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Conservation and similarity of bacterial and eukaryotic innate immunity

Nature Reviews Microbiology (2024)Cite this article

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An Author Correction to this article was published on 26 March 2024

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Abstract

Pathogens are ubiquitous and a constant threat to their hosts, which has led to the evolution of sophisticated immune systems in bacteria, archaea and eukaryotes. Bacterial immune systems encode an astoundingly large array of antiviral (antiphage) systems, and recent investigations have identified unexpected similarities between the immune systems of bacteria and animals. In this Review, we discuss advances in our understanding of the bacterial innate immune system and highlight the components, strategies and pathogen restriction mechanisms conserved between bacteria and eukaryotes. We summarize evidence for the hypothesis that components of the human immune system originated in bacteria, where they first evolved to defend against phages. Further, we discuss shared mechanisms that pathogens use to overcome host immune pathways and unexpected similarities between bacterial immune systems and interbacterial antagonism. Understanding the shared evolutionary path of immune components across domains of life and the successful strategies that organisms have arrived at to restrict their pathogens will enable future development of therapeutics that activate the human immune system for the precise treatment of disease.

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Fig. 1: General steps of innate immune signalling pathways.
Fig. 2: Components shared between bacterial, human and plant innate immune pathways.

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References

  1. Vance, R. E., Isberg, R. R. & Portnoy, D. A. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6, 10–21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rosadini, C. V. & Kagan, J. C. Early innate immune responses to bacterial LPS. Curr. Opin. Immunol. 44, 14–19 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. 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  CAS  PubMed  Google Scholar 

  4. Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Kranzusch, P. J. cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Curr. Opin. Struct. Biol. 59, 178–187 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Slavik, K. M. et al. cGAS-like receptors sense RNA and control 3′2′-cGAMP signalling in Drosophila. Nature 597, 109–113 (2021). This study finds that cGLRs have diversified within eukaryotes to sense PAMPs beyond double-stranded DNA, such as double-stranded RNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Kuchta, K., Knizewski, L., Wyrwicz, L. S., Rychlewski, L. & Ginalski, K. Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human. Nucleic Acids Res. 37, 7701–7714 (2009). This in-depth analysis of nucleotidyltransferase fold proteins identifies that humans encode a large range of cGAS-like proteins, many of which are of unknown function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sparrer, K. M. J. & Gack, M. U. Intracellular detection of viral nucleic acids. Curr. Opin. Microbiol. 26, 1–9 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kranzusch, P. J. et al. Structure-guided reprogramming of human cGAS dinucleotide linkage specificity. Cell 158, 1011–1021 (2014). This study recognized that the bacterial enzyme DncV was structurally homologous to the human enzyme cGAS, although the two share no appreciable sequence identity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Whiteley, A. T. et al. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 567, 194–199 (2019). This study demonstrates that bacteria encode a wide array of cGAS-like enzymes termed CD-NTases, which produce diverse cyclic di- and trinucleotide second messengers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Burroughs, A. M., Zhang, D., Schäffer, 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). This study bioinformatically identifies numerous antiphage systems (including CBASS, PYCSAR and Thoeris) using genomic network analysis and sensitive predictions of protein structure and function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Govande, A. A., Duncan-Lowey, B., Eaglesham, J. B., Whiteley, A. T. & Kranzusch, P. J. Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense. Cell Rep. 35, 109206 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. 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). This landmark study, together with ref. 15, establishes that operons encoding cGAS-like enzymes are antiphage systems, activation of which results in abortive infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kranzusch, P. J. et al. Ancient origin of cGAS-STING reveals mechanism of universal 2′,3′ cGAMP signaling. Mol. Cell 59, 891–903 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Margolis, S. R., Wilson, S. C. & Vance, R. E. Evolutionary origins of cGAS-STING signaling. Trends Immunol. 38, 733–743 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Burroughs, A. M. & Aravind, L. Identification of uncharacterized components of prokaryotic immune systems and their diverse eukaryotic reformulations. J. Bacteriol. 202, e00365-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morehouse, B. R. et al. Cryo-EM structure of an active bacterial TIR–STING filament complex. Nature 608, 803–807 (2022). This study demonstrates that bacterial STING has the same filamentation activation mechanism as human STING.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Yum, S., Li, M., Frankel, A. E. & Chen, Z. J. Roles of the cGAS-STING pathway in cancer immunosurveillance and immunotherapy. Annu. Rev. Cancer Biol. 3, 323–344 (2019).

    Article  Google Scholar 

  26. Hogrel, G. et al. Cyclic nucleotide-induced helical structure activates a TIR immune effector. Nature 608, 808–812 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. de Oliveira Mann, C. C. et al. Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation. Cell Rep. 27, 1165–1175.e5 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Margolis, S. R. et al. The cyclic dinucleotide 2′3′-cGAMP induces a broad antibacterial and antiviral response in the sea anemone Nematostella vectensis. Proc. Natl Acad. Sci. USA 118, e2109022118 (2021). This study shows that STING activates innate immune signalling in organisms that do not encode a type I interferon pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guo, H., Callaway, J. B. & Ting, J. P.-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Choi, G. H. et al. Molecular characterization of vegetative incompatibility genes that restrict hypovirus transmission in the chestnut blight fungus Cryphonectria parasitica. Genetics 190, 113–127 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Paoletti, M. & Saupe, S. J. Fungal incompatibility: evolutionary origin in pathogen defense? BioEssays 31, 1201–1210 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Saur, I. M. L., Panstruga, R. & Schulze-Lefert, P. NOD-like receptor-mediated plant immunity: from structure to cell death. Nat. Rev. Immunol. 21, 305–318 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Gao, L. A. et al. Prokaryotic innate immunity through pattern recognition of conserved viral proteins. Science 377, eabm4096 (2022). This exceptional study identifies phage protein structures, not amino acid sequence, which are recognized by bacterial STAND NTPases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kibby, E. M. et al. Bacterial NLR-related proteins protect against phage. Cell 186, 2410–2424.e18 (2023). This study demonstrates that NACHT modules in bacteria are widespread antiphage proteins that defend against DNA and RNA phages; this work also traces the horizontal gene transfer of NACHT modules into eukaryotes, including the predecessor of human NLRs.

    Article  CAS  PubMed  Google Scholar 

  35. Gao, L. et al. Diverse enzymatic activities mediate antiviral immunity in prokaryotes. Science 369, 1077–1084 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rousset, F. et al. Phages and their satellites encode hotspots of antiviral systems. Cell Host Microbe 30, 740–753.e5 (2022). This study determines that phages, including prophages, possess genomic hotspots enriched with antiphage systems and uses this observation to discover new antiphage systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Leipe, D. D., Koonin, E. V. & Aravind, L. STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer. J. Mol. Biol. 343, 1–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Sandall, C. F., Ziehr, B. K. & MacDonald, J. A. ATP-binding and hydrolysis in inflammasome activation. Molecules 25, 4572 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, F. et al. Human SAMD9 is a poxvirus-activatable anticodon nuclease inhibiting codon-specific protein synthesis. Sci. Adv. 9, eadh8502 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Koonin, E. V. & Aravind, L. The NACHT family – a new group of predicted NTPases implicated in apoptosis and MHC transcription activation. Trends Biochem. Sci. 25, 223–224 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Daskalov, A. Emergence of the fungal immune system. iScience 26, 106793 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vance, R. E. The NAIP/NLRC4 inflammasomes. Curr. Opin. Immunol. 32, 84–89 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Bi, G. et al. The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling. Cell 184, 3528–3541.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Cesari, S., Bernoux, M., Moncuquet, P., Kroj, T. & Dodds, P. N. A novel conserved mechanism for plant NLR protein pairs: the ‘integrated decoy’ hypothesis. Front. Plant Sci. 5, 606 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Clavé, C. et al. Fungal gasdermin-like proteins are controlled by proteolytic cleavage. Proc. Natl Acad. Sci. USA 119, e2109418119 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Broz, P., Pelegrín, P. & Shao, F. The gasdermins, a protein family executing cell death and inflammation. Nat. Rev. Immunol. 20, 143–157 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Daskalov, A., Mitchell, P. S., Sandstrom, A., Vance, R. E. & Glass, N. L. Molecular characterization of a fungal gasdermin-like protein. Proc. Natl Acad. Sci. USA 117, 18600–18607 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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  Google Scholar 

  50. Chin, K. C. & Cresswell, P. Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proc. Natl Acad. Sci. USA 98, 15125–15130 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gizzi, A. S. et al. A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature 558, 610–614 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Nimma, S. et al. Structural evolution of TIR-domain signalosomes. Front. Immunol. 12, 784484 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. O’Neill, L. A. J. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).

    Article  PubMed  Google Scholar 

  55. Gerdts, J., Summers, D. W., Sasaki, Y., DiAntonio, A. & Milbrandt, J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J. Neurosci. 33, 13569–13580 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tal, N. et al. Cyclic CMP and cyclic UMP mediate bacterial immunity against phages. Cell 184, 5728–5739.e16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wan, L. et al. TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death. Science 365, 799–803 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ofir, G. et al. Antiviral activity of bacterial TIR domains via immune signalling molecules. Nature 600, 116–120 (2021). This study expands the role of TIR domains in immune signalling by finding that Thoeris TIR domains use NAD+ to generate a variant of cyclic ADP-ribose that acts as a second messenger, activating an effector protein to further deplete the cell of NAD+.

    Article  CAS  PubMed  Google Scholar 

  59. 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 

  60. Ka, D., Oh, H., Park, E., Kim, J.-H. & Bae, E. Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD+ degradation. Nat. Commun. 11, 2816 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Oh, E., Akopian, D. & Rape, M. Principles of ubiquitin-dependent signaling. Annu. Rev. Cell Dev. Biol. 34, 137–162 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Iyer, L. M., Burroughs, A. M. & Aravind, L. The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like beta-grasp domains. Genome Biol. 7, R60 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hu, H. & Sun, S.-C. Ubiquitin signaling in immune responses. Cell Res. 26, 457–483 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jiang, W. et al. Ubiquitin ligase enzymes and de-ubiquitinating enzymes regulate innate immunity in the TLR, NLR, RLR, and cGAS–STING pathways. Immunol. Res. 71, 800–813 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Burroughs, A. M., Iyer, L. M. & Aravind, L. Natural history of the E1-like superfamily: implication for adenylation, sulfur transfer, and ubiquitin conjugation. Proteins 75, 895–910 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Millman, A. et al. An expanded arsenal of immune systems that protect bacteria from phages. Cell Host Microbe 30, 1556–1569.e5 (2022).

    Article  CAS  PubMed  Google Scholar 

  69. Hör, J., Wolf, S. G. & Sorek, R. Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly. Preprint at bioRxiv https://doi.org/10.1101/2023.09.04.556158 (2023).

  70. Chambers, L. R. et al. Bacterial antiviral defense pathways encode eukaryotic-like ubiquitination systems. Preprint at bioRxiv https://doi.org/10.1101/2023.09.26.559546 (2023).

  71. Gu, Y., Desai, A. & Corbett, K. D. Evolutionary dynamics and molecular mechanisms of HORMA domain protein signaling. Annu. Rev. Biochem. 91, 541–569 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Koopal, B., Mutte, S. K. & Swarts, D. C. A long look at short prokaryotic Argonautes. Trends Cell Biol. 33, 605–618 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Wu, J., Yang, J., Cho, W. C. & Zheng, Y. Argonaute proteins: structural features, functions and emerging roles. J. Adv. Res. 24, 317–324 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Janeway, C. A. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16 (1992).

    Article  CAS  PubMed  Google Scholar 

  75. Lightfield, K. L. et al. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat. Immunol. 9, 1171–1178 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tenthorey, J. L. et al. The structural basis of flagellin detection by NAIP5: a strategy to limit pathogen immune evasion. Science 358, 888–893 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, T. et al. Direct activation of a bacterial innate immune system by a viral capsid protein. Nature 612, 132–140 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Garb, J. et al. Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion. Nat. Microbiol. 7, 1849–1856 (2022). This study identifies the phage molecule sensed by an antiphage pathway using the elegant approach of phage mating.

    Article  CAS  PubMed  Google Scholar 

  79. Murray, N. E. Immigration control of DNA in bacteria: self versus non-self. Microbiology 148, 3–20 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Blumenthal, R. M. & Cheng, X. Modern Microbial Genetics (eds Streips, U. N. & Yasbin, R. E.) 177–225 (John Wiley & Sons, 2002).

  81. Schuberth-Wagner, C. et al. A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2′O-methylated self RNA. Immunity 43, 41–51 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Züst, R. et al. Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 12, 137–143 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ramanathan, A., Robb, G. B. & Chan, S.-H. mRNA capping: biological functions and applications. Nucleic Acids Res. 44, 7511–7526 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jurado, A. R., Tan, D., Jiao, X., Kiledjian, M. & Tong, L. Structure and function of pre-mRNA 5′-end capping quality control and 3′-end processing. Biochemistry 53, 1882–1898 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Decroly, E., Ferron, F., Lescar, J. & Canard, B. Conventional and unconventional mechanisms for capping viral mRNA. Nat. Rev. Microbiol. 10, 51–65 (2012).

    Article  CAS  Google Scholar 

  86. Lopes Fischer, N., Naseer, N., Shin, S. & Brodsky, I. E. Effector-triggered immunity and pathogen sensing in metazoans. Nat. Microbiol. 5, 14–26 (2019).

    Article  PubMed  Google Scholar 

  87. Hellmich, K. A. et al. Anthrax lethal factor cleaves mouse Nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS ONE 7, e49741 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chavarría-Smith, J. & Vance, R. E. Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLoS Pathog. 9, e1003452 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Sandstrom, A. et al. Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. Science 364, eaau1330 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Millman, A. et al. Bacterial retrons function in anti-phage defense. Cell 183, 1551–1561.e12 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. 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 

  92. Fontana, M. F. et al. Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLoS Pathog. 7, e1001289 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fineran, P. C. et al. The phage abortive infection system, ToxIN, functions as a protein–RNA toxin–antitoxin pair. Proc. Natl Acad. Sci. USA 106, 894–899 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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 

  95. Sloan, E., Orr, A. & Everett, R. D. MORC3, a component of PML nuclear bodies, has a role in restricting herpes simplex virus 1 and human cytomegalovirus. J. Virol. 90, 8621–8633 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Penner, M., Morad, I., Snyder, L. & Kaufmann, G. Phage T4-coded Stp: double-edged effector of coupled DNA and tRNA-restriction systems. J. Mol. Biol. 249, 857–868 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Hornung, V., Hartmann, R., Ablasser, A. & Hopfner, K.-P. OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. Nat. Rev. Immunol. 14, 521–528 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nelson, J. W. & Breaker, R. R. The lost language of the RNA World. Sci. Signal. 10, eaam8812 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Davies, B. W., Bogard, R. W., Young, T. S. & Mekalanos, J. J. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149, 358–370 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wu, J. et al. Cyclic GMP–AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  103. Niewoehner, O. et al. Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers. Nature 548, 543–548 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Ofir, G. et al. DISARM is a widespread bacterial defence system with broad anti-phage activities. Nat. Microbiol. 3, 90–98 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Bayless, A. M. et al. Plant and prokaryotic TIR domains generate distinct cyclic ADPR NADase products. Sci. Adv. 9, eade8487 (2022).

    Article  Google Scholar 

  106. 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 

  107. Sporny, M. et al. Structural evidence for an octameric ring arrangement of SARM1. J. Mol. Biol. 431, 3591–3605 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Hu, M., Qi, J., Bi, G. & Zhou, J.-M. Bacterial effectors induce oligomerization of immune receptor ZAR1 in vivo. Mol. Plant. 13, 793–801 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Wu, B. & Hur, S. How RIG-I like receptors activate MAVS. Curr. Opin. Virol. 12, 91–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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). This study demonstrated CD-NTases synthesizing cyclic oligonucleotides with 2′–5′ bonds.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bahar, A. & Ren, D. Antimicrobial peptides. Pharmaceuticals 6, 1543–1575 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Merle, N. S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part II: role in immunity. Front. Immunol. 6, 257 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kronheim, S. et al. A chemical defence against phage infection. Nature 564, 283–286 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Kutsch, M. & Coers, J. Human guanylate binding proteins: nanomachines orchestrating host defense. FEBS J. 288, 5826–5849 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Goldfarb, T. et al. BREX is a novel phage resistance system widespread in microbial genomes. EMBO J. 34, 169–183 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Gordeeva, J. et al. BREX system of Escherichia coli distinguishes self from non-self by methylation of a specific DNA site. Nucleic Acids Res. 47, 253–265 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. 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 

  118. Johnson, A. G. & Kranzusch, P. J. What bacterial cell death teaches us about life. PLoS Pathog. 18, e1010879 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Koonin, E. V. & Aravind, L. Origin and evolution of eukaryotic apoptosis: the bacterial connection. Cell Death Differ. 9, 394–404 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Tzipilevich, E., Pollak-Fiyaksel, O., Shraiteh, B. & Ben-Yehuda, S. Bacteria elicit a phage tolerance response subsequent to infection of their neighbors. EMBO J. 41, e109247 (2022).

    Article  CAS  PubMed  Google Scholar 

  122. Koonin, E. V. & Zhang, F. Coupling immunity and programmed cell suicide in prokaryotes: life-or-death choices. Bioessays 39, 1–9 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Hur, S. Double-stranded RNA sensors and modulators in innate immunity. Annu. Rev. Immunol. 37, 349–375 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hsu, J. C.-C., Laurent-Rolle, M. & Cresswell, P. Translational regulation of viral RNA in the type I interferon response. Curr. Res. Virol. Sci. 2, 100012 (2021).

    Article  CAS  Google Scholar 

  125. Chakrabarti, A., Jha, B. K. & Silverman, R. H. New insights into the role of RNase L in innate immunity. J. Interferon Cytokine Res. 31, 49–57 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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 

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

    Article  CAS  PubMed  Google Scholar 

  128. 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 

  129. Bitton, L., Klaiman, D. & Kaufmann, G. Phage T4-induced DNA breaks activate a tRNA repair-defying anticodon nuclease. Mol. Microbiol. 97, 898–910 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Blanga-Kanfi, S., Amitsur, M., Azem, A. & Kaufmann, G. PrrC-anticodon nuclease: functional organization of a prototypical bacterial restriction RNase. Nucleic Acids Res. 34, 3209–3219 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rousset, F. et al. A conserved family of immune effectors cleaves cellular ATP upon viral infection. Cell 186, 3619–3613.e13 (2023).

    Article  CAS  PubMed  Google Scholar 

  132. Vonderstein, K. et al. Viperin targets flavivirus virulence by inducing assembly of noninfectious capsid particles. J. Virol. 92, e01751-17 (2018).

    Article  PubMed  Google Scholar 

  133. Gough, J. Convergent evolution of domain architectures (is rare). Bioinformatics 21, 1464–1471 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Koonin, E. V. Comparative genomics, minimal gene-sets and the last universal common ancestor. Nat. Rev. Microbiol. 1, 127–136 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. 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 

  136. Cury, J. et al. Conservation of antiviral systems across domains of life reveals novel immune mechanisms in humans. Preprint at bioRxiv https://doi.org/10.1101/2022.12.12.520048 (2022).

  137. Huiting, E. & Bondy-Denomy, J. Defining the expanding mechanisms of phage-mediated activation of bacterial immunity. Curr. Opin. Microbiol. 74, 102325 (2023).

    Article  CAS  PubMed  Google Scholar 

  138. Borges, A. L., Davidson, A. R. & Bondy-Denomy, J. The discovery, mechanisms, and evolutionary impact of anti-CRISPRs. Annu. Rev. Virol. 4, 37–59 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Makarova, K. S., Wolf, Y. I., van der Oost, J. & Koonin, E. V. Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements. Biol. Direct 4, 29 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Rocha, E. P. C. & Bikard, D. Microbial defenses against mobile genetic elements and viruses: who defends whom from what? PLoS Biol. 20, e3001514 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Koonin, E. V., Makarova, K. S., Wolf, Y. I. & Krupovic, M. Evolutionary entanglement of mobile genetic elements and host defence systems: guns for hire. Nat. Rev. Genet. 21, 119–131 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Bernheim, A. & Sorek, R. The pan-immune system of bacteria: antiviral defence as a community resource. Nat. Rev. Microbiol. 18, 113–119 (2020). This perspective article introduces the idea that the bacterial immune system is distributed throughout the pangenome and antiphage systems are maintained by individuals in different combinations, which affords a benefit in the arms race against phages.

    Article  CAS  PubMed  Google Scholar 

  143. Dupuis, M.-È., Villion, M., Magadán, A. H. & Moineau, S. CRISPR–Cas and restriction–modification systems are compatible and increase phage resistance. Nat. Commun. 4, 2087 (2013).

    Article  PubMed  Google Scholar 

  144. Kaur, G., Burroughs, A. M., Iyer, L. M. & Aravind, L. Highly regulated, diversifying NTP-dependent biological conflict systems with implications for the emergence of multicellularity. eLife 9, e52696 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kaur, G., Iyer, L. M., Burroughs, A. M. & Aravind, L. Bacterial death and TRADD-N domains help define novel apoptosis and immunity mechanisms shared by prokaryotes and metazoans. eLife 10, e70394 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Aravind, L., Iyer, L. M. & Burroughs, A. M. Discovering biological conflict systems through genome analysis: evolutionary principles and biochemical novelty. Annu. Rev. Biomed. Data Sci. 5, 367–391 (2022).

    Article  CAS  PubMed  Google Scholar 

  147. Hochhauser, D., Millman, A. & Sorek, R. The defense island repertoire of the Escherichia coli pan-genome. PLoS Genet. 19, e1010694 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Koonin, E. V., Makarova, K. S. & Wolf, Y. I. Evolutionary genomics of defense systems in archaea and bacteria. Annu. Rev. Microbiol. 71, 233–261 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 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). This study hypothesized that antiphage genes co-localize into ‘defence islands’ within bacterial genomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Doron, S. et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359, eaar4120 (2018). This seminal study demonstrates that operons of unknown function that cluster with known phage defence genes, within so called ‘defence islands’, confer phage defence, setting the stage for the rapid advances in the field of antiphage system discovery.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Jaskólska, M., Adams, D. W. & Blokesch, M. Two defence systems eliminate plasmids from seventh pandemic Vibrio cholerae. Nature 604, 323–329 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Vassallo, C. N., Doering, C. R., Littlehale, M. L., Teodoro, G. I. C. & Laub, M. T. A functional selection reveals previously undetected anti-phage defence systems in the E. coli pangenome. Nat. Microbiol. 7, 1568–1579 (2022). This study uses metagenomic libraries to identify new phage defence systems, establishing a high-throughput approach and demonstrating that many antiphage systems are not located in defence islands.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. LaRock, C. N. & Cookson, B. T. The Yersinia virulence effector YopM binds caspase-1 to arrest inflammasome assembly and processing. Cell Host Microbe 12, 799–805 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sawyer, S. L., Wu, L. I., Emerman, M. & Malik, H. S. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proc. Natl Acad. Sci. USA 102, 2832–2837 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 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  CAS  PubMed  PubMed Central  Google Scholar 

  156. Zhao, L. et al. Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. Cell Host Microbe 11, 607–616 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cao, X. et al. Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides. Mol. Cell 84, 375–385.e7 (2024).

    Article  CAS  PubMed  Google Scholar 

  159. 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 

  160. Leavitt, A. et al. Viruses inhibit TIR gcADPR signalling to overcome bacterial defence. Nature 611, 326–331 (2022).

    Article  CAS  PubMed  Google Scholar 

  161. Elde, N. C., Child, S. J., Geballe, A. P. & Malik, H. S. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature 457, 485–489 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Kennaway, C. K. et al. The structure of M.EcoKI Type I DNA methyltransferase with a DNA mimic antirestriction protein. Nucleic Acids Res. 37, 762–770 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Velamoor, S. et al. Visualizing nudivirus assembly and egress. mBio 11, e01333-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Mendoza, S. D. et al. A bacteriophage nucleus-like compartment shields DNA from CRISPR nucleases. Nature 577, 244–248 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Malone, L. M. et al. A jumbo phage that forms a nucleus-like structure evades CRISPR–Cas DNA targeting but is vulnerable to type III RNA-based immunity. Nat. Microbiol. 5, 48–55 (2020).

    Article  CAS  PubMed  Google Scholar 

  166. Riley, M. A. & Wertz, J. E. Bacteriocin diversity: ecological and evolutionary perspectives. Biochimie 84, 357–364 (2002).

    Article  CAS  PubMed  Google Scholar 

  167. Hayes, C. S., Koskiniemi, S., Ruhe, Z. C., Poole, S. J. & Low, D. A. Mechanisms and biological roles of contact-dependent growth inhibition systems. Cold Spring Harb. Perspect. Med. 4, a010025 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Hernandez, R. E., Gallegos-Monterrosa, R. & Coulthurst, S. J. Type VI secretion system effector proteins: effective weapons for bacterial competitiveness. Cell. Microbiol. 22, e13241 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Spencer, B. L. & Doran, K. S. Evolving understanding of the type VII secretion system in Gram-positive bacteria. PLoS Pathog. 18, e1010680 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Koskiniemi, S. et al. Rhs proteins from diverse bacteria mediate intercellular competition. Proc. Natl Acad. Sci. USA 110, 7032–7037 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Bullen, N. P. et al. An ADP-ribosyltransferase toxin kills bacterial cells by modifying structured non-coding RNAs. Mol. Cell 82, 3484–3498.e11 (2022).

    Article  CAS  PubMed  Google Scholar 

  172. Ahmad, S. et al. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp. Nature 575, 674–678 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 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). This study showed that the nucleotide second messenger produced by DncV activates an adjacently encoded effector protein; these findings helped to solidify the signalling mechanism for what would later be called CBASS systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tak, U., Walth, P. & Whiteley, A. T. Bacterial cGAS-like enzymes produce 2′,3′-cGAMP to activate an ion channel that restricts phage replication. Preprint at bioRxiv https://doi.org/10.1101/2023.07.24.550367 (2023).

  175. 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 

  176. Ting, S.-Y. et al. Bifunctional immunity proteins protect bacteria against FtsZ-targeting ADP-ribosylating toxins. Cell 175, 1380–1392.e14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank members of the Whiteley laboratory for advice and helpful discussion. Work in the authors’ laboratory was funded by the NIH through the NIH Director’s New Innovator Award DP2AT012346 (A.T.W.), a Mallinckrodt Foundation Grant (A.T.W.), the Boettcher Foundation’s Webb-Waring Biomedical Research Program (A.T.W.) and the PEW Biomedical Scholars Program (A.T.W). H.E.L. is supported as a fellow of the Jane Coffin Childs Memorial Fund for Medical Research (61-1783).

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    Hannah E. Ledvina & Aaron T. Whiteley

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Ledvina, H.E., Whiteley, A.T. Conservation and similarity of bacterial and eukaryotic innate immunity. Nat Rev Microbiol (2024). https://doi.org/10.1038/s41579-024-01017-1

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