Phages and bacteria are seemingly engaged in an endless battle. In the presence of bacterial antiviral barriers, phages rely on several diverse counter-strategies to usurp their hosts and ensure phage propagation.
Phages can readily modify their receptor-binding protein to adsorb to evolving bacterial populations. Phages can also use strategies such as diversity-generating retroelements to facilitate the recognition of multiple bacterial receptors. Moreover, if host receptors are masked by capsular polysaccharides, some phages possess degrading enzymes to hydrolyse this material and access the receptor.
When the phage genome enters its bacterial host, it can be targeted by various nucleic acid cleavage enzymes such as restriction–modification and CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) systems. To protect against these systems, phages use an array of strategies, including anti-restriction–modification and anti-CRISPR systems, and point mutations in specific sequences.
Abortive-infection mechanisms lead to the altruistic death of a phage-infected cell (for example, through induction of a toxin), thereby limiting phage propagation. Phages circumvent this hurdle mainly by mutating specific genes or through the production or hijacking of antitoxins that neutralize the bacterial toxin.
This is a rapidly expanding field of research, but many antiphage systems and many strategies used to escape these bacterial defences remain to be discovered. A better understanding of phage–host interactions is also needed to minimize the negative impact of phages on food production and biotechnology applications, as well as to maximize the use of phages as antibacterial agents.
Bacteria and their viral predators (bacteriophages) are locked in a constant battle. In order to proliferate in phage-rich environments, bacteria have an impressive arsenal of defence mechanisms, and in response, phages have evolved counter-strategies to evade these antiviral systems. In this Review, we describe the various tactics that are used by phages to overcome bacterial resistance mechanisms, including adsorption inhibition, restriction–modification, CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) systems and abortive infection. Furthermore, we consider how these observations have enhanced our knowledge of phage biology, evolution and phage–host interactions.
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The authors thank B.-A. Conway for editorial assistance. This work was supported by the Natural Sciences and Engineering Research Council of Canada (the discovery and strategic programmes), the Canadian Institutes of Health Research (an emerging-team grant) and the Ministère de l'Enseignement Supérieur, de la Recherche, de la Science et de la Technologie du Québec (the PSR SIIRI programme). J.E.S is the recipient of a scholarship from the Fonds Québécois de la Recherche sur la Nature et les Technologies. S.M. holds a Tier 1 Canada Research Chair in Bacteriophages.
The authors declare no competing financial interests.
- Phage therapy
The use of phages as therapeutic agents to treat or prevent bacterial infection.
- Receptor-binding protein
A phage protein that is located at the tip of the phage tail and specifically recognizes its cognate receptor on the bacterial surface.
An outer-membrane porin that is used to transport maltose into bacterial cells. It is also the receptor of phage λ.
- Tail fibre
A structural phage fibre that participates in the binding of the phage to its bacterial receptor.
- Quorum sensing signal
A chemical molecule that is used by bacteria to communicate with each other. This signal usually causes a bacterial response, such as the modulation of gene expression or a change in the use of metabolic pathways.
- Phase variation
Variation in protein expression that results in a new phenotype, but without genetic modification. It is usually induced by environmental changes.
- His box
A GXHXH motif that is repeated six times in the receptor-binding protein encoded by phage T4 gp37; the motif is also widely represented in several other coliphages. Recombination between the His box repeats results in the generation of a range of host-recognition specificities.
- λ reverse
A hybrid phage λ that has recombined with the Rac prophage of Escherichia coli K-12.
- Temperate phages
Phages that can integrate their genome into the bacterial chromosome through a process called lysogeny. The bacterium is then a lysogen, and the integrated phage is in a prophage state.
- Phage-inducible chromosomal island-like element
An 18 kb chromosomal island that is found in Vibrio cholerae strains and resembles the phage-inducible chromosomal islands of Gram-positive bacteria, including the prototypical Staphylococcus aureus pathogenicity islands.
- Terminal transferase
An enzyme that catalyses the addition of nucleotides to the 3′ hydroxyl terminus of DNA without the need for a specific primer.
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Samson, J., Magadán, A., Sabri, M. et al. Revenge of the phages: defeating bacterial defences. Nat Rev Microbiol 11, 675–687 (2013). https://doi.org/10.1038/nrmicro3096