The cell-autonomous innate immune system enables animal cells to resist viral infection. This system comprises an array of sensors that, after detecting viral molecules, activate the expression of antiviral proteins and the interferon response. The repertoire of immune sensors and antiviral proteins has long been considered to be derived from extensive evolutionary innovation in vertebrates, but new data challenge this dogma. Recent studies show that central components of the cell-autonomous innate immune system have ancient evolutionary roots in prokaryotic genes that protect bacteria from phages. These include the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, Toll/IL-1 receptor (TIR) domain-containing pathogen receptors, the viperin family of antiviral proteins, SAMHD1-like nucleotide-depletion enzymes, gasdermin proteins and key components of the RNA interference pathway. This Perspective details current knowledge of the elements of antiviral immunity that are conserved from bacteria to humans, and presents possible evolutionary scenarios to explain the observed conservation.
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The authors thank P. Kranzusch, as well as the Sorek laboratory members, for fruitful discussion and comments on this manuscript. R.S. is supported, in part, by the European Research Council (grant ERC-AdG GA 101018520), Israel Science Foundation (grant ISF 296/21), the Deutsche Forschungsgemeinschaft (SPP 2330, grant 464312965), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Minerva Foundation with funding from the Federal German Ministry for Education and Research, and the Knell Family Center for Microbiology. T.W. is supported by a Minerva Foundation postdoctoral fellowship and by a European Molecular Biology Organization (EMBO) postdoctoral fellowship (ALTF 946-2020).
R.S. is a scientific cofounder and advisor of BiomX and Ecophage. T.W. declares no competing interests.
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Wein, T., Sorek, R. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat Rev Immunol 22, 629–638 (2022). https://doi.org/10.1038/s41577-022-00705-4