Single-cell approach dissecting agr quorum sensing dynamics in Staphylococcus aureus
- 1Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
- 2Department of Civil, Environmental and Geomatic Engineering, ETH Zurich, Zurich, Switzerland
- 3Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland. [email protected]
Abstract
Quorum sensing (QS) enables bacteria to coordinate collective behaviors by secreting and sensing diffusible signals. Understanding QS at single-cell resolution is essential because population-level measurements often obscure regulatory heterogeneity. In Staphylococcus aureus, the accessory gene regulator (agr) system is a major QS-controlled virulence regulator activated by autoinducing peptides (AIPs). Four agr-types exist, each defined by distinct AIPs and capable of cross-inhibition, yet their activation dynamics and interaction hierarchies remain poorly understood. Using microfluidics, time-lapse microscopy, and deep-learning-based image analysis, we quantified agr-activation in congenic and native agr-type strains. Agr-types differed in sensitivity to their homologous AIPs: agr-III was largely unresponsive, whereas agr-IV was highly sensitive with elevated basal activation. Agr-activation distribution was frequently bimodal (simultaneous existence of agr-ON and agr-OFF cells), driven by subpopulations that never activated or switched to agr-OFF despite constant stimulation. Combining homologous and heterologous AIPs, AIP‑IV suppressed pre‑activated agr-I, while AIP-I had no inhibitory effect on agr‑IV, indicating asymmetric cross‑inhibition. In spatially segregated cocultures, diffusional crosstalk resulted in four reproducible agr-interaction regimes, stable-dominance, stable-, delayed-, or unstable-dual-activation, determined by agr-type pairing and influenced by genetic background. Our approach links single-cell signaling to population outcomes and uncovers agr-type-specific asymmetries with potential consequences for strain competition and virulence.
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BibTeX
@article{bar2026singlecell,
title = {{Single-cell approach dissecting agr quorum sensing dynamics in Staphylococcus aureus}},
author = {Julian Bär and Mariane Pivard and Sam Charlton and Andrew G. Kempchinsky and Alejandro Gómez-Mejía and Giovanni Stefano Ugolini and Srikanth Mairpady Shambat and Eleonora Secchi and Annelies Sophie Zinkernagel},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-73552-9},
url = {https://doi.org/10.1038/s41467-026-73552-9},
note = {CC BY},
}
RIS
TY - JOUR
TI - Single-cell approach dissecting agr quorum sensing dynamics in Staphylococcus aureus
AU - Julian Bär
AU - Mariane Pivard
AU - Sam Charlton
AU - Andrew G. Kempchinsky
AU - Alejandro Gómez-Mejía
AU - Giovanni Stefano Ugolini
AU - Srikanth Mairpady Shambat
AU - Eleonora Secchi
AU - Annelies Sophie Zinkernagel
PY - 2026
DA - 2026/05/20
JO - Nature Communications
DO - 10.1038/s41467-026-73552-9
UR - https://doi.org/10.1038/s41467-026-73552-9
AB - Quorum sensing (QS) enables bacteria to coordinate collective behaviors by secreting and sensing diffusible signals. Understanding QS at single-cell resolution is essential because population-level measurements often obscure regulatory heterogeneity. In Staphylococcus aureus, the accessory gene regulator (agr) system is a major QS-controlled virulence regulator activated by autoinducing peptides (AIPs). Four agr-types exist, each defined by distinct AIPs and capable of cross-inhibition, yet their activation dynamics and interaction hierarchies remain poorly understood. Using microfluidics, time-lapse microscopy, and deep-learning-based image analysis, we quantified agr-activation in congenic and native agr-type strains. Agr-types differed in sensitivity to their homologous AIPs: agr-III was largely unresponsive, whereas agr-IV was highly sensitive with elevated basal activation. Agr-activation distribution was frequently bimodal (simultaneous existence of agr-ON and agr-OFF cells), driven by subpopulations that never activated or switched to agr-OFF despite constant stimulation. Combining homologous and heterologous AIPs, AIP‑IV suppressed pre‑activated agr-I, while AIP-I had no inhibitory effect on agr‑IV, indicating asymmetric cross‑inhibition. In spatially segregated cocultures, diffusional crosstalk resulted in four reproducible agr-interaction regimes, stable-dominance, stable-, delayed-, or unstable-dual-activation, determined by agr-type pairing and influenced by genetic background. Our approach links single-cell signaling to population outcomes and uncovers agr-type-specific asymmetries with potential consequences for strain competition and virulence.
SN - 2041-1723
ER -