Temperate bacteriophages integrate in bacterial genomes as prophages and represent an important source of genetic variation for bacterial evolution, frequently transmitting fitness-augmenting genes such as toxins responsible for virulence of major pathogens. However, only a fraction of bacteriophage infections are lysogenic and lead to prophage acquisition, whereas the majority are lytic and kill the infected bacteria. Unless able to discriminate lytic from lysogenic infections, mechanisms of immunity to bacteriophages are expected to act as a double-edged sword and increase the odds of survival at the cost of depriving bacteria of potentially beneficial prophages. We show that although restriction–modification systems as mechanisms of innate immunity prevent both lytic and lysogenic infections indiscriminately in individual bacteria, they increase the number of prophage-acquiring individuals at the population level. We find that this counterintuitive result is a consequence of phage–host population dynamics, in which restriction–modification systems delay infection onset until bacteria reach densities at which the probability of lysogeny increases. These results underscore the importance of population-level dynamics as a key factor modulating costs and benefits of immunity to temperate bacteriophages.
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Wilson, G. G. & Murray, N. E. Restriction and modification systems. Annu. Rev. Genet. 25, 585–627 (1991).
Vasu, K. & Nagaraja, V. Diverse functions of restriction–modification systems in addition to cellular defense. Microbiol. Mol. Biol. Rev. 77, 53–72 (2013).
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).
Murray, N. E. Immigration control of DNA in bacteria: self versus non-self. Microbiology 148, 3–20 (2002).
Abedon, S. T. Bacterial ‘immunity’ against bacteriophages. Bacteriophage 2, 50–54 (2012).
Tock, M. R. & Dryden, D. T. F. The biology of restriction and anti-restriction. Curr. Opin. Microbiol.. 8, 466–472 (2005).
Lwoff, A. Lysogeny. Bacteriol. Rev. 17, 269–337 (1953).
Bobay, L.-M., Rocha, E. P. C. & Touchon, M. The adaptation of temperate bacteriophages to their host genomes. Mol. Biol. Evol. 30, 737–751 (2013).
Casjens, S. Prophages and bacterial genomics: what have we learned so far? Mol. Microbiol. 49, 277–300 (2003).
Lin, L., Bitner, R. & Edlin, G. Increased reproductive fitness of Escherichia coli lambda lysogens. J. Virol. 21, 554–559 (1977).
Edlin, G., Lin, L. & Bitner, R. Reproductive fitness of P1, P2, and Mu lysogens of Escherichia coli. J. Virol. 21, 560–564 (1977).
Oliver, K., Degnan, P., Hunter, M. & Moran, N. Bacteriophages encode factors required for protection in a symbiotic mutualism. Science 325, 992–994 (2009).
Obeng, N., Pratama, A. A. & Elsas, J. D. The significance of mutualistic phages for bacterial ecology and evolution. Trends Microbiol. 24, 440–449 (2016).
O’Brien, A. D. et al. Shiga-like toxin-converting phages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea. Science 226, 694–696 (1984).
Barondess, J. J. & Beckwith, J. A bacterial virulence determinant encoded by lysogenic coliphage λ. Nature 346, 871–874 (1990).
Waldor, M. & Mekalanos, J. Lysogenic conversion by a filamentous phage encoding cholera toxin. Science 272, 1910–1914 (1996).
Brüssow, H., Canchaya, C., Hardt, W. & Bru, H. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol. Mol. Biol. Rev. 68, 560–602 (2004).
Wang, X. et al. Cryptic prophages help bacteria cope with adverse environments. Nat. Commun. 1, 147 (2010).
Rice, S. A. et al. The biofilm life cycle and virulence of Pseudomonas aeruginosa are dependent on a filamentous prophage. ISME J. 3, 271–282 (2009).
Bondy-Denomy, J. et al. Prophages mediate defense against phage infection through diverse mechanisms. ISME J. 22, 1–13 (2016).
Brown, S. P., Le Chat, L., De Paepe, M. & Taddei, F. Ecology of microbial invasions: amplification allows virus carriers to invade more rapidly when rare. Curr. Biol. 16, 2048–2052 (2006).
Davies, E. V. et al. Temperate phages both mediate and drive adaptive evolution in pathogen biofilms. Proc. Natl. Acad. Sci. USA 113, 8266–8271 (2016).
Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709–1712 (2007).
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).
Edgar, R. & Qimron, U. The Escherichia coli CRISPR system protects from λ lysogenization, lysogens, and prophage induction. J. Bacteriol. 192, 6291–6294 (2010).
Roberts, R. A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes. Nucleic Acids Res. 31, 1805–1812 (2003).
Pleška, M. et al. Bacterial autoimmunity due to a restriction–modification system. Curr. Biol. 26, 404–409 (2016).
St-Pierre, F. & Endy, D. Determination of cell fate selection during phage lambda infection. Proc. Natl. Acad. Sci. USA 105, 20705–20710 (2008).
Hong, J.-S., Smith, G. R. & Ames, B. N. Adenosine 3′:5′-cyclic monophosphate concentration in the bacterial host regulates the viral decision between lysogeny and lysis. Proc. Natl. Acad. Sci. USA 68, 2258–2262 (1971).
Deveau, H. et al. Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J. Bacteriol. 190, 1390–1400 (2008).
Houte, Svan et al. The diversity-generating benefits of a prokaryotic adaptive immune system. Nature 532, 385–388 (2016).
Touchon, M., Bernheim, A. & Rocha, E. P. Genetic and life-history traits associated with the distribution of prophages in bacteria. ISME J. 10, 1–11 (2016).
Clokie, M. R., Millard, A. D., Letarov, A. V. & Heaphy, S. Phages in nature. Bacteriophage 1, 31–45 (2011).
Canchaya, C., Fournous, G., Chibani-Chennoufi, S., Dillmann, M. L. & Brüssow, H. Phage as agents of lateral gene transfer. Curr. Opin. Microbiol. 6, 417–424 (2003).
Ochman, H., Lawrence, J. G. & Groisman, E. A. Lateral gene transfer and the nature of bacterial innovation. Nature 405, 299–304 (2000).
Lieb, M. The establishment of lysogenicity in Escherichia coli. J. Bacteriol. 65, 642–651 (1953).
Kourilsky, P. Lysogenization by bacteriophage lambda. MGG Mol. Gen. Genet.. 122, 183–195 (1973).
Zeng, L. et al. Decision making at a subcellular level determines the outcome of bacteriophage infection. Cell 141, 682–691 (2010).
Akerlund, T., Nordström, K. & Bernander, R. Analysis of cell size and DNA content in exponentially growing and stationary-phase batch cultures of Escherichia coli. J. Bacteriol. 177, 6791–6797 (1995).
Knowles, B. et al. Lytic to temperate switching of viral communities. Nature 531, 466–470 (2016).
Knowles, B. et al. Variability and host density independence in inductions-based estimates of environmental lysogeny. Nat. Microbiol.. 2, 17064 (2017).
Erez, Z. et al. Communication between viruses guides lysis–lysogeny decisions. Nature 541, 488–493 (2017).
Gandon, S. Why be temperate: lessons from bacteriophage λ. Trends Microbiol.. 24, 356–365 (2016).
Oliveira, P. H., Touchon, M. & Rocha, E. P. C. Regulation of genetic flux between bacteria by restriction–modification systems. Proc. Natl. Acad. Sci. USA 113, 5658–5663 (2016).
Naito, T., Kusano, K. & Kobayashi, I. Selfish behavior of restriction–modification systems. Science 267, 897–899 (1995).
Rocha, E. P. C., Danchin, A. & Viari, A. Evolutionary role of restriction–modification systems as revealed by comparative genome analysis. Genome Res. 11, 946–958 (2001).
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).
Korona, R. & Levin, B. Phage-mediated selection and the evolution and maintenance of restriction–modification. Evolution 47, 556–575 (1993).
Levin, B. R., Moineau, S., Bushman, M. & Barrangou, R. The population and evolutionary dynamics of phage and bacteria with CRISPR-mediated immunity. PLoS. Genet. 9, e1003312 (2013).
Westra, E. R. et al. Parasite exposure drives selective evolution of constitutive versus inducible defense. Curr. Biol. 25, 1043–1049 (2015).
Stewart, F. M. & Levin, B. R. The population biology of bacterial viruses: why be temperate. Theor. Popul. Biol. 26, 93–117 (1984).
Ripp, S. & Miller, R. V. The role of pseudolysogeny in bacteriophage–host interactions in a natural freshwater environment. Microbiology 143, 2065–2070 (1997).
Takahashi, N., Naito, Y., Handa, N. & Kobayashi, I. A DNA methyltransferase can protect the genome from postdisturbance attack by a restriction–modification gene complex. J. Bacteriol. 184, 6100–6108 (2002).
Blumenthal, R. M., Gregory, S. A. & Cooperider, J. S. Cloning of a restriction–modification system from Proteus vulgaris and its use in analyzing a methylase-sensitive phenotype in Escherichia coli. J. Bacteriol. 164, 501–509 (1985).
This work was funded by an HFSP Young Investigators’ grant (C.C.G.) and a grant from the United States National Institutes of Health (GM 091875) (B.R.L.). M.P. is a recipient of a DOC Fellowship of the Austrian Academy of Science at the Institute of Science and Technology Austria. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA Grant Agreement No. 291734. We wish to thank A. Bagwatt, R. Blumenthal, I. Kobayashi, S. Makovets, S. Moineau, I. Mruk and M. Szczelkun for providing us with RM plasmids and phages. We thank S. Abedon, N. Balaban, D. Siekhaus, G. Tkacik and members of the C.C.G. laboratory for in-depth discussions and comments on the manuscript. We especially thank V. Krishna KV for assistance with the experiments.
The authors declare no competing financial interests.
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Supplementary Figs. 1–9; Supplementary Tables 1–3; Supplementary Methods; Supplementary References.
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Pleška, M., Lang, M., Refardt, D. et al. Phage–host population dynamics promotes prophage acquisition in bacteria with innate immunity. Nat Ecol Evol 2, 359–366 (2018). https://doi.org/10.1038/s41559-017-0424-z