Abstract
The cell-autonomous innate immune system is responsible for sensing and mitigating viral infection at the level of individual cells. Many of the mechanisms used by the cell-autonomous innate immune system in eukaryotic cells are ancient and have evolutionary roots in bacterial systems that defend against phage infection. Studies from recent years have shown that modification of the free nucleotide pool is central to many of these conserved immune mechanisms. In this Review, we explain how immune pathways manipulate the available pool of nucleotides to deprive viruses of molecules essential for their replication, how immune proteins chemically modify nucleotides to generate immune signalling molecules, and how cell-autonomous innate immune mechanisms produce altered nucleotides that poison viral replication. We also discuss the mechanisms used by viruses to antagonize nucleotide-based immunity. Finally, we explore the evolutionary logic of using nucleotides as building blocks for immune responses.
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Acknowledgements
The authors thank the members of the Sorek laboratory, as well as T. Wein, for the constructive criticism of the manuscript. D.H. was supported, in part, by the Ministry of Absorption New Immigrant programme and by the Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center. R.S. was supported, in part, by the European Research Council (grant ERC-AdG GA 101018520), the Israel Science Foundation (MAPATS grant 2720/22), the Deutsche Forschungsgemeinschaft (SPP 2330, grant 464312965), the Minerva Foundation with funding from the Federal German Ministry for Education and Research, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a research grant from the Estate of Hermine Miller, the Institute for Environmental Sustainability (IES) and the Center for Immunotherapy at the Weizmann Institute of Science, and the Knell Family Center for Microbiology.
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Hochhauser, D., Sorek, R. Manipulation of the nucleotide pool in human, bacterial and plant immunity. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01206-w
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DOI: https://doi.org/10.1038/s41577-025-01206-w
