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The arms race between bacteria and their phage foes

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Abstract

Bacteria are under immense evolutionary pressure from their viral invaders—bacteriophages. Bacteria have evolved numerous immune mechanisms, both innate and adaptive, to cope with this pressure. The discovery and exploitation of CRISPR–Cas systems have stimulated a resurgence in the identification and characterization of anti-phage mechanisms. Bacteriophages use an extensive battery of counter-defence strategies to co-exist in the presence of these diverse phage defence mechanisms. Understanding the dynamics of the interactions between these microorganisms has implications for phage-based therapies, microbial ecology and evolution, and the development of new biotechnological tools. Here we review the spectrum of anti-phage systems and highlight their evasion by bacteriophages.

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Fig. 1: Anti-phage mechanisms act at different stages of the phage life cycle.
Fig. 2: Preventing phage adsorption.
Fig. 3: RM-like systems.
Fig. 4: CRISPR–Cas adaptive immunity and how phages overcome the CRISPR–Cas adaptive immune system.

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References

  1. Fortier, L.-C. & Sekulovic, O. Importance of prophages to evolution and virulence of bacterial pathogens. Virulence 4, 354–365 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Hurwitz, B. L., Hallam, S. J. & Sullivan, M. B. Metabolic reprogramming by viruses in the sunlit and dark ocean. Genome Biol. 14, R123 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dy, R. L., Richter, C., Salmond, G. P. C. & Fineran, P. C. Remarkable mechanisms in microbes to resist phage infections. Annu. Rev. Virol. 1, 307–331 (2014).

    Article  PubMed  CAS  Google Scholar 

  5. van Houte, S., Buckling, A. & Westra, E. R. Evolutionary ecology of prokaryotic immune mechanisms. Microbiol. Mol. Biol. Rev. 80, 745–763 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Samson, J. E., Magadán, A. H., Sabri, M. & Moineau, S. Revenge of the phages: defeating bacterial defences. Nat. Rev. Microbiol. 11, 675–687 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Gregory, A. C. et al. Marine DNA viral macro- and microdiversity from pole to pole. Cell 177, 1109–1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dedrick, R. M. et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat. Med. 25, 730–733 (2019). The first published study in which a genetically engineered phage cocktail is used to treat a bacterial infection in a human patient.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. O’Sullivan, L., Bolton, D., McAuliffe, O. & Coffey, A. Bacteriophages in food applications: from foe to friend. Annu. Rev. Food Sci. Technol. 10, 151–172 (2019).

    Article  PubMed  CAS  Google Scholar 

  10. Foss, D. V., Hochstrasser, M. L. & Wilson, R. C. Clinical applications of CRISPR-based genome editing and diagnostics. Transfusion 59, 1389–1399 (2019).

    Article  PubMed  Google Scholar 

  11. Ackermann, H. W. Tailed bacteriophages: the order Caudovirales. Adv. Virus Res. 51, 135–201 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Clokie, M. R. J., Millard, A. D., Letarov, A. V. & Heaphy, S. Phages in nature. Bacteriophage 1, 31–45 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Seed, K. D. et al. Evolutionary consequences of intra-patient phage predation on microbial populations. eLife 3, e03497 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Manning, A. J. & Kuehn, M. J. Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol. 11, 258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reyes-Robles, T. et al. Vibrio cholerae outer membrane vesicles inhibit bacteriophage infection. J. Bacteriol. 200, e00792-17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tzipilevich, E., Habusha, M. & Ben-Yehuda, S. Acquisition of phage sensitivity by bacteria through exchange of phage receptors. Cell 168, 186–199 (2017). This study showed that co-culturing of cells allowed for the transfer of phage receptors from sensitive bacteria to resistant bacteria.

    Article  CAS  PubMed  Google Scholar 

  17. Moxon, R., Bayliss, C. & Hood, D. Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. Annu. Rev. Genet. 40, 307–333 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Ohshima, Y., Schumacher-Perdreau, F., Peters, G. & Pulverer, G. The role of capsule as a barrier to bacteriophage adsorption in an encapsulated Staphylococcus simulans strain. Med. Microbiol. Immunol. 177, 229–233 (1988).

    CAS  PubMed  Google Scholar 

  19. Scanlan, P. D. & Buckling, A. Co-evolution with lytic phage selects for the mucoid phenotype of Pseudomonas fluorescens SBW25. ISME J. 6, 1148–1158 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Harvey, H. et al. Pseudomonas aeruginosa defends against phages through type IV pilus glycosylation. Nat. Microbiol. 3, 47–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Bondy-Denomy, J. et al. Prophages mediate defense against phage infection through diverse mechanisms. ISME J. 10, 2854–2866 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Meyer, J. R. et al. Repeatability and contingency in the evolution of a key innovation in phage lambda. Science 335, 428–432 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Petrie, K. L. et al. Destabilizing mutations encode nongenetic variation that drives evolutionary innovation. Science 359, 1542–1545 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Habusha, M., Tzipilevich, E., Fiyaksel, O. & Ben-Yehuda, S. A mutant bacteriophage evolved to infect resistant bacteria gained a broader host range. Mol. Microbiol. 111, 1463–1475 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Schwarzer, D. et al. A multivalent adsorption apparatus explains the broad host range of phage phi92: a comprehensive genomic and structural analysis. J. Virol. 86, 10384–10398 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fernandes, S. & São-José, C. Enzymes and mechanisms employed by tailed bacteriophages to breach the bacterial cell barriers. Viruses 10, 396 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  27. Nobrega, F. L. et al. Targeting mechanisms of tailed bacteriophages. Nat. Rev. Microbiol. 16, 760–773 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Oliveira, P. H., Touchon, M. & Rocha, E. P. C. The interplay of restriction–modification systems with mobile genetic elements and their prokaryotic hosts. Nucleic Acids Res. 42, 10618–10631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Loenen, W. A. M., Dryden, D. T. F., Raleigh, E. A., Wilson, G. G. & Murray, N. E. Highlights of the DNA cutters: a short history of the restriction enzymes. Nucleic Acids Res. 42, 3–19 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Sumby, P. & Smith, M. C. M. Genetics of the phage growth limitation (Pgl) system of Streptomyces coelicolor A3(2). Mol. Microbiol. 44, 489–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Hoskisson, P. A., Sumby, P. & Smith, M. C. M. The phage growth limitation system in Streptomyces coelicolor A(3)2 is a toxin/antitoxin system, comprising enzymes with DNA methyltransferase, protein kinase and ATPase activity. Virology 477, 100–109 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Goldfarb, T. et al. BREX is a novel phage resistance system widespread in microbial genomes. EMBO J. 34, 169–183 (2015). This study describes an RM-like system that prevents infection through a mechanism other than DNA cleavage or degradation.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Ofir, G. et al. DISARM is a widespread bacterial defence system with broad anti-phage activities. Nat. Microbiol. 3, 90–98 (2018). Discovery of a type of widespread RM-like phage-resistance system.

    Article  CAS  PubMed  Google Scholar 

  35. Krüger, D. H. & Bickle, T. A. Bacteriophage survival: multiple mechanisms for avoiding the deoxyribonucleic acid restriction systems of their hosts. Microbiol. Rev. 47, 345–360 (1983).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Vasu, K. & Nagaraja, V. Diverse functions of restriction–modification systems in addition to cellular defense. Microbiol. Mol. Biol. Rev. 77, 53–72 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Korona, R., Korona, B. & Levin, B. R. Sensitivity of naturally occurring coliphages to type I and type II restriction and modification. J. Gen. Microbiol. 139, 1283–1290 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Pleška, M. & Guet, C. C. Effects of mutations in phage restriction sites during escape from restriction–modification. Biol. Lett. 13, 20170646 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kulikov, E. E. et al. Genomic sequencing and biological characteristics of a novel Escherichia coli bacteriophage 9g, a putative representative of a new Siphoviridae genus. Viruses 6, 5077–5092 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Loenen, W. A. M. & Murray, N. E. Modification enhancement by the restriction alleviation protein (Ral) of bacteriophage λ. J. Mol. Biol. 190, 11–22 (1986).

    Article  CAS  PubMed  Google Scholar 

  41. Semerjian, A. V., Malloy, D. C. & Poteete, A. R. Genetic structure of the bacteriophage P22 PL operon. J. Mol. Biol. 207, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Murphy, J., Mahony, J., Ainsworth, S., Nauta, A. & van Sinderen, D. Bacteriophage orphan DNA methyltransferases: insights from their bacterial origin, function, and occurrence. Appl. Environ. Microbiol. 79, 7547–7555 (2013).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  43. Schlagman, S. L. & Hattman, S. Molecular cloning of a functional dam + gene coding for phage T4 DNA adenine methylase. Gene 22, 139–156 (1983).

    Article  CAS  PubMed  Google Scholar 

  44. Günthert, U. & Reiners, L. Bacillus subtilis phage SPR codes for a DNA methyltransferase with triple sequence specificity. Nucleic Acids Res. 15, 3689–3702 (1987).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Iida, S., Streiff, M. B., Bickle, T. A. & Arber, W. Two DNA antirestriction systems of bacteriophage P1, darA, and darB: characterization of darA phages. Virology 157, 156–166 (1987).

    Article  CAS  PubMed  Google Scholar 

  46. Piya, D., Vara, L., Russell, W. K., Young, R. & Gill, J. J. The multicomponent antirestriction system of phage P1 is linked to capsid morphogenesis. Mol. Microbiol. 105, 399–412 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Atanasiu, C., Su, T. J., Sturrock, S. S. & Dryden, D. T. F. Interaction of the ocr gene 0.3 protein of bacteriophage T7 with EcoKI restriction/modification enzyme. Nucleic Acids Res. 30, 3936–3944 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Walkinshaw, M. D. et al. Structure of Ocr from bacteriophage T7, a protein that mimics B-form DNA. Mol. Cell 9, 187–194 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Laity, C., Chater, K. F., Lewis, C. G. & Buttner, M. J. Genetic analysis of the φC31-specific phage growth limitation (Pgl) system of Streptomyces coelicolor A3(2). Mol. Microbiol. 7, 329–336 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Jackson, S. A. et al. CRISPR–Cas: adapting to change. Science 356, eaal5056 (2017).

    Article  PubMed  CAS  Google Scholar 

  52. Hille, F. et al. The biology of CRISPR–Cas: backward and forward. Cell 172, 1239–1259 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Koonin, E. V. & Makarova, K. S. Origins and evolution of CRISPR–Cas systems. Phil. Trans. R. Soc. B 374, 20180087 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Koonin, E. V., Makarova, K. S. & Zhang, F. Diversity, classification and evolution of CRISPR–Cas systems. Curr. Opin. Microbiol. 37, 67–78 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Makarova, K. S., Wolf, Y. I. & Koonin, E. V. Classification and nomenclature of CRISPR–Cas systems: where from here? CRISPR J. 1, 325–336 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Brouns, S. J. J. et al. Small CRISPR RNAs guide antiviral defense in prokaryotes. Science 321, 960–964 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. Semenova, E. et al. Interference by clustered regularly interspaced short palindromic repeat (CRISPR) RNA is governed by a seed sequence. Proc. Natl Acad. Sci. USA 108, 10098–10103 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  58. Datsenko, K. A. et al. Molecular memory of prior infections activates the CRISPR/Cas adaptive bacterial immunity system. Nat. Commun. 3, 945 (2012).

    Article  ADS  PubMed  CAS  Google Scholar 

  59. Strotskaya, A. et al. The action of Escherichia coli CRISPR–Cas system on lytic bacteriophages with different lifestyles and development strategies. Nucleic Acids Res. 45, 1946–1957 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Cady, K. C., Bondy-Denomy, J., Heussler, G. E., Davidson, A. R. & O’Toole, G. A. The CRISPR/Cas adaptive immune system of Pseudomonas aeruginosa mediates resistance to naturally occurring and engineered phages. J. Bacteriol. 194, 5728–5738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Westra, E. R. et al. Parasite exposure drives selective evolution of constitutive versus inducible defense. Curr. Biol. 25, 1043–1049 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Watson, B. N. J., Staals, R. H. J. & Fineran, P. C. CRISPR–Cas-mediated phage resistance enhances horizontal gene transfer by transduction. mBio 9, e02406-17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Taylor, H. N. et al. Structural basis of type IV CRISPR RNA biogenesis by a Cas6 endoribonuclease. RNA Biol. 16, 1438–1447 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Özcan, A. et al. Type IV CRISPR RNA processing and effector complex formation in Aromatoleum aromaticum. Nat. Microbiol. 4, 89–96 (2019).

    Article  PubMed  CAS  Google Scholar 

  65. Deng, L., Garrett, R. A., Shah, S. A., Peng, X. & She, Q. A novel interference mechanism by a type IIIB CRISPR–Cmr module in Sulfolobus. Mol. Microbiol. 87, 1088–1099 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Samai, P. et al. Co-transcriptional DNA and RNA cleavage during type III CRISPR–Cas immunity. Cell 161, 1164–1174 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jiang, W., Samai, P. & Marraffini, L. A. Degradation of phage transcripts by CRISPR-associated RNases enables type III CRISPR–Cas immunity. Cell 164, 710–721 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pyenson, N. C., Gayvert, K., Varble, A., Elemento, O. & Marraffini, L. A. Broad targeting specificity during bacterial type III CRISPR–Cas immunity constrains viral escape. Cell Host Microbe 22, 343–353 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Millen, A. M., Horvath, P., Boyaval, P. & Romero, D. A. Mobile CRISPR/Cas-mediated bacteriophage resistance in Lactococcus lactis. PLoS ONE 7, e51663 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tamulaitis, G. et al. Programmable RNA shredding by the type III-A CRISPR–Cas system of Streptococcus thermophilus. Mol. Cell 56, 506–517 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Goldberg, G. W., Jiang, W., Bikard, D. & Marraffini, L. A. Conditional tolerance of temperate phages via transcription-dependent CRISPR–Cas targeting. Nature 514, 633–637 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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  ADS  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Rostøl, J. T. & Marraffini, L. A. Non-specific degradation of transcripts promotes plasmid clearance during type III-A CRISPR–Cas immunity. Nat. Microbiol. 4, 656–662 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Varble, A. & Marraffini, L. A. Three new Cs for CRISPR: collateral, communicate, cooperate. Trends Genet. 35, 446–456 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McGinn, J. & Marraffini, L. A. CRISPR–Cas systems optimize their immune response by specifying the site of spacer integration. Mol. Cell 64, 616–623 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zetsche, B. et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR–Cas system. Cell 163, 759–771 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vlot, M. et al. Bacteriophage DNA glucosylation impairs target DNA binding by type I and II but not by type V CRISPR–Cas effector complexes. Nucleic Acids Res. 46, 873–885 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Abudayyeh, O. O. et al. C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353, aaf5573 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Meeske, A. J., Nakandakari-Higa, S. & Marraffini, L. A. Cas13-induced cellular dormancy prevents the rise of CRISPR-resistant bacteriophage. Nature 570, 241–245 (2019). This study demonstrates that a CRISPR–Cas variant can provide broad phage protection by inducing bacterial dormancy.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Watson, B. N. J. et al. Different genetic and morphological outcomes for phages targeted by single or multiple CRISPR–Cas spacers. Phil. Trans. R. Soc. B 374, 20180090 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Deveau, H. et al. Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J. Bacteriol. 190, 1390–1400 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Sun, C. L. et al. Phage mutations in response to CRISPR diversification in a bacterial population. Environ. Microbiol. 15, 463–470 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Martel, B. & Moineau, S. CRISPR–Cas: an efficient tool for genome engineering of virulent bacteriophages. Nucleic Acids Res. 42, 9504–9513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Paez-Espino, D. et al. CRISPR immunity drives rapid phage genome evolution in Streptococcus thermophilus. mBio 6, e00262-15 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Nicholson, T. J. et al. Bioinformatic evidence of widespread priming in type I and II CRISPR–Cas systems. RNA Biol. 16, 566–576 (2019).

    Article  PubMed  Google Scholar 

  87. Nussenzweig, P. M., McGinn, J. & Marraffini, L. A. Cas9 cleavage of viral genomes primes the acquisition of new immunological memories. Cell Host Microbe 26, 515–526 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bondy-Denomy, J., Pawluk, A., Maxwell, K. L. & Davidson, A. R. Bacteriophage genes that inactivate the CRISPR/Cas bacterial immune system. Nature 493, 429–432 (2013). The discovery and characterization of anti-CRISPRs.

    Article  ADS  CAS  PubMed  Google Scholar 

  89. Hwang, S. & Maxwell, K. L. Meet the anti-CRISPRs: widespread protein inhibitors of CRISPR–Cas systems. CRISPR J. 2, 23–30 (2019).

    Article  ADS  PubMed  Google Scholar 

  90. Trasanidou, D. et al. Keeping CRISPR in check: diverse mechanisms of phage-encoded anti-CRISPRS. FEMS Microbiol. Lett. 366, fnz098 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Bhoobalan-Chitty, Y., Baek Johansen, T., Di Cianni, N. & Peng, X. Inhibition of type III CRISPR–Cas immunity by an archaeal virus-encoded anti-CRISPR protein. Cell 179, 448–458 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Dong, L. et al. An anti-CRISPR protein disables type V Cas12a by acetylation. Nat. Struct. Mol. Biol. 26, 308–314 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Knott, G. J. et al. Broad-spectrum enzymatic inhibition of CRISPR–Cas12a. Nat. Struct. Mol. Biol. 26, 315–321 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Landsberger, M. et al. Anti-CRISPR phages cooperate to overcome CRISPR–Cas immunity. Cell 174, 908–916 (2018). This study demonstrates that phages cooperate through their anti-CRISPRs to immunosuppress the host CRISPR–Cas system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Borges, A. L. et al. Bacteriophage cooperation suppresses CRISPR–Cas3 and Cas9 immunity. Cell 174, 917–925 (2018). This work describes how phages cooperate through their anti-CRISPRs to inhibit bacterial adaptive immunity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Seed, K. D., Lazinski, D. W., Calderwood, S. B. & Camilli, A. A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity. Nature 494, 489–491 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hargreaves, K. R., Flores, C. O., Lawley, T. D. & Clokie, M. R. J. Abundant and diverse clustered regularly interspaced short palindromic repeat spacers in Clostridium difficile strains and prophages target multiple phage types within this pathogen. mBio 5, e01045-13 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Montgomery, M. T., Guerrero Bustamante, C. A., Dedrick, R. M., Jacobs-Sera, D. & Hatfull, G. F. Yet more evidence of collusion: a new viral defense system encoded by Gordonia phage CarolAnn. mBio 10, e02417-18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Page, R. & Peti, W. Toxin–antitoxin systems in bacterial growth arrest and persistence. Nat. Chem. Biol. 12, 208–214 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. 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  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  101. Al-Shayeb, B. et al. Clades of huge phage from across Earth’s ecosystems. Preprint at bioRxiv https://doi.org/10.1101/572362 (2019).

  102. Faure, G. et al. CRISPR–Cas in mobile genetic elements: counter-defence and beyond. Nat. Rev. Microbiol. 17, 513–525 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Chopin, M.-C., Chopin, A. & Bidnenko, E. Phage abortive infection in lactococci: variations on a theme. Curr. Opin. Microbiol. 8, 473–479 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Labrie, S. J., Samson, J. E. & Moineau, S. Bacteriophage resistance mechanisms. Nat. Rev. Microbiol. 8, 317–327 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Depardieu, F. et al. A eukaryotic-like serine/threonine kinase protects Staphylococci against phages. Cell Host Microbe 20, 471–481 (2016). This study describes the discovery of an Abi system with similarities to eukaryotic defences.

    Article  CAS  PubMed  Google Scholar 

  106. Parma, D. H. et al. The Rex system of bacteriophage lambda: tolerance and altruistic cell death. Genes Dev. 6, 497–510 (1992).

    Article  CAS  PubMed  Google Scholar 

  107. Gentile, G. M. et al. More evidence of collusion: a new prophage-mediated viral defense system encoded by mycobacteriophage Sbash. mBio 10, e00196-19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Samson, J. E., Spinelli, S., Cambillau, C. & Moineau, S. Structure and activity of AbiQ, a lactococcal endoribonuclease belonging to the type III toxin–antitoxin system. Mol. Microbiol. 87, 756–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Dy, R. L., Przybilski, R., Semeijn, K., Salmond, G. P. C. & Fineran, P. C. A widespread bacteriophage abortive infection system functions through a type IV toxin–antitoxin mechanism. Nucleic Acids Res. 42, 4590–4605 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Koga, M., Otsuka, Y., Lemire, S. & Yonesaki, T. Escherichia coli rnlA and rnlB compose a novel toxin–antitoxin system. Genetics 187, 123–130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hazan, R. & Engelberg-Kulka, H. Escherichia coli mazEF-mediated cell death as a defense mechanism that inhibits the spread of phage P1. Mol. Genet. Genomics 272, 227–234 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Snyder, L. Phage-exclusion enzymes: a bonanza of biochemical and cell biology reagents? Mol. Microbiol. 15, 415–420 (1995).

    Article  CAS  PubMed  Google Scholar 

  114. Otsuka, Y. & Yonesaki, T. Dmd of bacteriophage T4 functions as an antitoxin against Escherichia coli LsoA and RnlA toxins. Mol. Microbiol. 83, 669–681 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Labrie, S. J. & Moineau, S. Abortive infection mechanisms and prophage sequences significantly influence the genetic makeup of emerging lytic lactococcal phages. J. Bacteriol. 189, 1482–1487 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Blower, T. R., Evans, T. J., Przybilski, R., Fineran, P. C. & Salmond, G. P. C. Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. PLoS Genet. 8, e1003023 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sberro, H. et al. Discovery of functional toxin/antitoxin systems in bacteria by shotgun cloning. Mol. Cell 50, 136–148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Alawneh, A. M., Qi, D., Yonesaki, T. & Otsuka, Y. An ADP-ribosyltransferase Alt of bacteriophage T4 negatively regulates the Escherichia coli|MazF toxin of a toxin–antitoxin module. Mol. Microbiol. 99, 188–198 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Lossouarn, J. et al. Enterococcus faecalis Countermeasures defeat a virulent Picovirinae bacteriophage. Viruses 11, 48 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  120. Blower, T. R. et al. Evolution of Pectobacterium bacteriophage ΦM1 to escape two bifunctional type III toxin–antitoxin and abortive infection systems through mutations in a single viral gene. Appl. Environ. Microbiol. 83, e03229-16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chen, B., Akusobi, C., Fang, X. & Salmond, G. P. C. Environmental T4-family bacteriophages evolve to escape abortive infection via multiple routes in a bacterial host employing ‘altruistic suicide’ through type III toxin–antitoxin systems. Front. Microbiol. 8, 127 (2018).

    Article  CAS  Google Scholar 

  122. Cumby, N., Davidson, A. R. & Maxwell, K. L. The moron comes of age. Bacteriophage 2, e23146 (2012).

    Article  Google Scholar 

  123. Dedrick, R. M. et al. Prophage-mediated defence against viral attack and viral counter-defence. Nat. Microbiol. 2, 16251 (2017). Demonstration that mycobacterial prophages encode diverse anti-phage defence systems and the ways that phages can evade these defences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ko, C.-C. & Hatfull, G. F. Mycobacteriophage Fruitloop gp52 inactivates Wag31 (DivIVA) to prevent heterotypic superinfection. Mol. Microbiol. 108, 443–460 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Roux, S. et al. Cryptic inoviruses revealed as pervasive in bacteria and archaea across Earth’s biomes. Nat. Microbiol. 4, 1895–1906 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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 

  127. Doron, S. et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359, eaar4120–13 (2018). This study describes the identification of numerous new anti-phage systems in defence islands.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Willkomm, S., Makarova, K. S. & Grohmann, D. DNA silencing by prokaryotic Argonaute proteins adds a new layer of defense against invading nucleic acids. FEMS Microbiol. Rev. 42, 376–387 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hegge, J. W., Swarts, D. C. & van der Oost, J. Prokaryotic Argonaute proteins: novel genome-editing tools? Nat. Rev. Microbiol. 16, 5–11 (2018).

    Article  CAS  PubMed  Google Scholar 

  130. 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 

  131. Swarts, D. C. et al. Autonomous generation and loading of DNA guides by bacterial Argonaute. Mol. Cell 65, 985–998 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Olovnikov, I., Chan, K., Sachidanandam, R., Newman, D. K. & Aravin, A. A. Bacterial Argonaute samples the transcriptome to identify foreign DNA. Mol. Cell 51, 594–605 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. Zander, A. et al. Guide-independent DNA cleavage by archaeal Argonaute from Methanocaldococcus jannaschii. Nat. Microbiol. 2, 17034 (2017).

    Article  CAS  PubMed  Google Scholar 

  134. Cohen, D. et al. Cyclic GMP–AMP signalling protects bacteria against viral infection. Nature 574, 691–695 (2019). This study showed that a eukaryotic anti-viral signalling pathway is also present in prokaryotes, and that this pathway offers protection from a range of phages.

    Article  ADS  CAS  PubMed  Google Scholar 

  135. Ye, Q. et al. HORMA domain proteins and a Pch2-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity. Preprint at bioRxiv https://doi.org/10.1101/694695 (2019).

  136. Lau, R. K. et al. Structure and mechanism of a cyclic trinucleotide-activated bacterial endonuclease mediating bacteriophage immunity. Preprint at bioRxiv https://doi.org/10.1101/694703 (2019).

  137. Kronheim, S. et al. A chemical defence against phage infection. Nature 564, 283–286 (2018). The first example of chemical defences against phages.

    Article  ADS  CAS  PubMed  Google Scholar 

  138. Chaikeeratisak, V. et al. Assembly of a nucleus-like structure during viral replication in bacteria. Science 355, 194–197 (2017). This study describes how jumbophages can produce nucleus-like protein shells inside a bacterium for phage replication.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mendoza, S. D. et al. A bacteriophage nucleus-like compartment shields DNA from CRISPR nucleases. Nature https://doi.org/10.1038/s41586-019-1786-y (2019).

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  140. 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. https://doi.org/10.1038/s41564-019-0612-5 (2019).

    Article  PubMed  CAS  Google Scholar 

  141. Høyland-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  CAS  Google Scholar 

  142. Høyland-Kroghsbo, N. M. et al. Quorum sensing controls the Pseudomonas aeruginosa CRISPR–Cas adaptive immune system. Proc. Natl Acad. Sci. USA 114, 131–135 (2017).

    Article  PubMed  CAS  Google Scholar 

  143. Patterson, A. G. et al. Quorum sensing controls adaptive immunity through the regulation of multiple CRISPR–Cas systems. Mol. Cell 64, 1102–1108 (2016). Demonstration that bacteria use quorum-sensing communication to coordinate multiple CRISPR–Cas systems at a population level

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Erez, Z. et al. Communication between viruses guides lysis–lysogeny decisions. Nature 541, 488–493 (2017). This study reveals that phages use communication to guide the replication strategy used by progeny phages.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  145. Stokar-Avihail, A., Tal, N., Erez, Z., Lopatina, A. & Sorek, R. Widespread utilization of peptide communication in phages infecting soil and pathogenic bacteria. Cell Host Microbe 25, 746–755 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dou, C. et al. Structural and functional insights into the regulation of the lysis–lysogeny decision in viral communities. Nat. Microbiol. 3, 1285–1294 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Gallego del Sol, F., Penadés, J. R. & Marina, A. Deciphering the molecular mechanism underpinning phage arbitrium communication systems. Mol. Cell 74, 59–72 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Guan, Z. et al. Structural insights into DNA recognition by AimR of the arbitrium communication system in the SPbeta phage. Cell Discov. 5, 29 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Silpe, J. E. & Bassler, B. L. Phage-encoded LuxR-type receptors responsive to host-produced bacterial quorum-sensing autoinducers. mBio 10, e00638-19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Silpe, J. E. & Bassler, B. L. A Host-Produced Quorum-Sensing Autoinducer Controls a Phage Lysis-Lysogeny Decision. Cell 176, 268–280 (2019).

    Article  CAS  PubMed  Google Scholar 

  151. Hargreaves, K. R., Kropinski, A. M. & Clokie, M. R. J. What does the talking?: quorum sensing signalling genes discovered in a bacteriophage genome. PLoS ONE 9, e85131 (2014).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  152. Uribe, R. V. et al. Discovery and characterization of Cas9 inhibitors disseminated across seven bacterial phyla. Cell Host Microbe 25, 233–241 (2019).

    Article  CAS  PubMed  Google Scholar 

  153. 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 

  154. Dupuis, M.-È. V., 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  ADS  PubMed  CAS  Google Scholar 

  155. Silas, S. et al. Type III CRISPR–Cas systems can provide redundancy to counteract viral escape from type I systems. eLife 6, e27601 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Van den Bossche, A. et al. Systematic identification of hypothetical bacteriophage proteins targeting key protein complexes of Pseudomonas aeruginosa. J. Proteome Res. 13, 4446–4456 (2014).

    Article  PubMed  CAS  Google Scholar 

  157. Buckling, A. & Brockhurst, M. in Evolutionary Systems Biology Vol. 751 (ed. Soyer O.) 347–370 (Springer, 2012).

  158. Koskella, B. & Brockhurst, M. A. Bacteria–phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiol. Rev. 38, 916–931 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Scanlan, P. D. Bacteria–bacteriophage coevolution in the human gut: implications for microbial diversity and functionality. Trends Microbiol. 25, 614–623 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Horne, M. T. Coevolution of Escherichia coli and bacteriophages in chemostat culture. Science 168, 992–993 (1970).

    Article  ADS  CAS  PubMed  Google Scholar 

  161. Lenski, R. E. & Levin, B. R. Constraints on the coevolution of bacteria and virulent phage: a model, some experiments, and predictions for natural communities. Am. Nat. 125, 585–602 (1985).

    Article  Google Scholar 

  162. Buckling, A. & Rainey, P. B. Antagonistic coevolution between a bacterium and a bacteriophage. Proc. R. Soc. Lond. B 269, 931–936 (2002).

    Article  Google Scholar 

  163. Buckling, A. & Rainey, P. B. The role of parasites in sympatric and allopatric host diversification. Nature 420, 496–499 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  164. Brockhurst, M. A., Morgan, A. D., Fenton, A. & Buckling, A. Experimental coevolution with bacteria and phage: the Pseudomonas fluorescens—Φ2 model system. Infect. Genet. Evol. 7, 547–552 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Gómez, P. & Buckling, A. Bacteria–phage antagonistic coevolution in soil. Science 332, 106–109 (2011).

    Article  ADS  PubMed  CAS  Google Scholar 

  166. Andersson, A. F. & Banfield, J. F. Virus population dynamics and acquired virus resistance in natural microbial communities. Science 320, 1047–1050 (2008).

    Article  ADS  CAS  PubMed  Google Scholar 

  167. Stern, A., Mick, E., Tirosh, I., Sagy, O. & Sorek, R. CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome. Genome Res. 22, 1985–1994 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Emerson, J. B. et al. Virus–host and CRISPR dynamics in Archaea-dominated hypersaline Lake Tyrrell, Victoria, Australia. Archaea 2013, 370871 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Laanto, E., Hoikkala, V., Ravantti, J. & Sundberg, L. R. Long-term genomic coevolution of host–parasite interaction in the natural environment. Nat. Commun. 8, 111 (2017).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  170. Shmakov, S. et al. Discovery and Functional characterization of diverse class 2 CRISPR–Cas systems. Mol. Cell 60, 385–397 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Burstein, D. et al. New CRISPR–Cas systems from uncultivated microbes. Nature 542, 237–241 (2017).

    Article  ADS  CAS  PubMed  Google Scholar 

  172. Weissman, J. L. et al. Immune loss as a driver of coexistence during host–phage coevolution. ISME J. 12, 585–597 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Jackson, S. A., Birkholz, N., Malone, L. M. & Fineran, P. C. Imprecise spacer acquisition generates CRISPR–Cas immune diversity through primed adaptation. Cell Host Microbe 25, 250–260 (2019).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Research in the Fineran laboratory on phage defence systems is supported by the Marsden Fund, Royal Society of New Zealand, the Bio-Protection Centre of Research Excellence and the University of Otago. We thank N. Birkholz for providing input on the figures and members of the Fineran laboratory for discussions and comments on the manuscript.

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H.G.H., B.N.J.W. and P.C.F. contributed equally to all aspects of the manuscript.

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Hampton, H.G., Watson, B.N.J. & Fineran, P.C. The arms race between bacteria and their phage foes. Nature 577, 327–336 (2020). https://doi.org/10.1038/s41586-019-1894-8

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