Abstract
Horizontal gene transfer plays a key role in bacterial evolution, yet its efficiency under natural conditions, especially between genetically distinct strains, remains unclear. Using Staphylococcus aureus as a model, we found that gene transfer via various mechanisms is significantly restricted between strains from different clonal complexes (CCs), with the notable exception of lateral transduction, which occurs at high frequency. Interestingly, some strains exhibited a promiscuous ability to accept diverse mobile genetic elements. These strains were defective in key immune defences, specifically the Type I restriction-modification systems that normally protect against foreign DNA. A broader analysis revealed that such immune-deficient mutants are widespread within S. aureus populations. Our study uncovered a trade-off that may account for their persistence in nature: although these mutants are more susceptible to phage attack, they gain an evolutionary advantage by acquiring new genes - such as those conferring antibiotic resistance - which would enhance survival under selective pressure. These immune-deficient cells act as gateways for foreign DNA, which, once integrated and advantageous, can spread within the same CC. Our findings highlight the role of immune-deficient bacteria in facilitating the emergence of novel virulence factors and antibiotic resistance, emphasising their importance in shaping bacterial evolution.
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The genomics data generated in this study have been deposited in the GenBank database under accession code BioProject ID PRJNA1177260. The experimental data generated in this study are provided in the Source data file. Source data are provided with this paper.
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Acknowledgements
We would like to thank Prof Luca G. Guardabassi for gifting us the strains used in this study as recipients. We would like to thank Lorrie Maccario for her assistance with library preparation and hybrid assemblies. This work was supported by grants MR/X020223/1, MR/M003876/1, MR/V000772/1 and MR/S00940X/1 from the Medical Research Council (UK), BB/V002376/1 and BB/V009583/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK), EP/X026671/1 from the Engineering and Physical Sciences Research Council (EPSRC, UK), and ERC-2023-SyG Project 101118890—TalkingPhages to J.R.P., a research grant (VIL58733-Weaponizable satellites) from VILLUM FONDEN to R.I.-C, and grant BB/W014920/1 from the Biological Sciences Research Council, and the Biotechnology and Biological Sciences Research Council institute strategic grant BBS/E/D/20002173 to J.R.F.
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J.R.P. conceived the study; W.F., A.S. and R.I.C. conducted the experiments; W.F., J.G. performed the bioinformatics analyses; W.F., A.S., J.G., J.R.F. and J.R.P. analysed the data; W.F. made all figures, J.R.P. wrote the manuscript with inputs from all the authors.
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Figueroa, W., Sabnis, A., Ibarra-Chávez, R. et al. Immune-deficient bacteria serve as gateways to genetic exchange and microbial evolution. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71467-z
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DOI: https://doi.org/10.1038/s41467-026-71467-z
