgravity conditions (LSMMG), S. aureus has been reported to maintain a colonization rather than a pathogenic phenotype. Here, we show that the modulation of agr expression via reduced production of autoinducing peptide (AIP) signal molecules was responsible for this behavior. In an LSMMG environment, the S. aureus strains JE2 (methicillin-resistant) and SH1000 (methicillin-sensitive) both exhibited reduced cytotoxicity towards the human leukemia monocytic cell line (THP-1) and increased fibronectin binding. Using S. aureus agrP3::lux reporter gene fusions and mass spectrometry to quantify the AIP concentrations, the activation of agr, which depends on the binding of AIP to the transcriptional regulator AgrC, was delayed in the strains with an intact autoinducible agr system. This was because AIP production was reduced under these growth conditions compared with the ground controls. Under LSMMG, S. aureus agrP3::lux reporter strains that cannot produce endogenous AIPs still responded to exogenous AIPs. Provision of exogenous AIPs to S. aureus USA300 during microgravity culture restored the cytotoxicity of culture supernatants for the THP-1 cells. These data suggest that microgravity does not affect AgrC-AIP interactions but more likely the generation of AIPs.

Citation

Green, M. J., Murray, E. J., Williams, P., Ghaemmaghami, A. M., Aylott, J. W., & Williams, P. M. (2023). Modelled-Microgravity Reduces Virulence Factor Production in Staphylococcus aureus through Downregulation of agr-Dependent Quorum Sensing. International Journal of Molecular Sciences, 24(21), Article 15997. https://doi.org/10.3390/ijms242115997

Journal Article Type Article
Acceptance Date Oct 27, 2023
Online Publication Date Nov 6, 2023
Publication Date 2023-11
Deposit Date Nov 6, 2023
Publicly Available Date Nov 9, 2023
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 24
Issue 21
Article Number 15997
DOI https://doi.org/10.3390/ijms242115997
Keywords astropharmacy; Staphylococcus aureus; agr; quorum sensing; autoinducing peptide; microgravity; virulence; colonization; rotating cell culture system
Public URL https://nottingham-repository.worktribe.com/output/27072774
Publisher URL https://www.mdpi.com/1422-0067/24/21/15997

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