Backtracking metabolic dynamics in single cells predicts bacterial replication in human macrophages

Mariatou Dramé, Francisco-Javier Garcia-Rodriguez, Dmitry Ershov, Jessica E. Martyn, Jean-Yves Tinevez, Carmen Buchrieser () and Pedro Escoll ()
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Mariatou Dramé: Université Paris Cité, Biologie des Bactéries Intracellulaires
Francisco-Javier Garcia-Rodriguez: Université Paris Cité, Biologie des Bactéries Intracellulaires
Dmitry Ershov: Université Paris Cité, Image Analysis Hub
Jessica E. Martyn: Université Paris Cité, Biologie des Bactéries Intracellulaires
Jean-Yves Tinevez: Université Paris Cité, Image Analysis Hub
Carmen Buchrieser: Université Paris Cité, Biologie des Bactéries Intracellulaires
Pedro Escoll: Université Paris Cité, Biologie des Bactéries Intracellulaires

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Accurately tracking dynamic state transitions is crucial for modeling and predicting biological outcomes, as it captures heterogeneity of cellular responses. To build a model to predict bacterial infection in single cells, we have monitored in parallel infection progression and metabolic parameters in thousands of human primary macrophages infected with the intracellular pathogen Legionella pneumophila. By combining live-cell imaging with a tool for classifying cells based on infection outcomes, we were able to trace the specific evolution of metabolic parameters linked to distinct outcomes, such as bacterial replication or cell death. Our findings revealed that early changes in mitochondrial membrane potential (Δψm) and in the production of mitochondrial Reactive Oxygen Species (mROS) are associated with macrophages that will later support bacterial growth. We used these data to train an explainable machine-learning model and achieved 83% accuracy in predicting L. pneumophila replication in single, infected cells before bacterial replication starts. Our results highlight backtracking as a valuable tool to gain new insights in host-pathogen interactions and identify early mitochondrial alterations as key predictive markers of success of bacterial infection.

Date: 2025
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DOI: 10.1038/s41467-025-64225-0

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