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Shared principles of human and bacterial antiviral immunity – Nature

Shared principles of human and bacterial antiviral immunity – Nature

Iuliano, A. D. et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet 391, 1285–1300 (2018).Thank you for reading this post, don’t forget to subscribe! Article  PubMed  Google Scholar  Mazur, N. I., Caballero, M. T. & Nunes, M. C. Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies. Lancet

  • Iuliano, A. D. et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet 391, 1285–1300 (2018).

    Thank you for reading this post, don't forget to subscribe!

    Article 
    PubMed 

    Google Scholar 

  • Mazur, N. I., Caballero, M. T. & Nunes, M. C. Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies. Lancet 404, 1143–1156 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • He, W. T. et al. Virome characterization of game animals in China reveals a spectrum of emerging pathogens. Cell 185, 1117–1129.e8 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hou, X. et al. Using artificial intelligence to document the hidden RNA virosphere. Cell 187, 6929–6942.e16 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Li, J., Lai, S., Gao, G. F. & Shi, W. The emergence, genomic diversity and global spread of SARS-CoV-2. Nature 600, 408–418 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Laurenson-Schafer, H. et al. Description of the first global outbreak of mpox: an analysis of global surveillance data. Lancet Glob. Health 11, e1012–e1023 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Castro, M. C., Wilson, M. E. & Bloom, D. E. Disease and economic burdens of dengue. Lancet Infect. Dis. 17, e70–e78 (2017).

    Article 
    PubMed 

    Google Scholar 

  • Hendrix, R. W., Smith, M. C., Burns, R. N., Ford, M. E. & Hatfull, G. F. Evolutionary relationships among diverse bacteriophages and prophages: all the world’s a phage. Proc. Natl Acad. Sci. USA 96, 2192–2197 (1999).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Suttle, C. A. Marine viruses–major players in the global ecosystem. Nat. Rev. Microbiol. 5, 801–812 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bar-On, Y. M., Phillips, R. & Milo, R. The biomass distribution on Earth. Proc. Natl Acad. Sci. USA 115, 6506–6511 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tan, X., Sun, L., Chen, J. & Chen, Z. J. Detection of microbial infections through innate immune sensing of nucleic acids. Annu. Rev. Microbiol. 72, 447–478 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Marques, J. T., Meignin, C. & Imler, J. L. An evolutionary perspective to innate antiviral immunity in animals. Cell Rep. 43, 114678 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Fu, J., Schroder, K. & Wu, H. Mechanistic insights from inflammasome structures. Nat. Rev. Immunol. 24, 518–535 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McDougal, M. B., Boys, I. N., De La Cruz-Rivera, P. & Schoggins, J. W. Evolution of the interferon response: lessons from ISGs of diverse mammals. Curr. Opin. Virol. 53, 101202 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Newton, K., Strasser, A., Kayagaki, N. & Dixit, V. M. Cell death. Cell 187, 235–256 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Whiteley, A. T. et al. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 567, 194–199 (2019). References 16–19 identified thousands of cGAS-like signalling pathways and STING proteins in bacteria, revealing the evolutionary connection between human innate immunity and bacterial anti-phage defence.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cohen, D. et al. Cyclic GMP–AMP signalling protects bacteria against viral infection. Nature 574, 691–695 (2019).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Morehouse, B. R. et al. STING cyclic dinucleotide sensing originated in bacteria. Nature 586, 429–433 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Burroughs, A. M. & Aravind, L. Identification of uncharacterized components of prokaryotic immune systems and their diverse eukaryotic reformulations. J. Bacteriol. https://doi.org/10.1128/JB.00365-20 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gao, L. A. et al. Prokaryotic innate immunity through pattern recognition of conserved viral proteins. Science 377, eabm4096 (2022). References 20–29 identified new anti-phage defence pathways and extended the connection between human and bacterial immunity to include inflammasome pathways, argonaute proteins and viperin enzymes.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kibby, E. M. et al. Bacterial NLR-related proteins protect against phage. Cell 186, 2410–2424.e18 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Johnson, A. G. et al. Bacterial gasdermins reveal an ancient mechanism of cell death. Science 375, 221–225 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wein, T. et al. CARD domains mediate anti-phage defence in bacterial gasdermin systems. Nature 639, 727–734 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Swarts, D. C. et al. DNA-guided DNA interference by a prokaryotic Argonaute. Nature 507, 258–261 (2014).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kuzmenko, A. et al. DNA targeting and interference by a bacterial Argonaute nuclease. Nature 587, 632–637 (2020).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Bernheim, A. et al. Prokaryotic viperins produce diverse antiviral molecules. Nature 589, 120–124 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Lachowicz, J. C., Gizzi, A. S., Almo, S. C. & Grove, T. L. Structural Insight into the substrate scope of viperin and viperin-like enzymes from three domains of life. Biochemistry 60, 2116–2129 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van den Berg, D. F. et al. Bacterial homologs of innate eukaryotic antiviral defenses with anti-phage activity highlight shared evolutionary roots of viral defenses. Cell Host Microbe 32, 1427–1443.e8 (2024).

    Article 
    PubMed 

    Google Scholar 

  • Ye, Q. et al. HORMA domain proteins and a Trip13-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity. Mol. Cell 77, 709–722.e7 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Medzhitov, R. & Iwasaki, A. Exploring new perspectives in immunology. Cell 187, 2079–2094 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Boehm, T. Understanding vertebrate immunity through comparative immunology. Nat. Rev. Immunol. 25, 141–152 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Marraffini, L. A. CRISPR–Cas immunity in prokaryotes. Nature 526, 55–61 (2015).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Barrangou, R. & Horvath, P. A decade of discovery: CRISPR functions and applications. Nat. Microbiol. 2, 17092 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, J. Y., Pausch, P. & Doudna, J. A. Structural biology of CRISPR–Cas immunity and genome editing enzymes. Nat. Rev. Microbiol. 20, 641–656 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Daugherty, M. D. & Malik, H. S. Rules of engagement: molecular insights from host-virus arms races. Annu. Rev. Genet. 46, 677–700 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Daugherty, M. D., Schaller, A. M., Geballe, A. P. & Malik, H. S. Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals. eLife 5, e14228. https://doi.org/10.7554/eLife.14228 (2016).

  • Doron, S. et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359, eaar4120 (2018). References 37 and 38 revealed that bacterial immune components cluster together to form defence islands and led to the identification of hundreds of new systems that defend against phage infection.

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Makarova, K. S., Wolf, Y. I., Snir, S. & Koonin, E. V. Defense islands in bacterial and archaeal genomes and prediction of novel defense systems. J. Bacteriol. 193, 6039–6056 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Santos, M. E. & Drake, J. W. Rates of spontaneous mutation in bacteriophage T4 are independent of host fidelity determinants. Genetics 138, 553–564 (1994).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nottay, B. K., Kew, O. M., Hatch, M. H., Heyward, J. T. & Obijeski, J. F. Molecular variation of type 1 vaccine-related and wild polioviruses during replication in humans. Virology 108, 405–423 (1981).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Domingo, E., Sabo, D., Taniguchi, T. & Weissmann, C. Nucleotide sequence heterogeneity of an RNA phage population. Cell 13, 735–744 (1978).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Culbertson, E. M. & Levin, T. C. Eukaryotic CD-NTase, STING, and viperin proteins evolved via domain shuffling, horizontal transfer, and ancient inheritance from prokaryotes. PLoS Biol. 21, e3002436 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wein, T. & Sorek, R. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat. Rev. Immunol. 22, 629–638 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Aravind, L., Nicastro, G. G., Iyer, L. M. & Burroughs, A. M. The prokaryotic roots of eukaryotic immune systems. Annu. Rev. Genet. 58, 365–389 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Li, Y. et al. A choanoflagellate cGLR–STING pathway reveals evolutionary links between bacterial and animal immunity. Preprint at bioRxiv https://doi.org/10.1101/2025.09.04.674280 (2025).

  • Richmond-Buccola, D. et al. A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion. Cell Host Microbe 32, 1074–1088.e1075 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Burroughs, A. M., Zhang, D., Schaffer, D. E., Iyer, L. M. & Aravind, L. Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling. Nucleic Acids Res. 43, 10633–10654 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Millman, A., Melamed, S., Amitai, G. & Sorek, R. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Nat. Microbiol. 5, 1608–1615 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ofir, G. et al. Antiviral activity of bacterial TIR domains via immune signalling molecules. Nature 600, 116–120 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Rousset, F. & Sorek, R. The evolutionary success of regulated cell death in bacterial immunity. Curr. Opin. Microbiol. 74, 102312 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hobbs, S. J., Nomburg, J., Doudna, J. A. & Kranzusch, P. J. Animal and bacterial viruses share conserved mechanisms of immune evasion. Cell 187, 5530–5539.e8 (2024). References 51 and 52 revealed that mechanisms of viral immune evasion are shared across kingdoms of life.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nomburg, J. et al. Birth of protein folds and functions in the virome. Nature 633, 710–717 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cury, J. et al. Conservation of antiviral systems across domains of life reveals immune genes in humans. Cell Host Microbe 32, 1594–1607.e5 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bonhomme, D. et al. A human homolog of SIR2 antiphage proteins mediates immunity via the Toll-like receptor pathway. Science 389, eadr8536 (2025). References 54 and 138 leveraged the ancient connection with bacterial immunity to identify components of human immunity, including SIRal and cGLR proteins.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Perez Taboada, V. et al. Bacterial Schlafen proteins mediate phage defence. Nat Microbiol 11, 1037–1048 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Stremlau, M. et al. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 427, 848–853 (2004). References 56 and 57 identified TRIM5α as a restriction factor that inhibits retrovirus infection and established protein shape recognition as a key form of human antiviral defence.

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Sayah, D. M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Fernandez, S. G. et al. Human interferon stimulated genes target ancient features of animal and bacterial viral replication. Preprint at bioRxiv https://doi.org/10.64898/2026.06.11.731453 (2026). References 58 and 277 reveal that human immune proteins can target ancient features of viral replication shared between animal viruses and bacteriophages.

  • Takata, M. A. et al. CG dinucleotide suppression enables antiviral defence targeting non-self RNA. Nature 550, 124–127 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pindel, A. & Sadler, A. The role of protein kinase R in the interferon response. J. Interferon Cytokine Res. 31, 59–70 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kristiansen, H., Gad, H. H., Eskildsen-Larsen, S., Despres, P. & Hartmann, R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 31, 41–47 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Chan, S. H., Stoddard, B. L. & Xu, S. Y. Natural and engineered nicking endonucleases-from cleavage mechanism to engineering of strand-specificity. Nucleic Acids Res. 39, 1–18 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Loeff, L., Walter, A., Rosalen, G. T. & Jinek, M. DNA end sensing and cleavage by the Shedu anti-phage defense system. Cell 188, 721–733.e17 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hossain, A. A. et al. DNA glycosylases provide antiviral defence in prokaryotes. Nature 629, 410–416 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, T. et al. Direct activation of a bacterial innate immune system by a viral capsid protein. Nature 612, 132–140 (2022). References 66, 67 and 92–95 established direct recognition of viral structural proteins as a key form of immune sensing in bacterial anti-phage defence.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Patel, P. H. et al. A pore-forming antiphage defence is activated by oligomeric phage proteins. Nature 651, 1060–1067 (2026).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Remick, B. C., Gaidt, M. M. & Vance, R. E. Effector-triggered immunity. Annu. Rev. Immunol. 41, 453–481 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Barthes, K., Rousset, F. & Wein, T. Viral effectors trigger innate immunity across the tree of life. Philos. Trans. R. Soc. B 380, 20240077 (2025).

    Article 
    CAS 

    Google Scholar 

  • Ichinohe, T., Pang, I. K. & Iwasaki, A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 11, 404–410 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Robinson, K. S. et al. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science 370, eaay2002 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tsu, B. V. et al. Diverse viral proteases activate the NLRP1 inflammasome. eLife 10, e60609 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, Z. et al. Kiwa is a membrane-embedded defense supercomplex activated at phage attachment sites. Cell 188, 5862–5877.e23 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Osterman, I. et al. Bacteria sense virus-induced genome degradation via methylated mononucleotides. Science https://doi.org/10.1126/science.aed6782 (2026).

  • Bieniasz, P. D. Intrinsic immunity: a front-line defense against viral attack. Nat. Immunol. 5, 1109–1115 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gizzi, A. S. et al. A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature 558, 610–614 (2018). This study revealed that human viperin enzymes synthesize a modified nucleotide as a small-molecule inhibitor of viral replication.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hu, H. et al. Structure and mechanism of the Zorya anti-phage defence system. Nature 639, 1093–1101 (2025).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Saxton, D. S., DeWeird, P. C., Doering, C. R., Roney, I. J. & Laub, M. T. A membrane-bound nuclease directly cleaves phage DNA during genome injection. Nature 653, 861–869 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, S. Y. et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38, 92–105 (2013).

    Article 
    PubMed 

    Google Scholar 

  • Brass, A. L. et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139, 1243–1254 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Duncan-Lowey, B., McNamara-Bordewick, N. K., Tal, N., Sorek, R. & Kranzusch, P. J. Effector-mediated membrane disruption controls cell death in CBASS antiphage defense. Mol. Cell 81, 5039–5051.e5 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lowey, B. et al. CBASS immunity uses CARF-related effectors to sense 3’-5’- and 2’-5’-linked cyclic oligonucleotide signals and protect bacteria from phage infection. Cell 182, 38–49.e17 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sabonis, D. et al. TIR domains produce histidine-ADPR as an immune signal in bacteria. Nature 642, 467–473 (2025).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Barreiro, L. B., Marioni, J. C., Blekhman, R., Stephens, M. & Gilad, Y. Functional comparison of innate immune signaling pathways in primates. PLoS Genet. 6, e1001249 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Choe, J., Kelker, M. S. & Wilson, I. A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585 (2005). References 86–90 provided a mechanism that explains how human cells sense foreign nucleic acids to detect and respond to viral infection.

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Diebold, S. S. et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Banh, D. V. et al. Bacterial cGAS senses a viral RNA to initiate immunity. Nature 623, 1001–1008 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Roberts, C. G. et al. Bacterial TIR-based immune systems sense phage capsids to initiate defense. Nat. Microbiol. 10, 2892–2902 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Garb, J. et al. Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion. Nat. Microbiol. 7, 1849–1856 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lee, H. et al. Diverse bacterial pattern recognition receptors sense the core phage proteome. Nature https://doi.org/10.1038/s41586-026-10852-6 (2026).

  • Nagy, T. A., Gersabeck, G. W., Conte, A. N. & Whiteley, A. T. A phage protein screen identifies triggers of the bacterial innate immune system. Nat. Microbiol. 11, 597–609 (2026).

  • den Boon, J. A., Diaz, A. & Ahlquist, P. Cytoplasmic viral replication complexes. Cell Host Microbe 8, 77–85 (2010).

    Article 

    Google Scholar 

  • Baum, A., Sachidanandam, R. & Garcia-Sastre, A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc. Natl Acad. Sci. USA 107, 16303–16308 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Depardieu, F. et al. A eukaryotic-like serine/threonine kinase protects staphylococci against phages. Cell Host Microbe 20, 471–481 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Rousset, F. et al. Phages and their satellites encode hotspots of antiviral systems. Cell Host Microbe 30, 740–753.e5 (2022). References 99, 249, 267 and 268 demonstrated that phage encode clusters of defence systems dedicated to restricting replication of competing phages.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hor, J., Wolf, S. G. & Sorek, R. Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly. Nature 631, 850–856 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Zhang, T. et al. Bacterial immune activation via supramolecular assembly with phage triggers. Nature 651, 1051–1059 (2026).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Langley, C. A., Dietzen, P. A., Emerman, M., Tenthorey, J. L. & Malik, H. S. Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes. Proc. Natl Acad. Sci. USA 122, e2416811122 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yuping, L. et al. Jumbo phage killer immune system targets early infection of nucleus-forming phages. Cell 188, 2127–2140.e21 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, T. et al. A bacterial immunity protein directly senses two disparate phage proteins. Nature 635, 728–735 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Robbins, L. K. et al. A bacterial NLR-related protein senses distinct phage triggers through a single interface. Preprint at bioRxiv https://doi.org/10.1101/2024.12.17.629029 (2026).

  • Amundsen, S. K. & Smith, G. R. RecBCD enzyme: mechanistic insights from mutants of a complex helicase-nuclease. Microbiol. Mol. Biol. Rev. 87, e0004123 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ferguson, B. J., Mansur, D. S., Peters, N. E., Ren, H. & Smith, G. L. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1, e00047 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, X. et al. Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than type I IFN. J. Immunol. 186, 4541–4545 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Daffis, S. et al. 2’-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 468, 452–456 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hornung, V. et al. 5’-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006). References 110 and 111 identified the mechanism of RIG-I activation and established that human cells sense nucleic acid modification status to detect viral infection.

    Article 
    ADS 
    PubMed 

    Google Scholar 

  • Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314, 997–1001 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Gaidt, M. M. et al. Self-guarding of MORC3 enables virulence factor-triggered immunity. Nature 600, 138–142 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pecota, D. C. & Wood, T. K. Exclusion of T4 phage by the hok/sok killer locus from plasmid R1. J. Bacteriol. 178, 2044–2050 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guegler, C. K. & Laub, M. T. Shutoff of host transcription triggers a toxin-antitoxin system to cleave phage RNA and abort infection. Mol. Cell 81, 2361–2373.e9 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bhutta, M. S., Gallo, E. S. & Borenstein, R. Multifaceted role of AMPK in viral infections. Cells 10, 1118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yamaguchi, S. et al. Nucleotide signals coordinate activation and inhibition of bacterial immunity. Nature 652, 978–985 (2026).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Song, X. Y. et al. Bacterial reverse transcriptase synthesizes long poly(A)-rich cDNA for antiphage defense. Science 388, eads4639 (2025).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Cheng, R. et al. A nucleotide-sensing endonuclease from the Gabija bacterial defense system. Nucleic Acids Res. 49, 5216–5229 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xu, Z. et al. The Ppl protein senses 3’-hydroxyl DNA overhangs and NTP depletion to halt phage infection. Mol. Cell 86, 180–193.e186 (2026).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Severin, G. B. et al. Activation of a Vibrio cholerae CBASS anti-phage system by quorum sensing and folate depletion. mBio 14, e0087523 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brenzinger, S. et al. The Vibrio cholerae CBASS phage defence system modulates resistance and killing by antifolate antibiotics. Nat. Microbiol. 9, 251–262 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Juozapaitis, J. et al. Deoxydinucleotides activate the bacterial anti-phage defense system ApeA. Preprint at bioRxiv https://doi.org/10.64898/2026.01.26.701840 (2026).

  • Tuck, O. T. et al. Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex. Cell 187, 6914–6928.e20 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • York, A. G. et al. Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling. Cell 163, 1716–1729 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Landau, L. M. et al. pLxIS-containing domains are biochemically flexible regulators of interferons and metabolism. Mol. Cell 84, 2436–2454.e10 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Macdonald, E. et al. The novel anti-phage system Shield co-opts an RmuC domain to mediate phage defense across Pseudomonas species. PLoS Genet. 19, e1010784 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Stokar-Avihail, A. et al. Discovery of phage determinants that confer sensitivity to bacterial immune systems. Cell 186, 1863–1876.e16 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yu, C. et al. Phage SSB detection by retron Eco8 msDNA unleashes nuclease-mediated immunity. Mol. Cell 85, 4243–4253.e4 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hooper, M. M. et al. Phage-encoded factor stimulates DNA degradation by the Hna anti-phage defense system. Nat. Commun. 18, 6544 (2026).

  • Bari, S. M. N. et al. A unique mode of nucleic acid immunity performed by a multifunctional bacterial enzyme. Cell Host Microbe 30, 570–582.e7 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sasaki, T. et al. Phage single-stranded DNA-binding protein or host DNA damage triggers the activation of the AbpAB phage defense system. mSphere 8, e0037223 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bouchard, J. D. & Moineau, S. Lactococcal phage genes involved in sensitivity to AbiK and their relation to single-strand annealing proteins. J. Bacteriol. 186, 3649–3652 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tan, J. M. J. et al. A DNA-gated molecular guard controls bacterial Hailong anti-phage defence. Nature 643, 794–800 (2025). References 133–135 demonstrated that bacterial immune systems can synthesize inhibitory nucleotide immune signals to negatively regulate immune activation.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sullivan, A. E. et al. The Panoptes system uses decoy cyclic nucleotides to defend against phage. Nature 647, 988–996 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Doherty, E. E. et al. A miniature CRISPR–Cas10 enzyme confers immunity by inhibitory signalling. Nature 647, 997–1004 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hobbs, S. J. & Kranzusch, P. J. Nucleotide immune signaling in CBASS, Pycsar, Thoeris, and CRISPR antiphage defense. Annu. Rev. Microbiol. 78, 255–276 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kagan, J. C., Magupalli, V. G. & Wu, H. SMOCs: supramolecular organizing centres that control innate immunity. Nat. Rev. Immunol. 14, 821–826 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Y. et al. cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell 186, 3261–3276.e20 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tesson, F. et al. Systematic and quantitative view of the antiviral arsenal of prokaryotes. Nat. Commun. 13, 2561 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Payne, L. J. et al. PADLOC: a web server for the identification of antiviral defence systems in microbial genomes. Nucleic Acids Res. 50, W541–W550 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gao, P. et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094–1107 (2013). References 141–144 identified the cGAS product 2′3′-cGAMP as a nucleotide immune signal that controls activation of human immunity.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ablasser, A. et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Diner, E. J. et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 3, 1355–1361 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Slavik, K. M. et al. cGAS-like receptors sense RNA and control 3’2’-cGAMP signalling in Drosophila. Nature 597, 109–113 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holleufer, A. et al. Two cGAS-like receptors induce antiviral immunity in Drosophila. Nature 597, 114–118 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Fatma, S., Chakravarti, A., Zeng, X. & Huang, R. H. Molecular mechanisms of the CdnG–Cap5 antiphage defense system employing 3’,2’-cGAMP as the second messenger. Nat. Commun. 12, 6381 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tal, N. et al. Cyclic CMP and cyclic UMP mediate bacterial immunity against phages. Cell 184, 5728–5739.e5716 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Niewoehner, O. et al. Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers. Nature 548, 543–548 (2017). References 149 and 150 revealed that cyclic oligonucleotides act as nucleotide immune signals that control type III CRISPR immunity.

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Kazlauskiene, M., Kostiuk, G., Venclovas, C., Tamulaitis, G. & Siksnys, V. A cyclic oligonucleotide signaling pathway in type III CRISPR–Cas systems. Science 357, 605–609 (2017).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Zeng, Z. et al. Base-modified nucleotides mediate immune signaling in bacteria. Science 388, eads6055 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Leavitt, A. et al. Viruses inhibit TIR gcADPR signalling to overcome bacterial defence. Nature 611, 326–331 (2022). References 152 and 153 identified cADPR isomers as signals in Thoeris anti-phage defence and defined how TIR enzymes synthesize nucleotide immune signals.

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Manik, M. K. et al. Cyclic ADP ribose isomers: production, chemical structures, and immune signaling. Science 377, eadc8969 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yirmiya, E. et al. Systematic discovery of TIR-based immune signaling systems in bacteria. Preprint at bioRxiv https://doi.org/10.64898/2025.12.03.692087 (2025).

  • Rousset, F. et al. TIR signaling activates caspase-like immunity in bacteria. Science 387, 510–516 (2025).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Huang, S. et al. Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity. Science 377, eabq3297 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jia, A. et al. TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity. Science 377, eabq8180 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Garb, J. et al. The SARM1 TIR domain produces glycocyclic ADPR molecules as minor products. PLoS ONE 19, e0302251 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chi, H. et al. Antiviral type III CRISPR signalling via conjugation of ATP and SAM. Nature 622, 826–833 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yu, D. et al. TIR domains of plant immune receptors are 2’,3’-cAMP/cGMP synthetases mediating cell death. Cell 185, 2370–2386.e18 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ledvina, H. E. et al. An E1–E2 fusion protein primes antiviral immune signalling in bacteria. Nature 616, 319–325 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eaglesham, J. B., Pan, Y., Kupper, T. S. & Kranzusch, P. J. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS–STING signalling. Nature 566, 259–263 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hobbs, S. J. et al. Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity. Nature 605, 522–526 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Athukoralage, J. S., Rouillon, C., Graham, S., Gruschow, S. & White, M. F. Ring nucleases deactivate type III CRISPR ribonucleases by degrading cyclic oligoadenylate. Nature 562, 277–280 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jenson, J. M., Li, T., Du, F., Ea, C. K. & Chen, Z. J. Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence. Nature 616, 326–331 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huiting, E. et al. Bacteriophages inhibit and evade cGAS-like immune function in bacteria. Cell 186, 864–876.e21 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chang, R. B. et al. A widespread family of viral sponge proteins reveals specific inhibition of nucleotide signals in anti-phage defense. Mol. Cell 85, 3151–3165.e6 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cai, H. et al. The virus-induced cyclic dinucleotide 2′3′-c-di-GMP mediates STING-dependent antiviral immunity in Drosophila. Immunity 56, 1991–2005.e9 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cadena, C. & Hur, S. Filament-like assemblies of intracellular nucleic acid sensors: commonalities and differences. Mol. Cell 76, 243–254 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002). This paper reported the discovery of the inflammasome as a multi-component assembly responsible for activation of caspase proteases and induction of immune signalling.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156, 1193–1206 (2014).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lin, S. C., Lo, Y. C. & Wu, H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885–890 (2010). This paper determined the structure of the Myddosome, revealing how human cells use supramolecular complex formation to control activation of antiviral immunity.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461 (2011).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wu, B. et al. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152, 276–289 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Zhang, C. et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature 567, 394–398 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morehouse, B. R. et al. Cryo-EM structure of an active bacterial TIR-STING filament complex. Nature 608, 803–807 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, L. & Zhou, W. Phase separation as a new form of regulation in innate immunity. Mol. Cell 84, 2410–2422 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Du, M. & Chen, Z. J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361, 704–709 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Slavik, K. M. & Kranzusch, P. J. CBASS to cGAS–STING: the origins and mechanisms of nucleotide second messenger immune signaling. Annu. Rev. Virol. 10, 423–453 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Chambers, L. R. et al. A eukaryotic-like ubiquitination system in bacterial antiviral defence. Nature 631, 843–849 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wassarman, D. R. et al. Deazaguanylation is a nucleobase–protein conjugation required for type IV CBASS immunity. Science 389, 1347–1352 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Duncan-Lowey, B. et al. Cryo-EM structure of the RADAR supramolecular anti-phage defense complex. Cell 186, 987–998.e15 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gao, Y. et al. Molecular basis of RADAR anti-phage supramolecular assemblies. Cell 186, 999–1012.e20 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Antine, S. P. et al. Structural basis of Gabija anti-phage defence and viral immune evasion. Nature 625, 360–365 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Li, J. et al. Structures and activation mechanism of the Gabija anti-phage system. Nature 629, 467–473 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Li, Y. et al. PtuA and PtuB assemble into an inflammasome-like oligomer for anti-phage defense. Nat. Struct. Mol. Biol. 31, 413–423 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yuan, L. et al. Molecular mechanism of Eco8-mediated anti-phage defense. Mol. Cell 85, 4229–4242.e4 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, C. et al. Disassembly activates Retron-Septu for antiphage defense. Science 389, eadv3344 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ma, F. et al. Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS. J. Immunol. 194, 1545–1554 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schoggins, J. W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011). This study developed a large-scale screen that defined how individual human interferon-stimulated genes function to inhibit viral infection.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Maltbaek, J. H., Cambier, S., Snyder, J. M. & Stetson, D. B. ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP. Immunity 55, 1799–1812.e4 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Luteijn, R. D. et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 573, 434–438 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lahey, L. J. et al. LRRC8A:C/E heteromeric channels are ubiquitous transporters of cGAMP. Mol. Cell 80, 578–591.e5 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Franklin, B. S. et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15, 727–737 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Baroja-Mazo, A. et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738–748 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hoyland-Kroghsbo, N. M., Maerkedahl, R. B. & Svenningsen, S. L. A quorum-sensing-induced bacteriophage defense mechanism. mBio 4, e00362-12 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xuan, G., Lin, H., Tan, L., Zhao, G. & Wang, J. Quorum sensing promotes phage infection in Pseudomonas aeruginosa PAO1. mBio 13, e0317421 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Paoli, L. et al. Environment and physiology shape antiphage system expression. Preprint at bioRxiv https://doi.org/10.64898/2025.12.14.694197 (2025).

  • Oshiro, R. T. et al. Surviving phage attack dynamically regulates bacterial immunity to defeat counterdefenses. Preprint at bioRxiv https://doi.org/10.1101/2025.11.13.688357 (2025).

  • Bridgeman, A. et al. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349, 1228–1232 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gentili, M. et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349, 1232–1236 (2015).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Parson, K. A. & Snustad, D. P. Host DNA degradation after infection of Escherichia coli with bacteriophage T4: dependence of the alternate pathway of degradation which occurs in the absence of both T4 endonuclease II and nuclear disruption on T4 endonuclease IV. J. Virol. 15, 221–224 (1975).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Taddeo, B. & Roizman, B. The virion host shutoff protein (UL41) of herpes simplex virus 1 is an endoribonuclease with a substrate specificity similar to that of RNase A. J. Virol. 80, 9341–9345 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jagger, B. W. et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337, 199–204 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bonderoff, J. M., Larey, J. L. & Lloyd, R. E. Cleavage of poly(A)-binding protein by poliovirus 3 C proteinase inhibits viral internal ribosome entry site-mediated translation. J. Virol. 82, 9389–9399 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Thoms, M. et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science 369, 1249–1255 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Delgado, T. et al. Induction of the Warburg effect by Kaposi’s sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells. Proc. Natl Acad. Sci. USA 107, 10696–10701 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Diamond, D. L. et al. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics. PLoS Pathog. 6, e1000719 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Studier, F. W. Bacteriophage T7. Science 176, 367–376 (1972).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Etchison, D., Milburn, S. C., Edery, I., Sonenberg, N. & Hershey, J. W. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J. Biol. Chem. 257, 14806–14810 (1982).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Xu, D. et al. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 619, 819–827 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Reyes-Robles, T. et al. Vibrio cholerae outer membrane vesicles inhibit bacteriophage infection. J. Bacteriol. https://doi.org/10.1128/JB.00792-17 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rodero, M. P. et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat. Commun. 8, 2176 (2017).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Crow, Y. J. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi–Goutieres syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Domachowske, J. B., Bonville, C. A., Dyer, K. D. & Rosenberg, H. F. Evolution of antiviral activity in the ribonuclease A gene superfamily: evidence for a specific interaction between eosinophil-derived neurotoxin (EDN/RNase 2) and respiratory syncytial virus. Nucleic Acids Res. 26, 5327–5332 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Espert, L. et al. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses. J. Biol. Chem. 278, 16151–16158 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lau, R. K. et al. Structure and mechanism of a cyclic trinucleotide-activated bacterial endonuclease mediating bacteriophage immunity. Mol. Cell 77, 723–733.e6 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pradhan, B. et al. Loop-extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex. Mol. Cell 85, 107–116.e5 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Haudiquet, M. et al. Structural basis for Lamassu-based antiviral immunity and its evolution from DNA repair machinery. Proc. Natl Acad. Sci. USA 122, e2519643122 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ragucci, A. E. et al. Nuclease–NTPase antiphage defence systems use conserved molecular features to control bacterial immunity. Nat. Microbiol. 11, 1424–1436 (2026).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, R. et al. A bacterial defense system targeting modified cytosine of phage genomic DNA. Nat. Commun. 17, 1920 (2026).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, H., Li, W. X. & Ding, S. W. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319–1321 (2002).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Maillard, P. V. et al. Antiviral RNA interference in mammalian cells. Science 342, 235–238 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Aravin, A. A., Sachidanandam, R., Girard, A., Fejes-Toth, K. & Hannon, G. J. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316, 744–747 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sheehy, A. M., Gaddis, N. C., Choi, J. D. & Malim, M. H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650 (2002).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • LeRoux, M. et al. The DarTG toxin-antitoxin system provides phage defence by ADP-ribosylating viral DNA. Nat. Microbiol. 7, 1028–1040 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hrecka, K. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011). References 232 and 233 identified SAMHD1 as an antiviral protein and demonstrated that human cells can deplete the nucleotide pool to inhibit viral replication.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rousset, F. et al. A conserved family of immune effectors cleaves cellular ATP upon viral infection. Cell 186, 3619–3631.e13 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tal, N. et al. Bacteria deplete deoxynucleotides to defend against bacteriophage infection. Nat. Microbiol. 7, 1200–1209 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hsueh, B. Y. et al. Phage defence by deaminase-mediated depletion of deoxynucleotides in bacteria. Nat. Microbiol. 7, 1210–1220 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Koopal, B. et al. Short prokaryotic Argonaute systems trigger cell death upon detection of invading DNA. Cell 185, 1471–1486.e19 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, L. et al. SARM1 senses dsDNA to promote NAD+ degradation and cell death. Cell 188, 7137–7154.e21 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ou, Y., Wang, S. J., Li, D., Chu, B. & Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl Acad. Sci. USA 113, E6806–E6812 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ernst, L. et al. DNA-intercalating antiphage molecules trigger abortive infection through mutual destruction and synergize with bacterial immunity. Proc. Natl Acad. Sci. USA 123, e2602073123 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shomar, H. et al. A family of lanthipeptides with anti-phage function. Cell Host Microbe https://doi.org/10.1016/j.chom.2026.06.017 (2026).

  • Lynch, M. & Marinov, G. K. The bioenergetic costs of a gene. Proc. Natl Acad. Sci. USA 112, 15690–15695 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vassallo, C. N., Doering, C. R. & Laub, M. T. Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation. Nature 636, 190–197 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meurs, E. et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62, 379–390 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Culviner, P. H. & Laub, M. T. Global analysis of the E. coli toxin MazF reveals widespread cleavage of mRNA and the inhibition of rRNA maturation and ribosome biogenesis. Mol. Cell 70, 868–880.e10 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nikolic, N., Pleska, M., Bergmiller, T. & Guet, C. C. A bacterial toxin-antitoxin system as a native defence element against RNA phages. Biol. Lett. 21, 20250080 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meineke, B. & Shuman, S. Determinants of the cytotoxicity of PrrC anticodon nuclease and its amelioration by tRNA repair. RNA 18, 145–154 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Govande, A. A. et al. OLD amputates the anticodon arm of tRNAs during P2–Lambda interference. Nucleic Acids Res. 53, gkaf874 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sargen, M. R. et al. A prophage-encoded abortive infection protein preserves host and prophage spread. Nature 652, 201–208 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cai, Y. et al. A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems. Sci. Adv. 6, eabb6651 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Songailiene, I. et al. HEPN-MNT toxin-antitoxin system: the HEPN ribonuclease is neutralized by oligoAMPylation. Mol. Cell 80, 955–970.e7 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Dmytrenko, O. et al. RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity. Nature 649, 1312–1321 (2026).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, M. et al. Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature 491, 125–128 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yue, T. et al. SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity. Science 372, eaba4220 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xia, B. et al. MLKL forms cation channels. Cell Res. 26, 517–528 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • VanderWal, A. R. et al. Csx28 is a membrane pore that enhances CRISPR–Cas13b-dependent antiphage defense. Science 380, 410–415 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tak, U. et al. Bacterial 2’,3’-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication. Cell Host Microbe 34, 720–733.e7 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016). This study determined the molecular basis of pyroptosis, demonstrating that gasdermin cleavage releases an N-terminal domain that oligomerizes to form membrane pores and induce human cell death.

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang, J. et al. Cyclic-dinucleotide-induced filamentous assembly of phospholipases governs broad CBASS immunity. Cell 188, 3744–3756.e16 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Severin, G. B. et al. Direct activation of a phospholipase by cyclic GMP-AMP in El Tor Vibrio cholerae. Proc. Natl Acad. Sci. USA 115, E6048–E6055 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kayagaki, N. et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591, 131–136 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Ruan, J., Xia, S., Liu, X., Lieberman, J. & Wu, H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557, 62–67 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xia, S. et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 593, 607–611 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Johnson, A. G. et al. Structure and assembly of a bacterial gasdermin pore. Nature 628, 657–663 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Neil, S. J., Zang, T. & Bieniasz, P. D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430 (2008).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Patel, P. H. et al. Anti-phage defence through inhibition of virion assembly. Nat. Commun. 15, 1644 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Boyd, C. M. & Seed, K. D. A phage satellite manipulates the viral DNA packaging motor to inhibit phage and promote satellite spread. Nucleic Acids Res. 52, 10431–10446 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lopatina, A., Tal, N. & Sorek, R. Abortive infection: bacterial suicide as an antiviral immune strategy. Annu. Rev. Virol. 7, 371–384 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Aframian, N. & Eldar, A. Abortive infection antiphage defense systems: separating mechanism and phenotype. Trends Microbiol. 31, 1003–1012 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Williams, M. C. et al. Restriction endonuclease cleavage of phage DNA enables resuscitation from Cas13-induced bacterial dormancy. Nat. Microbiol. 8, 400–409 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Maguin, P., Varble, A., Modell, J. W. & Marraffini, L. A. Cleavage of viral DNA by restriction endonucleases stimulates the type II CRISPR–Cas immune response. Mol. Cell 82, 907–919.e7 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hynes, A. P., Villion, M. & Moineau, S. Adaptation in bacterial CRISPR–Cas immunity can be driven by defective phages. Nat. Commun. 5, 4399 (2014).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Huiting, E. et al. CBASS limits bacteriophage production while maintaining cell viability in Pseudomonas aeruginosa. Cell Host Microbe https://doi.org/10.1016/j.chom.2026.05.024 (2026).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mordret, E. et al. Protein and genomic language models uncover the unexplored diversity of bacterial immunity. Science 392, eadv8275 (2026). References 275 and 276 developed advanced bioinformatics models that uncovered thousands of uncharacterized proteins that are likely to be involved in bacterial anti-phage defence.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • DeWeirdt, P. C., Mahoney, E. M. & Laub, M. T. DefensePredictor: a machine learning model to discover prokaryotic immune systems. Science 392, eadv7924 (2026).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Santos, C. R. et al. Bacterial and human exonucleases mediate interkingdom antiviral immunity. Preprint at bioRxiv https://doi.org/10.64898/2026.06.30.735675 (2026).

  • Koonin, E. V. & Bernheim, A. The paradox of immune systems conservation between prokaryotes and eukaryotes. Nat. Rev. Microbiol. 24, 233–234 (2026).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gilbert, W. Origin of life: The RNA world. Nature 319, 618–618 (1986).

    Article 
    ADS 

    Google Scholar 

  • Drobysheva, A., Velasco Gomariz, M., Ahmad, S., Reichardt, S. & Hör, J. ApeA cleaves genomic RNA to defend against RNA phage infection. Preprint at bioRxiv https://doi.org/10.64898/2026.03.20.713152 (2026).

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