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Microbial defense system

Microbial defense system

Proteins that were encoded within three open Mixrobial frames ORFs either side defensr the Micronial gene clusters were then pooled Electrolyte balance challenges give a set of putative defence-associated proteins. Ryazansky, S. Koonin E. Supplementary Figure 6. F exclusion of bacteriophage T7 occurs at the cell membrane. Moreover, phage defense systems are often strain-specific [ 78 ], i. The correlation values relate to all subtypes.

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The Immune System of Bacteria: Beyond CRISPR

Rejuvenation therapies Bacterial defense systems Submission status Open.

Open for submission Oats and natural fiber 18 August Submission deadline 31 May Microbial evolution is driven Microbial defense system a systek interaction between bacteria and Microbiaal bacteriophages.

Micdobial avoid cell death or genomic invasion, bacteria have developed several sophisticated defene strategies, like preventing cell entry defsnse. Electrolyte balance challenges syste Electrolyte balance challenges or variation and Micrboial e.

Electrolyte balance challenges systems and adaptive mechanisms Energy-boosting diet. the CRISPR-Cas systems. Systdm, bacteriophages have Microbial defense system Microobial to evade or counteract many of these defense systems, e.

anti-CRISPR and antirestriction proteins. Bacterial defense systems are therefore under constant selective pressure by bacteriophage attack, and they rapidly evolve to combat phage infection and parasitism.

The overall goal of the collection is to explore the diverse strategies employed by bacteria to combat challenges such as phage attacks, antimicrobial agents, environmental stresses, and interactions with other microorganisms.

Articles 2 in this collection Genome-wide transcriptional response to silver stress in extremely halophilic archaeon Haloferax alexandrinus DSM T Authors first, second and last of 5 Doriana Mădălina Buda Edina Szekeres Horia Leonard Banciu.

Lipopolysaccharide O-antigen profiles of Helicobacter pylori strains from Southwest China Authors first, second and last of 8 Xiaoqiong Tang Peng Wang Hong Li.

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Bacterial cGAS senses a viral RNA to initiate immunity. Depardieu, F. Cell Host Microbe 20 , — Zhang, T. Direct activation of a bacterial innate immune system by a viral capsid protein.

Rousset, F. Phages and their satellites encode hotspots of antiviral systems. This study uncovered a new method to bioinformatically predict antiphage systems by identifying defensive hotspots in phages and phage satellites and demonstrates that antiphage systems of satellites can benefit their helper phage.

Parma, D. The Rex system of bacteriophage lambda: tolerance and altruistic cell death. Genes Dev. Durmaz, E. Abortive phage resistance mechanism abiz speeds the lysis clock to cause premature lysis of phage-infected lactococcus lactis.

The DarTG toxin—antitoxin system provides phage defence by ADP-ribosylating viral DNA. Guegler, C. Shutoff of host transcription triggers a toxin—antitoxin system to cleave phage RNA and abort infection.

Cell 81 , — e9 This study describes a toxin — antitoxin system type III with antiphage activity, which encodes an endoribonuclease toxin that degrades viral transcript.

Diverse enzymatic activities mediate antiviral immunity in prokaryotes. Science , — This study uses a bioinformatic prediction method to validates 29 novel defence systems.

Bacterial retrons function in anti-phage defense. e12 This study shows that retrons can function as antiphage sensors that guard the RecBCD complex and trigger toxic effectors when activated. Bobonis, J. Bacterial retrons encode phage-defending tripartite toxin—antitoxin systems. Bacteria deplete deoxynucleotides to defend against bacteriophage infection.

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Genetics , — Uzan, M. Post-transcriptional control by bacteriophage T4: mRNA decay and inhibition of translation initiation. Athukoralage, J. Cyclic nucleotide signaling in phage defense and counter-defense.

Steens, J. The diverse arsenal of type III CRISPR—Cas-associated CARF and SAVED effectors. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Whiteley, A. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals.

Leavitt, A. Viruses inhibit TIR gcADPR signaling to overcome bacterial defense. The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling.

eL ife 9 , e Google Scholar. Nussenzweig, P. Molecular mechanisms of CRISPR—Cas immunity in bacteria. LeGault, K. A phage parasite deploys a nicking nuclease effector to inhibit viral host replication.

Doron, S. Systematic discovery of antiphage defense systems in the microbial pangenome. Science , eaar This study develops a bioinformatic prediction method and experimentally validates nine novel antiphage systems.

Jaskólska, M. Two defence systems eliminate plasmids from seventh pandemic vibrio cholerae. Lau, R. Structure and mechanism of a cyclic trinucleotide-activated bacterial endonuclease mediating bacteriophage immunity. Cell 77 , — Cheng, R. A nucleotide-sensing endonuclease from the Gabija bacterial defense system.

Davidov, E. RloC: a wobble nucleotide-excising and zinc-responsive bacterial tRNase. Williams, M. Restriction endonuclease cleavage of phage DNA enables resuscitation from Casinduced bacterial dormancy.

Bari, S. A unique mode of nucleic acid immunity performed by a multifunctional bacterial enzyme. Morehouse, B. STING cyclic dinucleotide sensing originated in bacteria. Gao, Y. Molecular basis of RADAR anti-phage supramolecular assemblies.

e20 Duncan-Lowey, B. Cryo-EM structure of the RADAR supramolecular anti-phage defense complex. e15 Bernheim, A. Prokaryotic viperins produce diverse antiviral molecules. Johnson, A. Bacterial gasdermins reveal an ancient mechanism of cell death.

This study uncovers the existence of bacterial Gasdermins that, similar to eukaryotic ones, form pores leading to immunity-related cell death. VanderWal, A. CRISPR-Csx28 forms a Cas13b-activated membrane pore required for robust CRISPR-Cas adaptive immunity. Cheng, X.

F exclusion of bacteriophage T7 occurs at the cell membrane. Virology , — Schmitt, C. Genes 1. Effector-mediated membrane disruption controls cell death in CBASS antiphage defense. Piel, D. Phage—host coevolution in natural populations.

Samson, J. Revenge of the phages: defeating bacterial defences. Labrie, S. Bacteriophage resistance mechanisms. Puigbò, P. Reconstruction of the evolution of microbial defense systems.

BMC Evol. Payne, L. Identification and classification of antiviral defence systems in bacteria and archaea with PADLOC reveals new system types. Fillol-Salom, A. Bacteriophages benefit from mobilizing pathogenicity islands encoding immune systems against competitors. Vassallo, C. A functional selection reveals previously undetected anti-phage defence systems in the E.

coli pangenome. In this study, the authors developed a new high-throughput method for the discovery of antiphage systems through random cloning of genomic fragments of E. coli isolates, uncovering 21 novel systems. Benler, S. Cargo genes of Tn7-like transposons comprise an enormous diversity of defense systems, mobile genetic elements, and antibiotic resistance genes.

mBio 12 , e Hochhauser, D. The defense island repertoire of the Escherichia coli pan-genome. PLoS Genet. Temporal shifts in antibiotic resistance elements govern phage-pathogen conflicts.

Science , eabg This study demonstrates that V. cholerae resistance to phages is determined by the turnover of SXT integrative and conjugative elements, which often encode both antibiotic resistance genes and antiphage systems. Picton, D.

The phage defence island of a multidrug resistant plasmid uses both BREX and type IV restriction for complementary protection from viruses. Wu, Y. Defence systems provide synergistic anti-phage activity in E. Rocha, E. Microbial defenses against mobile genetic elements and viruses: who defends whom from what?

PLoS Biol. Hussain, F. Rapid evolutionary turnover of mobile genetic elements drives bacterial resistance to phages. This study shows that in a set of nearly clonal V.

lentus strains, phage host range is largely explained by the rapid turnover of phage defence elements. The pan-immune system of bacteria: antiviral defence as a community resource. Dedrick, R. Prophage-mediated defence against viral attack and viral counter-defence.

Gentile, G. More evidence of collusion: a new prophage-mediated viral defense system encoded by mycobacteriophage Sbash. mBio 10 , e Montgomery, M. Yet more evidence of collusion: a new viral defense system encoded by Gordonia Phage CarolAnn. mBio 10 , e—e Owen, S. Prophages encode phage-defense systems with cognate self-immunity.

Cell Host Microbe 29 , — e8 Ali, Y. Temperate Streptococcus thermophilus phages expressing superinfection exclusion proteins of the Ltp type.

Yu, Y. Translation elongation factor Tu cleaved by a phage-exclusion system. USA 91 , — Koonin, E. Evolutionary entanglement of mobile genetic elements and host defence systems: guns for hire. Anantharaman, V. Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing.

Direct 8 , 15 Lowey, B. Cell , 38— e17 Francois, R. A conserved family of immune effectors cleaves cellular ATP upon viral infection. Aravind, L. Discovering biological conflict systems through genome analysis: evolutionary principles and biochemical novelty.

Data Sci. Stern, A. The phage-host arms race: shaping the evolution of microbes. Bioessays 33 , 43—51 Dupuis, M.

CRISPR—Cas and restriction—modification systems are compatible and increase phage resistance. Costa, A. Accumulation of defense systems drives panphage resistance in Pseudomonas aeruginosa. Srikant, S. The evolution of a counter-defense mechanism in a virus constrains its host range.

eLife 11 , e Maguin, P. Cleavage of viral DNA by restriction endonucleases stimulates the type II CRISPR—Cas immune response. Zheng, Z. The CRISPR—Cas systems were selectively inactivated during evolution of Bacillus cereus group for adaptation to diverse environments.

ISME J. Vasu, K. Diverse functions of restriction—modification systems in addition to cellular defense. Varble, A. Recombination between phages and CRISPR—Cas loci facilitates horizontal gene transfer in staphylococci. Watson, B. CRISPR-Cas-mediated phage resistance enhances horizontal gene transfer by transduction.

mBio 9 , e—e Hsu, B. Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model. Cell Host Microbe 25 , — Braga, L.

Impact of phages on soil bacterial communities and nitrogen availability under different assembly scenarios. Microbiome 8 , 52 Kellner, M. SHERLOCK: nucleic acid detection with CRISPR nucleases. Loenen, W. Highlights of the DNA cutters: a short history of the restriction enzymes. Lopez, S. Precise genome editing across kingdoms of life using retron-derived DNA.

Pennisi, E. The CRISPR craze. Schubert, M. High-throughput functional variant screens via in vivo production of single-stranded DNA. USA , e Alseth, E.

Bacterial biodiversity drives the evolution of CRISPR-based phage resistance. Shaer Tamar, E. Multistep diversification in spatiotemporal bacterial-phage coevolution. Jacob, F.

Evolution and tinkering. Kibby, E. Bacterial NLR-related proteins protect against phage. e18 Wein, T. Bacterial origins of human cell-autonomous innate immune mechanisms.

Cury, J. Conservation of antiviral systems across domains of life reveals novel immune mechanisms in humans. Article Google Scholar. Warren, R. Modified bases in bacteriophage DNAs.

Liu, Y. Covalent modifications of the bacteriophage genome confer a degree of resistance to bacterial CRISPR systems. Hobbs, S. Phage anti-CBASS and anti-PYCSAR nucleases subvert bacterial immunity. Borges, A. Bacteriophage cooperation suppresses CRISPR-Cas3 and Cas9 immunity. e10 Landsberger, M.

Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity. Blower, T. Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. Makarova, K. Defense islands in bacterial and archaeal genomes and prediction of novel defense systems.

Bondy-Denomy, J. Prophages mediate defense against phage infection through diverse mechanisms. Scholl, D. Ohshima, Y. The role of capsule as a barrier to bacteriophage adsorption in an encapsulated Staphylococcus simulans strain.

Scanlan, P. Co-evolution with lytic phage selects for the mucoid phenotype of Pseudomonas fluorescens SBW Seed, K. Evolutionary consequences of intra-patient phage predation on microbial populations. eLife 3 , e Harvey, H. Pseudomonas aeruginosa defends against phages through type IV pilus glycosylation.

Tzipilevich, E. Bacteria elicit a phage tolerance response subsequent to infection of their neighbors. Wohlfarth, J. l -form conversion in Gram-positive bacteria enables escape from phage infection.

PubMed PubMed Central CAS Google Scholar. Ongenae, V. Reversible bacteriophage resistance by shedding the bacterial cell wall. Dillingham, M. RecBCD enzyme and the repair of double-stranded DNA breaks. Guo, L. A bacterial dynamin-like protein confers a novel phage resistance strategy on the population level in Bacillus subtilis.

Stokar-Avihail, A. Discovery of phage determinants that confer sensitivity to bacterial immune systems. This study systematically uncovers triggers of antiphage defence systems and major trends of sensing mechanisms of antiphage immunity. An anti-CRISPR viral ring nuclease subverts type III CRISPR immunity.

Huiting, E. Bacteriophages inhibit and evade cGAS-like immune function in bacteria. e21 Pawluk, A. Anti-CRISPR: discovery, mechanism and function. Download references. The authors are grateful to A. Millman, G. Ofir and F. Rousset for their very useful feedback on early versions of this manuscript.

The authors also thank all members of the Molecular Diversity of Microbes Lab for their comments and suggestions during the writing process. and A. are supported by the ERC Starting Grant PECAN To promote gender equality and inclusivity in research, we are convinced of the importance of acknowledging gender bias in research article citation.

Molecular Diversity of Microbes Lab, Institut Pasteur, Université Paris Cité, INSERM, Paris, France. You can also search for this author in PubMed Google Scholar. These elements can be costly, even deadly, and cells use numerous defense systems to filter, control, or inactivate them. Recent studies have shown that prophages, conjugative elements, their parasites phage satellites and mobilizable elements , and other poorly described MGEs encode defense systems homologous to those of bacteria.

These constitute a significant fraction of the repertoire of cellular defense genes. As components of MGEs, these defense systems have presumably evolved to provide them, not the cell, adaptive functions. While the interests of the host and MGEs are aligned when they face a common threat such as an infection by a virulent phage, defensive functions carried by MGEs might also play more selfish roles to fend off other antagonistic MGEs or to ensure their maintenance in the cell.

MGEs are eventually lost from the surviving host genomes by mutational processes and their defense systems can be co-opted when they provide an advantage to the cell. Citation: Rocha EPC, Bikard D Microbial defenses against mobile genetic elements and viruses: Who defends whom from what?

PLoS Biol 20 1 : e Copyright: © Rocha, Bikard. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist. Horizontal gene transfer HGT allows bacteria and archaea to rapidly match novel ecological challenges and opportunities. HGT is most frequently mediated by mobile genetic elements MGEs like bacteriophages phages and conjugative elements that are present in most genomes, often in multiple copies for definitions, see Box 1.

These elements can autonomously transfer themselves from one cell to another using viral particles or conjugative pili, processes that also contribute to the exchange of chromosomal DNA. Besides their ability to drive HGT, many MGEs encode traits adaptive to the host cell.

For example, key virulence factors in many human pathogens are encoded in prophages, and the transfer of antibiotic resistance genes is driven by conjugative elements [ 1 , 2 ].

By increasing the host fitness in specific contexts, these traits contribute to the proliferation of MGEs in communities, i. In other contexts, these traits can be costly and, together with the costs of vertical and horizontal transfer, lower the host fitness [ 3 ]. As a result of these costs, MGEs rarely remain in genomes for long periods of time [ 4 ], and different strains tend to carry very different repertoires of prophages, plasmids, or transposable elements [ 5 — 8 ].

Abortive infection : process by which an infected cell induces its own death before the phage can complete its replication cycle. This strategy is employed by a large diversity of defense systems that sense infection and trigger cell death through various mechanisms.

Allelic recombination : a process, usually using homologous recombination, which results in allelic exchanges between very similar genes present in different genomes. One uses the term recombination for exchanges leading to transfer of polymorphism in conserved genes gene conversion from one bacterium to another and HGT for transfer of novel genes.

Balancing selection : evolutionary process where there is selection to maintain polymorphism in the population. For example, it can favor the diversity of alleles in genomes e. Chromosome hotspots : regions of bacterial chromosomes with high turnover of genetic material, i.

Conjugative elements : plasmids or integrative conjugative elements ICEs can produce a mating pair formation structure at the cell envelope to transfer DNA between neighboring cells.

These sequences guide nucleases to destroy cognate invading genetic elements. Homologous recombination : molecular process that results in the joining of two DNA molecules at a region of homology. Can result in the exchange of polymorphism between the chromosome and exogenous DNA sequences.

Horizontal gene transfer HGT : transfer of novel genes from one microbial cell to another. Mobile genetic elements MGEs : semiautonomous genetic elements that are capable of mobility within or between genomes.

They include phages and conjugative elements capable of autonomous transfer between cells, satellites and mobilizable elements capable of hijacking the former ones, and many other elements whose means of horizontal transfer are unknown.

Mobilizable elements : plasmids or integrative mobilizable elements IMEs capable of hijacking mating pore formation structures of conjugative elements for their own transfer.

Phage satellites : MGEs capable of hijacking phage particles produced by phages for their own transfer. Restriction—modification R—M systems : use specific methylation patterns to distinguish self from nonself. Incoming MGEs lacking compatible methylation patterns are degraded by a nuclease.

Retron : genomic elements encoding a reverse transcriptase and a noncoding RNA that is partly reverse transcribed to form a RNA—DNA hybrid.

Some retrons have been recently shown to be antiphage defense systems. Transduction : processes by which phage particles transfer bacterial DNA between cells.

Conjugative elements and phages also have molecular parasites that use their mechanisms of horizontal transmission to transfer between cells. For example, viral particles produced by phages can be hijacked by phage satellites [ 9 ], and conjugative pili can be used by so-called mobilizable elements [ 10 ].

Many other MGEs lack known mechanisms of horizontal transmission and may transfer between cells by exploiting phages and conjugative elements [ 10 ]. It must be noted that the presence of a MGE affects the frequency of other MGEs in the cell.

This is the case of the mobility of multiple conjugative plasmids in cells [ 11 ], of the abovementioned mobilizable plasmids and phage satellites that cotransfer in synchrony with conjugative elements and phages, and of phages that use the conjugative pilus as a receptor for cell infection [ 12 ].

Finally, infection by a MGE may spur the transfer of others. Phage infection favors the transfer of SXT-like integrative conjugative elements ICEs [ 13 ] and conjugation-induced SOS response activates MGEs in the recipient cells [ 14 ].

Transposable elements are a particularly important family of mobile elements that is very abundant within other MGEs and facilitates genetic exchanges between them and with the host [ 15 ]. The cellular genome thus harbors a large diversity of MGEs establishing complex interactions among each other and with the host cell.

The associations between the host and its MGEs lay on a continuum going from pure parasitism to intimate mutualism because vertical and horizontal transmission of MGEs impose fitness costs to the cell that may eventually be outweighed by advantageous traits encoded by them. Virulent phages are at the edge of maximal virulence in this continuum since their successful infection implicates cell death.

The fitness effects of the remaining MGEs, and of the accessory traits they encode, are more diverse and vary with the physiological state of the cell and the presence of competing MGEs. Temperate phages are striking examples of such ambiguity. Their integration in the genome can provide novel adaptive traits [ 16 ], but their subsequent excision from the genome usually ends in host death [ 17 ].

The richness of the interactions between MGEs and the host make their impact contingent on a specific cellular context, i.

MGEs that are parasites of other MGEs impact the fitness of the latter. If this impact is very high and the parasitized MGE is deleterious to bacteria, then the parasite of the parasite benefits the host cell. For example, some satellites can abolish phage transmission by release of viral particles exclusively packaged with the satellite genome [ 18 ].

Although this process still ends in cell death, the inhibitory effect of the satellite on phage reproduction blocks its epidemic growth, thereby protecting the microbial population. Since most genomes contain plasmids, prophages, and other MGEs [ 10 , 19 ], and virulent phages are extremely abundant in the environment [ 20 ], the fate of cells often hangs in the outcome of their interaction with MGEs and that of MGEs among themselves.

The potential for conflicts in the interactions between MGEs and the host led to the evolution of defense mechanisms to filter, control, or inactivate them [ 21 , 22 ].

These systems are now being unraveled at fast pace even though their mechanisms are in many cases still poorly understood [ 23 , 24 ]. The extensive description of these systems falls outside the scope of this text and can be found elsewhere [ 25 — 28 ].

Some defenses are part of core cellular systems and provide protection from MGEs as part of a broader set of cellular functions Fig 1. For example, RecBCD is a powerful exonuclease involved in the repair of double-strand breaks by homologous recombination.

It degrades linear double-stranded DNA until it meets a Chi site beyond which it loads the recombinase RecA. Phages lacking Chi sites are rapidly degraded by the enzyme [ 29 ]. Hence, generic defense systems that are part of the host core genome may nourish more specialized systems for more specific protection.

Interestingly, Lambdoid phages in Escherichia coli either lack Chi sites, in which case they usually encode anti-RecBCD systems to block RecBCD and produce their own recombination systems, or have many Chi sites and use the host homologous recombination machinery for their own replication [ 32 ].

Bacteria have evolved responses to protect themselves from phage-encoded anti-RecBCD systems. A retron was recently discovered that induces cell death when the RecBCD function is compromised, i. Homologous recombination via the RecBCD pathway can defend from MGEs because RecBCD is a powerful exonuclease that degrades linear double-stranded DNA but is inactivated by some phage encoded proteins, like Gam.

Epigenetic modifications are the basis of many defense systems that can be counteracted by phage proteins, like Ocr in phage T7, or by epigenetic modification of phage DNA. Abortive infection is a costly defense strategy that induces cell growth arrest or death when a threat to the cell is detected.

Contrary to RecBCD, many defense systems are not involved in core cellular processes. Instead, they are specialized in providing innate or adaptive immunity. Restriction—modification R—M systems, by far the most abundant defense systems in bacterial genomes [ 34 , 35 ], provide excellent illustrations of the evolutionary processes resulting in the evolution of defense and counter-defense systems Fig 1.

They imprint epigenetically the cellular genome and inactivate restrict infecting MGEs lacking the adequate DNA modifications. As a response, some phages counteract the activity of R—M systems by either producing anti-restriction proteins or by extensively modifying their DNA [ 36 , 37 ].

Anti-restriction functions can, in turn, be recognized by bacterial anti-anti-restriction systems that provide a second layer of resistance when R—M fails, e.

As a complement, phages with extensive modifications in their DNA can be recognized by specific bacterial antimethylation restriction systems [ 39 , 40 ]. The evolution of this tit-for-tat mechanisms can go very far.

For example, phage T4 encodes an anti-restriction system that can be recognized by hosts encoding an anti-anti-restriction system that induce cell death by tRNA cleavage. This abortive infection system can be canceled by T4 because it can repair the cleaved tRNAs using a pair of proteins that constitute an anti-anti-anti-restriction system [ 41 ].

Defense and counter-defense systems are often studied in the light of the antagonistic interaction between one host and a virulent phage.

But the reality is much more complex and interesting because many of the systems found in bacterial genomes and once thought to be dedicated to the defense of the cell are actually encoded in MGEs.

This includes systems encoded in temperate phages [ 8 , 42 — 45 ], satellites [ 38 , 46 , 47 ], conjugative elements [ 13 , 48 — 50 ], mobilizable plasmids [ 34 ], and genomic islands acquired by HGT [ 8 , 44 , 51 ].

It is important to note that the presence of occasional defense systems in phages or plasmids has been known for decades. What these recent observations highlight is that a large fraction of the so-called cell defense systems are encoded in MGEs.

This raises intriguing questions concerning the role, function, and evolution of the so-called cellular defense systems Fig 2. Defense and antidefense systems are often studied in the context of the interaction between one host and one MGE, usually a virulent phage left.

Yet, the presence of numerous MGEs in populations and their ability to encode their own defense systems renders the picture more complex right. Virulent phages establish antagonistic interactions with the other MGEs and the cell 1.

But the associations between the other MGEs and the cell can be more diverse 2 to 7. Temperate phages and conjugative plasmids exploit their cellular host 2 and 4 and can be exploited by other MGEs 3 and 5.

Plasmids often encode systems that are effective barriers to phages, e. Phages are a threat to plasmids when they kill the host cell 6.

Satellites may benefit the host by diminishing phage infection 7. Most of these interactions 2 to 8 can at times be beneficial to both partners, e. MGE, mobile genetic element.

For example, the first 2 sequenced genomes of Helicobacter pylori encode a total of more than 20 putative R—M systems [ 52 ], and genomes with multiple CRISPR arrays and Cas systems are frequent [ 53 ]. The fast pace of discovery of novel defense and counter-defense systems suggests that they may account for a significant number of the unknown function genes in genomes.

It could also facilitate building up multiple layers of cell defenses that may culminate in cell death when all else fails [ 27 ]. In this view, cell defense systems are numerous because they make a multilayered immune system to tackle different elements.

Yet, defense systems can be costly [ 54 ], because of production costs when they are required at high concentration [ 55 ], because their activity can be energetically costly [ 56 ], or because they may be incompatible with other cellular mechanisms [ 57 ].

They can also kill the cell by autoimmunity [ 58 ]. Hence, the number of systems under selection for defense by the host cell is expected to depend on the balance between these costs and the rewards given by their ability to protect hosts from MGEs.

The observations that genomes have many MGEs and that these encode many defense systems provide an alternative or complementary explanation for why genomes contain so many such systems. Genomes contain many defense systems because they are acquired within the multiple MGEs that infect microbial cells.

Since there are many MGEs in a cell, these sum up to a considerable number of defense genes. Such MGE-encoded defenses may also be multilayered. For example, E. coli plasmids encoding both BREX and type IV restriction systems have recently been shown to provide complementary protection from phages [ 59 ].

This does not exclude the possibility that cells select for multiple systems of defense, but does suggest that to understand their frequency in cells one must also account for the infectivity of MGEs.

This means that the multiplicity of systems in cellular genomes might be a consequence of the high transmissibility and abundance of MGEs, not only the result of natural selection for protection of the cell. It is therefore possible that cells encode more defense systems than the theoretical optimal number expected for a host cell, simply because many of the systems are selected for their presence in the MGE, not in the host.

Defense systems tend to be different across strains of a species [ 21 , 51 ] and are a significant part of the genetic differences between closely related strains of Vibrio spp. Why are defense systems so different among strains of a species? The coevolutionary dynamics between defenses and counter-defenses contributes to an endless process of genetic diversification that is often understood in the context of balancing selection [ 60 ].

These are processes where natural selection favors the existence of genetic polymorphism. Interestingly, balancing selection resulting in the presence of diverse defense systems in populations is observed in many immune systems, from bacteria to humans [ 61 ]. Balancing selection can occur by multiple mechanisms.

First, it is harder for a parasite to spread in a population with diverse host defenses even in simple systems [ 62 ]. The presence of various systems providing immunity from MGEs within microbial populations increases the likelihood that some individuals are protected, in what has been described as distributed pan immunity [ 26 ].

Relative to microbial genomes, MGEs are more constrained in the number of genes they can carry, especially those packaged in viral particles. Yet, some also carry multiple defense systems [ 8 , 13 , 38 , 44 ], which may allow them to infect different hosts or fend off different MGEs.

Second, variations in time and space of the density, type, and behavior of MGEs may favor different cellular defense systems in different situations. The distribution of MGEs varies across bacterial habitats [ 64 ] and across environmental conditions within habitats [ 65 ]. Hence, locally adapted microbial populations may select for different systems that tackle different types of MGEs resulting in variable defense repertoires across a bacterial species.

This is also applicable to defense systems encoded in MGEs. Their defense systems can be under balancing selection because the hosts and MGEs they encounter vary in space and time. Third, clones that are more abundant in a habitat are more susceptible to phages, because of their density [ 66 ].

In this context, negative frequency—dependent selection may result in selection of rare alleles [ 67 ], i. As the population of individuals with the rare adaptive defense increases, antagonists with the ability to infect it also rise in frequency because they have more hosts available.

This decreases the advantage of the initial clone and eventually cancels it when novel rare clones resistant to the MGEs emerge, thereby restarting the process of negative frequency—dependent selection. While negative frequency dependence in host—pathogen interactions has been extensively studied [ 61 ], there is a paucity of data on its role in MGE—host interactions.

What are the molecular mechanisms driving the variation of bacterial defenses? Some systems have dedicated molecular mechanisms for their own variation.

Some R—M systems can also rapidly change their sequence specificity through recombination [ 68 ]. Yet, the available evidence suggests that HGT and gene loss have major complementary roles in the diversification of defense repertoires at the species level.

The abundance of defense systems in MGEs suggests a very straightforward mechanism for the acquisitions of defense systems by the host: Systems are transferred across strains by the MGEs encoding them.

Furthermore, MGEs are gained at high rates because of their infectiousness explaining acquisition , and they are frequently lost from populations because of their cost explaining loss.

The rates of gain and loss of defense systems may thus be partly caused by the mobility and lability of the mobile elements encoding them. Beyond explaining the acquisition of novel systems, the presence of defense systems in MGEs also offers some clues on how entirely novel defense strategies emerge.

The recent discovery of many antiphage systems shows that they frequently consist in an assemblage of protein domains that are also present in proteins implicated in other cellular processes such as nucleases, kinases, deaminases, proteases, or ATPases [ 71 ].

For instance, the Stk2 defense kinase is part of a family of kinases whose members are implicated in various cellular process such as the control of the cell cycle or the exit of dormancy [ 72 ]. The antiphage viperins are close homologues to GTP cyclases involved in other functions [ 73 ].

The co-option of proteins, or protein domains, with other functions, and the creation of novel assemblages leading to genetic innovation by recombination and mutation are likely facilitated by the horizontal transfer of defense systems across genetic backgrounds [ 74 ].

While successful functional innovations by co-option of these systems may be unlikely, the very frequent transfer of systems and their rapid evolution may result in such a high rate of novel combinations of domains that some will eventually evolve to become novel defense systems.

Such processes of co-option may have been at the independent origins of both Cas-9 and Cas proteins from transposon-encoded RNA-guided endonucleases [ 75 , 76 ].

Novel defense systems, even if initially not part of MGEs, will eventually be captured by MGEs for their own use, with the consequence that they will be spread across microbial lineages. Transposases may play key roles in the process of translocating these systems from the chromosome to MGEs and vice versa.

The subsequent transfer of defense systems to different genetic backgrounds is expected to favor the spread of defense systems that are robust to such changes. Accordingly, there is a broad distribution of most defense systems across the bacterial kingdom [ 35 ]. It is also interesting to note the surprisingly broad activity of some defense systems recently described [ 23 ].

Cloning these genetic systems from distant species into E. coli and Bacillus subtilis yields defense phenotypes.

The presence of defense systems on MGE that move across species might thus favor broad defense capabilities and mechanisms tolerant to changes in the genetic background. The rapid pace of discovery of novel defense systems has been facilitated by the use of assays where cells are challenged by virulent phages.

As a result, the role of defense systems tends to be discussed in the light of phage—bacteria interactions. It does seem reasonable to assume that systems present in a microbial genome for a long time are protecting it from MGEs and especially against virulent phages given their lethality for the cell.

Yet, systems encoded in MGEs are more likely to be selected because they benefit the MGE. In certain cases, a system increases the fitness of both MGE and host. For example, defense systems encoded in P4-like satellites were shown experimentally to protect the cell from several phages that the P4 element cannot exploit [ 38 ].

In this case, the satellite and the cell have the same interest in preventing infection by phages that can kill the cell. In general, both MGEs and hosts will gain from preventing infection by virulent phages, explaining why MGEs defenses seem to target them frequently.

The interests of the MGE and the cell may not be so well aligned in other circumstances. In some cases, the advantage of the MGE defense system to the cell may be transient. Temperate phages that defend the cells from virulent phages are common [ 8 , 43 , 77 ] and provide a temporary relief to the host.

But they may have little long-term impact in bacterial fitness if the victorious temperate phage is induced and lyses the cell. This is also exemplified by the exclusion systems encoded by conjugative systems or phages to fend off closely related elements [ 78 , 79 ].

Historically, these mechanisms have not been included in defense systems, but they are costly mechanisms that protect the cell from infection by MGEs, i. For example, the surface exclusion system of plasmid F prevents infection by similar plasmids thanks to the production of thousands of copies of an outer membrane protein that accounts for a large part of the plasmid carrier cost [ 80 ].

An even more extreme case concerns phages encoding defense or antidefense systems against their satellites. These are engaging in an interaction with their parasites in a way that resembles their own interaction with the cell but with their own position reversed as they are now the ones being exploited [ 47 ].

Such phage-encoded defense systems could be highly deleterious to the cell because they remove a protective satellite and favor a phage that will eventually kill the host.

The misalignment of interests between MGEs and the host is particularly striking when it concerns abortive infection systems, because these are extremely costly to the cell [ 27 ]. The traditional view is that such strategies can only be selected in very particular cases favoring cooperation between individuals, e.

A recent investigation of abortive infection provided by retron elements suggests that retron-encoding bacteria lose in competition with bacteria lacking the retron when challenged by a phage even in a structured environment [ 82 ].

Yet, genomic data suggest that abortive infection systems are very frequent [ 35 ], which requires an explanation. The presence of abortive infection systems on MGEs could facilitate the control of epidemics of competitive elements and would justify their abundance in the host.

Such systems could be deleterious to the host if they drive cell death upon infection by elements with little negative impact on its fitness. But in other circumstances, the presence of these systems in MGEs could benefit the host by enforcing cooperation [ 83 ], since the transfer of the MGEs to sensitive hosts spreads the abortive system and therefore favors the cooperative process.

To understand the fitness impact of defense systems, it is thus important to know if they are encoded in MGEs. The identification of functional MGEs is difficult both computationally and experimentally, since many MGEs are poorly known and many of the others are defective [ 74 ].

It is often even more difficult to predict which genetic elements are being targeted by the defense system. That many systems are effective against virulent phages may be in part the result of ascertainment biases, since virulent phages are often used to identify defense systems.

One might also argue that virulent phages are going to be targeted by hosts and most MGEs because they kill the host and its MGEs.

However, many systems, among which all those using epigenetic markers like R—M, target generic exogenous DNA independently of it being part of a phage genome. This makes it particularly hard to know who they were selected to target. The analysis of the spacer content can thus inform on the selection pressure that maintain CRISPR immunity.

These results suggest that systems encoded in MGEs may be targeting other competing MGE that are not costly to the cell. They may even be targeting elements that are adaptive to the cell or targeting the cell itself e.

Knowing which genetic elements are being targeted in nature will require a better mechanistic understanding of the defense systems and the ecological contexts where they are selected for. Acquisition of defense systems requires HGT, but defense systems are expected to decrease the rates of transfer of MGEs, and thus decrease HGT.

Gene flow, including allelic recombination and acquisition of novel genes by HGT, is a key driver of bacterial evolution, and there is an evolutionary cost to restricting it.

For example, epidemic Vibrio cholerae strains depend on a prophage for a key virulence factor the cholera toxin. When they are infected by SXT-like conjugative elements carrying defense systems, they are hampered in their ability to acquire the toxin [ 13 ].

More generally, a computational analysis of approximately 80 species showed that gene flow is decreased between strains with incompatible R—M systems [ 85 ].

As a result, defense systems have the potential to fragment gene flow within bacterial populations. When a population has a single R—M system left , HGT between cells is not affected by restriction.

As the diversity of systems increases phylogenetic tree at the center , the subpopulations of individuals with similar R—M systems exchange genes at higher rates high flow than those with different R—M systems low gene flow, right top , leading to fragmentation of gene flow in populations right bottom.

HGT, horizontal gene transfer; R—M, restriction—modification. The presence of mechanisms of defense may impact gene flow in diverse ways. The negative impact of defense systems on gene flow has been regarded as a costly by-product of selection for protection of the cell.

But MGE defense systems may be selected exactly because they block HGT to prevent the cell from acquiring competitor MGEs. The resulting sexual barriers are advantageous for the MGE but can be deleterious to the cell.

Yet, these barriers are not unbreakable. The presence of multiple MGEs in genomes is in itself an indication of this. Accordingly, R—M systems only provide transient protection from phages [ 88 ], because one single successful infection is enough to result in correctly methylated phages that can pass the restriction barrier and then propagate across the population.

Further work is needed to quantify the impact of different defense systems in gene flow, to identify the types of MGEs that are most affected, and to understand how defenses affect host evolvability.

The effect of defense systems on gene flow is not always negative. In this case, the defense system facilitates gene flow. While many systems have been called defensive relative to their ability to defend bacteria or MGEs from other MGEs, they may be addictive or attack systems when part of MGEs. A striking example is provided by phage—satellite interactions.

The reproduction of virulent phages of the ICP1 family in V. cholerae is abolished by phage-inducible chromosomal island-like elements PLEs [ 18 ]. In this context, they could be regarded as attack systems from the point of view of the bacterium, because their success results in cell death.

They could also be regarded as phage counter-defenses, if satellites are considered as a bacterial defense system. There is thus some ambiguity between functions of defense, counter-defense, and attack, depending on the perspective of the observer.

Some systems may have multiple roles specifically when encoded in MGEs. R—M systems contribute to the stabilization of plasmids in the cell by acting as poison—antidote addictive systems [ 91 ]. In such cases, loss of the plasmid and its R—M system prevents further expression of the latter.

Since endonucleases have longer half-lives than methylases, this eventually results in genomes that are restricted because they are insufficiently methylated.

R—Ms are thus part of the attack arsenal of plasmids. Yet, these R—M systems can also protect the consortium cell and plasmid from infection by other MGEs, thereby acting as cell defense systems. Plasmids also frequently encode toxin—antitoxin systems that behave as addiction systems [ 92 ], some of which are implicated in phage defense.

Homologues of cell defense systems encoded in MGEs can thus be addiction tools with positive side effects in cellular defense. It is possible that such systems have started as genetic elements that propagate selfishly in genomes because of their addictive properties and have later been co-opted to become defense systems although the inverse scenario cannot be excluded at this stage.

It was observed a decade ago that defense systems are often clustered in a few loci in microbial chromosomes [ 93 ]. This characteristic was leveraged into a systematic method to discover novel systems by colocalization with known ones [ 23 ].

The clustering of these systems could result from selection for the coregulation of their expression, but there is very little evidence of that. The presence of defense systems in MGEs provides a simple explanation for the colocalization of defense and counter-defense systems in a few locations of the bacterial chromosome Fig 4.

Genes acquired by HGT, and MGEs in particular, tend to integrate at a small number of chromosome hotspots [ 95 — 98 ], and some of these were found to have defense systems over a decade ago [ 51 ].

These MGEs may degenerate by the accumulation of mutations, deletions, and insertions. Chromosome hotspots are thus littered with remnants of previous events of transfer.

As MGEs are integrated and eventually degrade in the hotspot, some genes may remain functional because they are adaptive for the cell [ 74 ]. Since MGEs often carry defense and antidefense systems, their rapid turnover in hotspots may be accompanied by selection for the conservation of some of their defense systems.

Ultimately, this could result in their co-option by the host cell. MGEs tend to integrate the chromosome at a few hotspots and may subsequently be inactivated by mutations resulting in the loss of genes that are not adaptive to the host. The clustering of defense systems may facilitate the evolution of functional interactions between them or the coregulation of their expression.

These systems are often colocalized [ 53 ]. Even if advantages of their colocalization in the genome are yet unclear, it may facilitate cotranscription or coevolution of the systems. The clustering of these systems in islands could also facilitate their subsequent transfer as a block by HGT to other cells.

This could occur by mechanisms able to transfer large genetic loci such as conjugation starting a conjugative element integrated in the chromosome or lateral transduction starting from a neighboring phage [ 47 ]. MGEs of bacteria and archaea encode accessory functions of adaptive value for the host.

That many of these accessory functions concern systems facilitating host infection or MGE protection from other elements testifies to the importance of such interactions for the fitness of MGEs. These defense systems may also be adaptive to the host, but this should not be taken for granted.

Having this conceptual framework in mind can aid the field move forward along the following lines. Their study will shed novel light on the function, evolution, and ecology of microbes. The authors thank Aude Bernheim, Frédérique Le Roux, and Maria Pilar Garcillan Barcia for comments and suggestions and Marie Touchon for discussions and graphical elements for the figures.

Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Prokaryotes have numerous mobile genetic elements MGEs that mediate horizontal gene transfer HGT between cells. Introduction: Mobile genetic elements drive gene flow at a sometimes hefty cost Horizontal gene transfer HGT allows bacteria and archaea to rapidly match novel ecological challenges and opportunities.

Box 1. Defense islands : chromosomal loci with high density of defense systems. Phages : bacterial viruses. Download: PPT. Why are there so many defense systems in each genome?

Why are defense systems very diverse within species? How is immunity gained? Defending whom from what? How do defense systems affect gene flow? Fig 3. Diversification of R—M systems changes gene flow within species. Is it defense, counter-defense, addiction, or something else?

Background Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. In case sytem Microbial defense system. The colours Non-GMO condiments the CRISPR-cas subtype. Tesson, F. It degrades linear double-stranded DNA until it meets a Chi site beyond which it loads the recombinase RecA. Systematic discovery of anti-phage defense systems in the microbial pan-genome.
Diversity of microbial defence systems | Nature Reviews Microbiology

This raises intriguing questions concerning the role, function, and evolution of the so-called cellular defense systems Fig 2. Defense and antidefense systems are often studied in the context of the interaction between one host and one MGE, usually a virulent phage left.

Yet, the presence of numerous MGEs in populations and their ability to encode their own defense systems renders the picture more complex right. Virulent phages establish antagonistic interactions with the other MGEs and the cell 1. But the associations between the other MGEs and the cell can be more diverse 2 to 7.

Temperate phages and conjugative plasmids exploit their cellular host 2 and 4 and can be exploited by other MGEs 3 and 5. Plasmids often encode systems that are effective barriers to phages, e. Phages are a threat to plasmids when they kill the host cell 6.

Satellites may benefit the host by diminishing phage infection 7. Most of these interactions 2 to 8 can at times be beneficial to both partners, e.

MGE, mobile genetic element. For example, the first 2 sequenced genomes of Helicobacter pylori encode a total of more than 20 putative R—M systems [ 52 ], and genomes with multiple CRISPR arrays and Cas systems are frequent [ 53 ]. The fast pace of discovery of novel defense and counter-defense systems suggests that they may account for a significant number of the unknown function genes in genomes.

It could also facilitate building up multiple layers of cell defenses that may culminate in cell death when all else fails [ 27 ]. In this view, cell defense systems are numerous because they make a multilayered immune system to tackle different elements. Yet, defense systems can be costly [ 54 ], because of production costs when they are required at high concentration [ 55 ], because their activity can be energetically costly [ 56 ], or because they may be incompatible with other cellular mechanisms [ 57 ].

They can also kill the cell by autoimmunity [ 58 ]. Hence, the number of systems under selection for defense by the host cell is expected to depend on the balance between these costs and the rewards given by their ability to protect hosts from MGEs.

The observations that genomes have many MGEs and that these encode many defense systems provide an alternative or complementary explanation for why genomes contain so many such systems. Genomes contain many defense systems because they are acquired within the multiple MGEs that infect microbial cells.

Since there are many MGEs in a cell, these sum up to a considerable number of defense genes. Such MGE-encoded defenses may also be multilayered. For example, E. coli plasmids encoding both BREX and type IV restriction systems have recently been shown to provide complementary protection from phages [ 59 ].

This does not exclude the possibility that cells select for multiple systems of defense, but does suggest that to understand their frequency in cells one must also account for the infectivity of MGEs.

This means that the multiplicity of systems in cellular genomes might be a consequence of the high transmissibility and abundance of MGEs, not only the result of natural selection for protection of the cell.

It is therefore possible that cells encode more defense systems than the theoretical optimal number expected for a host cell, simply because many of the systems are selected for their presence in the MGE, not in the host.

Defense systems tend to be different across strains of a species [ 21 , 51 ] and are a significant part of the genetic differences between closely related strains of Vibrio spp. Why are defense systems so different among strains of a species?

The coevolutionary dynamics between defenses and counter-defenses contributes to an endless process of genetic diversification that is often understood in the context of balancing selection [ 60 ]. These are processes where natural selection favors the existence of genetic polymorphism.

Interestingly, balancing selection resulting in the presence of diverse defense systems in populations is observed in many immune systems, from bacteria to humans [ 61 ].

Balancing selection can occur by multiple mechanisms. First, it is harder for a parasite to spread in a population with diverse host defenses even in simple systems [ 62 ]. The presence of various systems providing immunity from MGEs within microbial populations increases the likelihood that some individuals are protected, in what has been described as distributed pan immunity [ 26 ].

Relative to microbial genomes, MGEs are more constrained in the number of genes they can carry, especially those packaged in viral particles. Yet, some also carry multiple defense systems [ 8 , 13 , 38 , 44 ], which may allow them to infect different hosts or fend off different MGEs.

Second, variations in time and space of the density, type, and behavior of MGEs may favor different cellular defense systems in different situations. The distribution of MGEs varies across bacterial habitats [ 64 ] and across environmental conditions within habitats [ 65 ].

Hence, locally adapted microbial populations may select for different systems that tackle different types of MGEs resulting in variable defense repertoires across a bacterial species. This is also applicable to defense systems encoded in MGEs.

Their defense systems can be under balancing selection because the hosts and MGEs they encounter vary in space and time. Third, clones that are more abundant in a habitat are more susceptible to phages, because of their density [ 66 ].

In this context, negative frequency—dependent selection may result in selection of rare alleles [ 67 ], i. As the population of individuals with the rare adaptive defense increases, antagonists with the ability to infect it also rise in frequency because they have more hosts available.

This decreases the advantage of the initial clone and eventually cancels it when novel rare clones resistant to the MGEs emerge, thereby restarting the process of negative frequency—dependent selection.

While negative frequency dependence in host—pathogen interactions has been extensively studied [ 61 ], there is a paucity of data on its role in MGE—host interactions. What are the molecular mechanisms driving the variation of bacterial defenses?

Some systems have dedicated molecular mechanisms for their own variation. Some R—M systems can also rapidly change their sequence specificity through recombination [ 68 ].

Yet, the available evidence suggests that HGT and gene loss have major complementary roles in the diversification of defense repertoires at the species level. The abundance of defense systems in MGEs suggests a very straightforward mechanism for the acquisitions of defense systems by the host: Systems are transferred across strains by the MGEs encoding them.

Furthermore, MGEs are gained at high rates because of their infectiousness explaining acquisition , and they are frequently lost from populations because of their cost explaining loss.

The rates of gain and loss of defense systems may thus be partly caused by the mobility and lability of the mobile elements encoding them. Beyond explaining the acquisition of novel systems, the presence of defense systems in MGEs also offers some clues on how entirely novel defense strategies emerge.

The recent discovery of many antiphage systems shows that they frequently consist in an assemblage of protein domains that are also present in proteins implicated in other cellular processes such as nucleases, kinases, deaminases, proteases, or ATPases [ 71 ]. For instance, the Stk2 defense kinase is part of a family of kinases whose members are implicated in various cellular process such as the control of the cell cycle or the exit of dormancy [ 72 ].

The antiphage viperins are close homologues to GTP cyclases involved in other functions [ 73 ]. The co-option of proteins, or protein domains, with other functions, and the creation of novel assemblages leading to genetic innovation by recombination and mutation are likely facilitated by the horizontal transfer of defense systems across genetic backgrounds [ 74 ].

While successful functional innovations by co-option of these systems may be unlikely, the very frequent transfer of systems and their rapid evolution may result in such a high rate of novel combinations of domains that some will eventually evolve to become novel defense systems.

Such processes of co-option may have been at the independent origins of both Cas-9 and Cas proteins from transposon-encoded RNA-guided endonucleases [ 75 , 76 ]. Novel defense systems, even if initially not part of MGEs, will eventually be captured by MGEs for their own use, with the consequence that they will be spread across microbial lineages.

Transposases may play key roles in the process of translocating these systems from the chromosome to MGEs and vice versa. The subsequent transfer of defense systems to different genetic backgrounds is expected to favor the spread of defense systems that are robust to such changes.

Accordingly, there is a broad distribution of most defense systems across the bacterial kingdom [ 35 ]. It is also interesting to note the surprisingly broad activity of some defense systems recently described [ 23 ].

Cloning these genetic systems from distant species into E. coli and Bacillus subtilis yields defense phenotypes. The presence of defense systems on MGE that move across species might thus favor broad defense capabilities and mechanisms tolerant to changes in the genetic background.

The rapid pace of discovery of novel defense systems has been facilitated by the use of assays where cells are challenged by virulent phages. As a result, the role of defense systems tends to be discussed in the light of phage—bacteria interactions.

It does seem reasonable to assume that systems present in a microbial genome for a long time are protecting it from MGEs and especially against virulent phages given their lethality for the cell.

Yet, systems encoded in MGEs are more likely to be selected because they benefit the MGE. In certain cases, a system increases the fitness of both MGE and host. For example, defense systems encoded in P4-like satellites were shown experimentally to protect the cell from several phages that the P4 element cannot exploit [ 38 ].

In this case, the satellite and the cell have the same interest in preventing infection by phages that can kill the cell. In general, both MGEs and hosts will gain from preventing infection by virulent phages, explaining why MGEs defenses seem to target them frequently.

The interests of the MGE and the cell may not be so well aligned in other circumstances. In some cases, the advantage of the MGE defense system to the cell may be transient. Temperate phages that defend the cells from virulent phages are common [ 8 , 43 , 77 ] and provide a temporary relief to the host.

But they may have little long-term impact in bacterial fitness if the victorious temperate phage is induced and lyses the cell. This is also exemplified by the exclusion systems encoded by conjugative systems or phages to fend off closely related elements [ 78 , 79 ].

Historically, these mechanisms have not been included in defense systems, but they are costly mechanisms that protect the cell from infection by MGEs, i. For example, the surface exclusion system of plasmid F prevents infection by similar plasmids thanks to the production of thousands of copies of an outer membrane protein that accounts for a large part of the plasmid carrier cost [ 80 ].

An even more extreme case concerns phages encoding defense or antidefense systems against their satellites. These are engaging in an interaction with their parasites in a way that resembles their own interaction with the cell but with their own position reversed as they are now the ones being exploited [ 47 ].

Such phage-encoded defense systems could be highly deleterious to the cell because they remove a protective satellite and favor a phage that will eventually kill the host. The misalignment of interests between MGEs and the host is particularly striking when it concerns abortive infection systems, because these are extremely costly to the cell [ 27 ].

The traditional view is that such strategies can only be selected in very particular cases favoring cooperation between individuals, e. A recent investigation of abortive infection provided by retron elements suggests that retron-encoding bacteria lose in competition with bacteria lacking the retron when challenged by a phage even in a structured environment [ 82 ].

Yet, genomic data suggest that abortive infection systems are very frequent [ 35 ], which requires an explanation. The presence of abortive infection systems on MGEs could facilitate the control of epidemics of competitive elements and would justify their abundance in the host.

Such systems could be deleterious to the host if they drive cell death upon infection by elements with little negative impact on its fitness. But in other circumstances, the presence of these systems in MGEs could benefit the host by enforcing cooperation [ 83 ], since the transfer of the MGEs to sensitive hosts spreads the abortive system and therefore favors the cooperative process.

To understand the fitness impact of defense systems, it is thus important to know if they are encoded in MGEs. The identification of functional MGEs is difficult both computationally and experimentally, since many MGEs are poorly known and many of the others are defective [ 74 ].

It is often even more difficult to predict which genetic elements are being targeted by the defense system. That many systems are effective against virulent phages may be in part the result of ascertainment biases, since virulent phages are often used to identify defense systems.

One might also argue that virulent phages are going to be targeted by hosts and most MGEs because they kill the host and its MGEs. However, many systems, among which all those using epigenetic markers like R—M, target generic exogenous DNA independently of it being part of a phage genome.

This makes it particularly hard to know who they were selected to target. The analysis of the spacer content can thus inform on the selection pressure that maintain CRISPR immunity. These results suggest that systems encoded in MGEs may be targeting other competing MGE that are not costly to the cell.

They may even be targeting elements that are adaptive to the cell or targeting the cell itself e. Knowing which genetic elements are being targeted in nature will require a better mechanistic understanding of the defense systems and the ecological contexts where they are selected for.

Acquisition of defense systems requires HGT, but defense systems are expected to decrease the rates of transfer of MGEs, and thus decrease HGT. Gene flow, including allelic recombination and acquisition of novel genes by HGT, is a key driver of bacterial evolution, and there is an evolutionary cost to restricting it.

For example, epidemic Vibrio cholerae strains depend on a prophage for a key virulence factor the cholera toxin. When they are infected by SXT-like conjugative elements carrying defense systems, they are hampered in their ability to acquire the toxin [ 13 ]. More generally, a computational analysis of approximately 80 species showed that gene flow is decreased between strains with incompatible R—M systems [ 85 ].

As a result, defense systems have the potential to fragment gene flow within bacterial populations. When a population has a single R—M system left , HGT between cells is not affected by restriction. As the diversity of systems increases phylogenetic tree at the center , the subpopulations of individuals with similar R—M systems exchange genes at higher rates high flow than those with different R—M systems low gene flow, right top , leading to fragmentation of gene flow in populations right bottom.

HGT, horizontal gene transfer; R—M, restriction—modification. The presence of mechanisms of defense may impact gene flow in diverse ways. The negative impact of defense systems on gene flow has been regarded as a costly by-product of selection for protection of the cell.

But MGE defense systems may be selected exactly because they block HGT to prevent the cell from acquiring competitor MGEs. The resulting sexual barriers are advantageous for the MGE but can be deleterious to the cell.

Yet, these barriers are not unbreakable. The presence of multiple MGEs in genomes is in itself an indication of this. Accordingly, R—M systems only provide transient protection from phages [ 88 ], because one single successful infection is enough to result in correctly methylated phages that can pass the restriction barrier and then propagate across the population.

Further work is needed to quantify the impact of different defense systems in gene flow, to identify the types of MGEs that are most affected, and to understand how defenses affect host evolvability.

The effect of defense systems on gene flow is not always negative. In this case, the defense system facilitates gene flow. While many systems have been called defensive relative to their ability to defend bacteria or MGEs from other MGEs, they may be addictive or attack systems when part of MGEs.

A striking example is provided by phage—satellite interactions. The reproduction of virulent phages of the ICP1 family in V. cholerae is abolished by phage-inducible chromosomal island-like elements PLEs [ 18 ]. In this context, they could be regarded as attack systems from the point of view of the bacterium, because their success results in cell death.

They could also be regarded as phage counter-defenses, if satellites are considered as a bacterial defense system. There is thus some ambiguity between functions of defense, counter-defense, and attack, depending on the perspective of the observer.

Some systems may have multiple roles specifically when encoded in MGEs. R—M systems contribute to the stabilization of plasmids in the cell by acting as poison—antidote addictive systems [ 91 ].

In such cases, loss of the plasmid and its R—M system prevents further expression of the latter. Since endonucleases have longer half-lives than methylases, this eventually results in genomes that are restricted because they are insufficiently methylated.

R—Ms are thus part of the attack arsenal of plasmids. Yet, these R—M systems can also protect the consortium cell and plasmid from infection by other MGEs, thereby acting as cell defense systems.

Plasmids also frequently encode toxin—antitoxin systems that behave as addiction systems [ 92 ], some of which are implicated in phage defense. Homologues of cell defense systems encoded in MGEs can thus be addiction tools with positive side effects in cellular defense.

It is possible that such systems have started as genetic elements that propagate selfishly in genomes because of their addictive properties and have later been co-opted to become defense systems although the inverse scenario cannot be excluded at this stage. It was observed a decade ago that defense systems are often clustered in a few loci in microbial chromosomes [ 93 ].

This characteristic was leveraged into a systematic method to discover novel systems by colocalization with known ones [ 23 ]. The clustering of these systems could result from selection for the coregulation of their expression, but there is very little evidence of that. The presence of defense systems in MGEs provides a simple explanation for the colocalization of defense and counter-defense systems in a few locations of the bacterial chromosome Fig 4.

Genes acquired by HGT, and MGEs in particular, tend to integrate at a small number of chromosome hotspots [ 95 — 98 ], and some of these were found to have defense systems over a decade ago [ 51 ]. These MGEs may degenerate by the accumulation of mutations, deletions, and insertions.

Chromosome hotspots are thus littered with remnants of previous events of transfer. As MGEs are integrated and eventually degrade in the hotspot, some genes may remain functional because they are adaptive for the cell [ 74 ]. Since MGEs often carry defense and antidefense systems, their rapid turnover in hotspots may be accompanied by selection for the conservation of some of their defense systems.

Ultimately, this could result in their co-option by the host cell. MGEs tend to integrate the chromosome at a few hotspots and may subsequently be inactivated by mutations resulting in the loss of genes that are not adaptive to the host. The clustering of defense systems may facilitate the evolution of functional interactions between them or the coregulation of their expression.

These systems are often colocalized [ 53 ]. Even if advantages of their colocalization in the genome are yet unclear, it may facilitate cotranscription or coevolution of the systems.

The clustering of these systems in islands could also facilitate their subsequent transfer as a block by HGT to other cells. This could occur by mechanisms able to transfer large genetic loci such as conjugation starting a conjugative element integrated in the chromosome or lateral transduction starting from a neighboring phage [ 47 ].

MGEs of bacteria and archaea encode accessory functions of adaptive value for the host. That many of these accessory functions concern systems facilitating host infection or MGE protection from other elements testifies to the importance of such interactions for the fitness of MGEs.

These defense systems may also be adaptive to the host, but this should not be taken for granted. Having this conceptual framework in mind can aid the field move forward along the following lines.

Their study will shed novel light on the function, evolution, and ecology of microbes. The authors thank Aude Bernheim, Frédérique Le Roux, and Maria Pilar Garcillan Barcia for comments and suggestions and Marie Touchon for discussions and graphical elements for the figures.

Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Prokaryotes have numerous mobile genetic elements MGEs that mediate horizontal gene transfer HGT between cells. Introduction: Mobile genetic elements drive gene flow at a sometimes hefty cost Horizontal gene transfer HGT allows bacteria and archaea to rapidly match novel ecological challenges and opportunities.

Box 1. Defense islands : chromosomal loci with high density of defense systems. Phages : bacterial viruses. Download: PPT. Why are there so many defense systems in each genome? Why are defense systems very diverse within species? How is immunity gained?

Defending whom from what? How do defense systems affect gene flow? Fig 3. Diversification of R—M systems changes gene flow within species. Is it defense, counter-defense, addiction, or something else?

Fig 4. MGE turnover at hotspots may result in defense islands. Outlook MGEs of bacteria and archaea encode accessory functions of adaptive value for the host. Many defense systems are poorly known and probably many more remain to be uncovered. The recent expansion in the number and type of defense systems occurred because researchers searched for novel systems colocalizing with previously known ones.

Many novel systems may be awaiting discovery among the countless MGEs present across microbial genomes. Since these genes are often found at specific locations in MGEs, e. Most of the studies on the mechanisms of defense systems use virulent phages as targets.

Yet, systems encoded by MGEs may target different elements and having this information may result in the discovery of novel molecular mechanisms, especially among systems targeting specific MGE functions. Recent works have revealed defense systems targeting specific molecular mechanisms of phages [ 73 , ].

Maybe other defense systems target mechanisms of conjugative elements or other MGEs. Counter-defense mechanisms are now being identified for the best-known mechanisms of defense.

Integrating the knowledge of the existence of mechanism of defense in an element, its molecular mechanism, and the elements being targeted could provide important clues on where to find novel antidefense systems from known or novel defense systems.

As defense systems provide multiple layers of defense against MGEs, it is important to understand what these layers are and how they interact. Ultimately, immune systems of bacteria might rely on complex networks of functional and genetic interactions between defense systems that provide a robust and thorough response to most parasites.

These networks may resemble those of the eukaryotic immune system. These evolutionary mechanisms may also share similarities across the tree of life, since some regulatory elements or components of the immune system of vertebrates and plants also derive from co-options of MGEs [ , ].

Balancing selection seems to explain the evolutionary patterns of defense systems in bacteria, plants and animals [ 60 ]. Yet, one must keep in mind that a lot of the variation in the bacterial immune response is associated with rapid gain and loss of defense systems, many of which in MGEs, which is different from the processes driving the diversification of immune systems of vertebrates.

Knowing the mechanisms of defense systems carried by a specific MGE can hint at their possible targets and therefore reveal the MGEs or host affected by the element. This can be leveraged to map antagonistic interactions between MGEs.

Virulence factors and antimicrobial resistance genes are frequently carried by MGEs. A better understanding of the defense, addiction, or attack systems that these elements employ to ensure their propagation might lead to the identification of novel strategies to counteract the spread of these costly elements, for instance, by favoring competing harmless MGEs.

The presence of antiphage systems on MGEs could also promote the rapid evolution of resistance to phage therapies, and conversely, the identification of counter-defenses deployed by phages and other MGEs might provide solutions for the selection or engineering of more potent therapeutic phages.

Acknowledgments The authors thank Aude Bernheim, Frédérique Le Roux, and Maria Pilar Garcillan Barcia for comments and suggestions and Marie Touchon for discussions and graphical elements for the figures.

References 1. Taylor VL, Fitzpatrick AD, Islam Z, Maxwell KL. The diverse impacts of phage morons on bacterial fitness and virulence. Adv Virus Res.

Bennett P. Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria. Br J Pharmacol. Baltrus DA. Exploring the costs of horizontal gene transfer. Trends Ecol Evol.

Croucher NJ, Mostowy R, Wymant C, Turner P, Bentley SD, Fraser C. Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict. PLoS Biol. Touchon M, Rocha EP. Causes of insertion sequences abundance in prokaryotic genomes.

Mol Biol Evol. De Toro M, Garcillán-Barcia MP, De La Cruz F. Plasmid diversity and adaptation analyzed by massive sequencing of Escherichia coli plasmids.

Microbiol Spectr. Bobay LM, Touchon M, Rocha EPC. Pervasive domestication of defective prophages by bacteria. Proc Natl Acad Sci U S A. Hussain FA, Dubert J, Elsherbini J, Murphy M, VanInsberghe D, Arevalo P, et al. Rapid evolutionary turnover of mobile genetic elements drives bacterial resistance to phages.

Penadés JR, Christie GE. The phage-inducible chromosomal islands: a family of highly evolved molecular parasites.

AnnuRev Virol. Smillie C, Pilar Garcillan-Barcia M, Victoria Francia M, Rocha EPC, de la Cruz F. Mobility of Plasmids. Microbiol Mol Biol Rev. Gama JA, Zilhão R, Dionisio F.

Harb L, Chamakura K, Khara P, Christie PJ, Young R, Zeng L. ssRNA phage penetration triggers detachment of the F-pilus. LeGault K, Hays SG, Angermeyer A, McKitterick AC, Johura F-t, Sultana M, et al.

Temporal shifts in antibiotic resistance elements govern virus-pathogen conflicts. Baharoglu Z, Bikard D, Mazel D. Conjugative DNA transfer induces the bacterial SOS response and promotes antibiotic resistance development through integron activation. PLoS Genet. He S, Chandler M, Varani AM, Hickman AB, Dekker JP, Dyda F.

Mechanisms of evolution in high-consequence drug resistance plasmids. Wagner PL, Waldor MK. Bacteriophage control of bacterial virulence. Infect Immun. Paul JH. Prophages in marine bacteria: dangerous molecular time bombs or the key to survival in the seas?

ISME J. Seed KD, Lazinski DW, Calderwood SB, Camilli A. Touchon M, Bernheim A, Rocha EP. Genetic and life-history traits associated with the distribution of prophages in bacteria.

Wigington CH, Sonderegger D, Brussaard CPD, Buchan A, Finke JF, Fuhrman JA, et al. Re-examination of the relationship between marine virus and microbial cell abundances. Nat Microbiol. van Houte S, Buckling A, Westra ER.

Evolutionary ecology of prokaryotic immune mechanisms. Hampton HG, Watson BN, Fineran PC. The arms race between bacteria and their phage foes.

Doron S, Melamed S, Ofir G, Leavitt A, Lopatina A, Keren M, et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Gao L, Altae-Tran H, Böhning F, Makarova KS, Segel M, Schmid-Burgk JL, et al. Diverse enzymatic activities mediate antiviral immunity in prokaryotes.

González-Delgado A, Mestre MR, Martínez-Abarca F, Toro N. Prokaryotic reverse transcriptases: from retroelements to specialized defense systems. FEMS Microbiol Rev. Bernheim A, Sorek R. The pan-immune system of bacteria: antiviral defence as a community resource.

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Enter keywords to search for news articles: Submit. Browse By. Breadcrumb MIT News MIT scientists discover new antiviral defense system in bacteria. MIT scientists discover new antiviral defense system in bacteria.

Prokaryotes can detect hallmark viral proteins and trigger cell death through a process seen across all domains of life. Leah Eisenstadt Broad Institute. Publication Date :.

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The study appears in Science. Structural analysis For a detailed look at how the microbial STAND ATPases detect the viral proteins, the researchers used cryo-electron microscopy to examine their molecular structure when bound to the viral proteins.

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The highly diverse antiphage defence systems of bacteria

At the genus level, the defence systems also exhibited patchy distribution Supplementary Figure S6 , indicative of horizontal transfer, congruent with the function of these systems as phage defences.

To determine whether the new Doron system subtypes were divergent from those of the archetypal systems, we analysed the sequence similarity of their core components i.

the proteins present in both the new and canonical types Supplementary Figure S7, Table S4. In most cases, the core components of the new subtypes were divergent from those of the canonical systems, being present in the same or closely related clans.

This sequence divergence could correlate with the acquisition of the additional gene s followed by subsequent functional specialisation, although this remains to be determined. Overall, each new defence system subtype exhibited typical defence system characteristics including conserved operon-like genetic architecture, presence in diverse genetic contexts and distribution across distantly related organisms.

Abundance of defence systems identified with PADLOC in bacteria and archaea. All genomes from RefSeq v Archaea and Bacteria were searched with PADLOC. The values in the boxes represent, for each phylum, the average percentage of genomes in each species encoding a system, grouped using GTDB taxonomy 44 ; system prevalence is weighted in this way to limit biases in phyla that contain many closely related genomes of the same species.

The colouring in each box provides a visual representation of these values. Shown are phyla with more than five genomes and at least one type of system. A species-level comparison is provided in Supplementary Figure S6 and the full data are provided in Supplementary Table S5.

Many diverse defence systems have evolved in bacteria and archaea to defend against phages and other MGEs 1. Recently, there has been a surge in the discovery of new types of phage defence systems. However, the systematic identification and annotation of defence systems remains a challenge for biologists interested in searching the genome of their organism of interest.

To address the lack in capability of current tools to identify newly discovered types of phage defence systems, we developed PADLOC. When benchmarked against the genomes searched by Doron et al. This demonstrates that PADLOC can identify multi-gene defence systems with high accuracy and specificity.

One limitation of PADLOC is that, due to the constraint of genetic synteny, defence systems that are split by breaks in contigs will not be detected. However, this is an important trade-off in reducing false positives, firstly because HMMs detect proteins with greater sensitivity than traditional BLAST methods 38 and secondly because defence system proteins often comprise domains that are ubiquitous in other molecular systems.

yaml files that require only two defence genes to be present and co-localised. The raw HMMER outputs can also be inspected, allowing users to identify potential orphan defence genes or highly divergent homologues.

Using PADLOC, we identified several clusters of Doron system genes that had strong associations with additional proteins. Based on these associations, we propose new types of Druantia, Hachiman, Lamassu, Septu, Thoeris, and Zorya systems. Septu type II was recently discovered independently and classified as a Type I-A bacterial retron 14 , 57 , Members of the Type I-A retrons include Ec73 from E.

coli and Vc95 from Vibrio cholerae , which provide defence against phages 14 , Our detection of Septu type II demonstrates the capability of our approach for identification of variant defence systems. ZorA and ZorB from Zorya systems share sequence similarity with the inner membrane flagella motor proteins MotA and MotB, respectively However, ZorAB are not sufficient for defence and it has been proposed that a ZorAB complex forms a proton channel that facilitates abortive infection, whereas ZorC, ZorD, and ZorE perform additional essential roles as phage sensors or activators of ZorAB Since our data demonstrate activity of the Zorya type III system comprised of ZorA, ZorB, ZorF and ZorG, we propose that ZorF and ZorG function are regulators of ZorAB activity in place of ZorC, ZorD and ZorE.

From the other new system types we identified, DruL, HamC, and LmuC comprise domains of unknown function. An NMR structure for the HamC protein of Rhodospirillum rubrum ATCC has been solved PDB ID: 2K0M; DOI: However, the function of HamC in phage defence remains unknown.

Altogether, the data presented here extend the spectrum of potential defence systems and provide a foundation for further experimental study of their mechanisms. The discovery of new defence systems is progressing rapidly, and importantly PADLOC can be updated to incorporate these systems as they are characterised.

Using our modular approach to the organisation of HMMs and system classifications, defence systems can be easily added or updated as required.

For greater accessibility, we have also developed a PADLOC webserver that allows users to analyse their genomes of choice or browse a pre-computed database of defence systems identified in RefSeq genomes.

PADLOC is an open-source project, with code, HMMs, and system classifications available on GitHub. Additional curation of high quality HMMs for additional defence systems will be required to establish PADLOC as a comprehensive resource for defence system identification.

We encourage the community to submit new defence system data for addition to the PADLOC database. Supplementary Data are available at NAR Online. We thank Chris Palmer Department of Mathematics and Statistics, University of Otago and members of the Information Technology Services Division at the University of Otago for assistance in establishing the PADLOC webserver.

We thank members of the Fineran laboratory for helpful discussions. We acknowledge the use of the New Zealand eScience Infastructure NeSI high-performance computing facilities in this research. Royal Society of New Zealand Te Apārangi RSNZ Marsden Fund; School of Biomedical Sciences Bequest Fund from the University of Otago; L.

was supported by a University of Otago Doctoral Scholarship. Funding for open access charge: Laboratory research funding. Hampton H. The arms race between bacteria and their phage foes.

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Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. MATERIALS AND METHODS. Journal Article. Identification and classification of antiviral defence systems in bacteria and archaea with PADLOC reveals new system types.

Leighton J Payne , Leighton J Payne. Department of Microbiology and Immunology, University of Otago. Oxford Academic. Thomas C Todeschini. School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton.

Yi Wu. Benjamin J Perry. Clive W Ronson. Peter C Fineran. Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago. Franklin L Nobrega. Simon A Jackson. To whom correspondence should be addressed.

jackson otago. Revision received:. PDF Split View Views. Select Format Select format. ris Mendeley, Papers, Zotero.

How is immunity gained? Defending whom from what? How do defense systems affect gene flow? Fig 3. Diversification of R—M systems changes gene flow within species. Is it defense, counter-defense, addiction, or something else? Fig 4. MGE turnover at hotspots may result in defense islands.

Outlook MGEs of bacteria and archaea encode accessory functions of adaptive value for the host. Many defense systems are poorly known and probably many more remain to be uncovered.

The recent expansion in the number and type of defense systems occurred because researchers searched for novel systems colocalizing with previously known ones. Many novel systems may be awaiting discovery among the countless MGEs present across microbial genomes.

Since these genes are often found at specific locations in MGEs, e. Most of the studies on the mechanisms of defense systems use virulent phages as targets.

Yet, systems encoded by MGEs may target different elements and having this information may result in the discovery of novel molecular mechanisms, especially among systems targeting specific MGE functions. Recent works have revealed defense systems targeting specific molecular mechanisms of phages [ 73 , ].

Maybe other defense systems target mechanisms of conjugative elements or other MGEs. Counter-defense mechanisms are now being identified for the best-known mechanisms of defense. Integrating the knowledge of the existence of mechanism of defense in an element, its molecular mechanism, and the elements being targeted could provide important clues on where to find novel antidefense systems from known or novel defense systems.

As defense systems provide multiple layers of defense against MGEs, it is important to understand what these layers are and how they interact. Ultimately, immune systems of bacteria might rely on complex networks of functional and genetic interactions between defense systems that provide a robust and thorough response to most parasites.

These networks may resemble those of the eukaryotic immune system. These evolutionary mechanisms may also share similarities across the tree of life, since some regulatory elements or components of the immune system of vertebrates and plants also derive from co-options of MGEs [ , ].

Balancing selection seems to explain the evolutionary patterns of defense systems in bacteria, plants and animals [ 60 ]. Yet, one must keep in mind that a lot of the variation in the bacterial immune response is associated with rapid gain and loss of defense systems, many of which in MGEs, which is different from the processes driving the diversification of immune systems of vertebrates.

Knowing the mechanisms of defense systems carried by a specific MGE can hint at their possible targets and therefore reveal the MGEs or host affected by the element. This can be leveraged to map antagonistic interactions between MGEs. Virulence factors and antimicrobial resistance genes are frequently carried by MGEs.

A better understanding of the defense, addiction, or attack systems that these elements employ to ensure their propagation might lead to the identification of novel strategies to counteract the spread of these costly elements, for instance, by favoring competing harmless MGEs.

The presence of antiphage systems on MGEs could also promote the rapid evolution of resistance to phage therapies, and conversely, the identification of counter-defenses deployed by phages and other MGEs might provide solutions for the selection or engineering of more potent therapeutic phages.

Acknowledgments The authors thank Aude Bernheim, Frédérique Le Roux, and Maria Pilar Garcillan Barcia for comments and suggestions and Marie Touchon for discussions and graphical elements for the figures. References 1.

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Microbial defense system To provide Microbjal against viral infection derense limit the uptake Defensw mobile genetic elements, bacteria and archaea have evolved Energy conservation techniques diverse Microbkal systems. The discovery Immune system modulation application of CRISPR-Cas adaptive immune systems eystem spurred recent interest in the sysetm and classification of MMicrobial types of defence systems. Many new Electrolyte balance challenges Microbiak have Electrolyte balance challenges anti-viral essential oils Microbial defense system but there is a lack of accessible tools available to identify homologs of these systems in different genomes. Here, we report the P rokaryotic A ntiviral D efence LOC ator PADLOCa flexible and scalable open-source tool for defence system identification. We show that PADLOC identifies defence systems with high accuracy and sensitivity. Our modular approach to organising the HMMs and system classifications allows additional defence systems to be easily integrated into the PADLOC database. To demonstrate application of PADLOC to biological questions, we used PADLOC to identify six new subtypes of known defence systems and a putative novel defence system comprised of a helicase, methylase and ATPase.

Author: Maukus

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