Abstract
Pathogenic bacteria rely on the stringent response to adapt to hostile environments encountered within the host. However, the mechanisms by which host-induced stress activates this response remain poorly understood. Here, we identify iron-sulfur (Fe-S) cluster damage as a conserved trigger of the stringent response in major Gram-negative pathogens, including Salmonella enterica, Enterobacter cloacae, and Klebsiella pneumoniae. We demonstrate that Fe-S cluster disruption—triggered by oxidative stress or metal imbalance—limits intracellular pools of sulfur-containing and branched-chain amino acids, thereby activating the (p)ppGpp synthetase RelA. We further show that during Fe-S cluster stress, (p)ppGpp plays a dual role: enhancing bacterial fitness and promoting virulence by upregulating the Salmonella SPI-2 type III secretion system. These findings reveal a conserved mechanism by which pathogenic bacteria integrate host-associated stresses into an adaptive transcriptional response that promotes fitness and virulence, highlighting Fe-S cluster integrity as a central hub for environmental sensing during infection.
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Data availability
Raw and processed RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) repository at the National Center for Biotechnology Information (NCBI) under accession number GSE305564. Data generated in this study are provided in the source data file. Biological materials are available upon request to the corresponding author. Source data are provided with this paper.
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Acknowledgements
We thank all members of the Hallez lab, the BRM unit and Benjamin Ezraty for fruitful scientific discussions. We are also grateful to Jean-François Collet, Hélène Andrews-Polymenis, Michael McClelland, and Athanasios Typas for providing the Salmonella Single Gene Deletion library. We also thank Sophie Helaine for her critical reading of the manuscript. This work was supported by the Marie Sklodowska Curie COFUND action (No 101034383) and the ATIP-Avenir program to S.R., the CARE ANR grant (22-PAMR-0002) to C.M., and the Welbio Starting Grant (WELBIO-CR-2019S-05) to R.H. R.H. is a senior research associates of the F.R.S. – FNRS.
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S.R. conceived and designed the experiments. E.M., L.R., C.M., and S.R. performed the experiments. C.L., L.B. and C.M. analyzed the RNA-seq data. C.M., V.C. and R.H. provided intellectual input and contributed reagents, materials, and analysis tools. S.R. wrote the manuscript with input from all the authors.
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Michaud, E., Ricci, L., Lallement, C. et al. Stress-induced iron-sulfur cluster damage as a conserved trigger of the bacterial stringent response. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70079-x
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DOI: https://doi.org/10.1038/s41467-026-70079-x
