Bacterial Toxin–Antitoxin Systems: More Than Selfish Entities?

Bacterial toxin–antitoxin (TA) systems are diverse and widespread in the prokaryotic kingdom. They are composed of closely linked genes encoding a stable toxin that can harm the host cell and its cognate labile antitoxin, which protects the host from the toxin's deleterious effect. TA systems are thought to invade bacterial genomes through horizontal gene transfer. Some TA systems might behave as selfish elements and favour their own maintenance at the expense of their host. As a consequence, they may contribute to the maintenance of plasmids or genomic islands, such as super-integrons, by post-segregational killing of the cell that loses these genes and so suffers the stable toxin's destructive effect. The function of the chromosomally encoded TA systems is less clear and still open to debate. This Review discusses current hypotheses regarding the biological roles of these evolutionarily successful small operons. We consider the various selective forces that could drive the maintenance of TA systems in bacterial genomes

The relBE2Spn Toxin-Antitoxin System of Streptococcus pneumoniae: Role in Antibiotic Tolerance and Functional Conservation in Clinical Isolates

Type II (proteic) chromosomal toxin-antitoxin systems (TAS) are widespread in Bacteria and Archaea but their precise function is known only for a limited number of them. Out of the many TAS described, the relBE family is one of the most abundant, being present in the three first sequenced strains of Streptococcus pneumoniae (D39, TIGR4 and R6). To address the function of the pneumococcal relBE2Spn TAS in the bacterial physiology, we have compared the response of the R6-relBE2Spn wild type strain with that of an isogenic derivative, ΔrelB2Spn under different stress conditions such as carbon and amino acid starvation and antibiotic exposure. Differences on viability between the wild type and mutant strains were found only when treatment directly impaired protein synthesis. As a criterion for the permanence of this locus in a variety of clinical strains, we checked whether the relBE2Spn locus was conserved in around 100 pneumococcal strains, including clinical isolates and strains with known genomes. All strains, although having various types of polymorphisms at the vicinity of the TA region, contained a functional relBE2Spn locus and the type of its structure correlated with the multilocus sequence type. Functionality of this TAS was maintained even in cases where severe rearrangements around the relBE2Spn region were found. We conclude that even though the relBE2Spn TAS is not essential for pneumococcus, it may provide additional advantages to the bacteria for colonization and/or infection

ccd TA systems, are just selfish genes?

Les systèmes toxine-antitoxine (TA) sont très répandus au sein des génomes bactériens. Ces opérons bicistroniques de petite taille ont été découverts sur des plasmides à bas nombre de copies. Dans ce contexte génétique, les systèmes TA confèrent un avantage sélectif à leurs molécules-hôtes en tuant les bactéries-filles qui ne les ont pas héritées par le mécanisme de tuerie post-ségrégationnelle (PSK, post-segregational killing). Ces systèmes génétiques sont également appelés modules d’addiction étant donné qu’ils rendent la descendance des bactéries qui les contiennent dépendantes de leur présence. Alors que leur rôle dans les molécules d’ADN épisomiques est relativement bien établi, le sens biologique de la présence d’homologues à ces systèmes épisomiques au sein des chromosomes bactériens est sujet à d’intenses débats. L’idée que les systèmes TA chromosomiques confèrent un avantage sélectif a été mise en évidence dans plusieurs modèles. Selon ces modèles, les systèmes TA permettent aux bactéries de mieux faire face à des conditions environnementales stressantes. Entre-temps, la compréhension de l’évolution des génomes bactériens a connu des avancées significatives. L’impressionnante capacité d’adaptation des bactéries est aujourd’hui majoritairement attribuée au transfert horizontal de gènes (THG) provoqué par les éléments génétiques mobiles (phages, plasmides, transposons…). Dans le débat du rôle des systèmes TA chromosomiques, très peu d’attention a été accordée aux relations phylogénétiques et interactions entre systèmes plasmidiques et chromosomiques co-existant au sein d’un même hôte ainsi qu’à l’impact du THG sur leur évolution. Notre travail de thèse vise à mieux comprendre la biologie des systèmes TA en tenant compte de ces paramètres. Nous nous sommes intéressés à des systèmes homologues au système plasmidique ccdF. Nous avons étudié expérimentalement les 4 systèmes ccd (ccd1, ccd2, ccd3 et ccd4) qui co-habitent au sein du chromosome d’Erwinia chrysanthemi 3937 (une bactérie phytopathogène), leurs interactions intragénomiques et les interactions de ces systèmes avec le système plasmidique ccdF. Ce cadre expérimental a mené à la construction du modèle d’anti-addiction. Ce modèle propose que certains systèmes chromosomiques puissent conférer un avantage sélectif à leurs hôtes bactériens en interférant avec le PSK médié par leurs homologues plasmidiques. Cet avantage sélectif pourrait permettre la fixation de systèmes TA latéralement acquis au sein des populations bactériennes. Nous avons également recherché de nouveaux systèmes ccd au sein des génomes bactériens afin d’avoir un aperçu de leur distribution, des contextes génétiques dans lesquels ils existent et de l’implication du THG dans leur dispersion. Les réflexions qui ont accompagné notre recherche nous ont mené à proposer une synthèse sur le rôle des systèmes TA (plasmidiques et chromosomiques). Celle-ci se nourrit des avancées qui ont été effectuées, ces dernières années, dans la compréhension de l’évolution des génomes bactériens, de la théorie hiérarchique de la sélection naturelle et des processus non-adaptatifs et contingents qui pourraient expliquer la présence et la propagation des systèmes TA au sein des génomes bactériens sans que ceux-ci en soient les agents causaux. Doctorat en sciences, Spécialisation biologie moléculaireinfo:eu-repo/semantics/nonPublishe

Chromosomal Toxin-Antitoxin Systems May Act as Antiaddiction Modules▿

Toxin-antitoxin (TA) systems are widespread among bacterial chromosomes and mobile genetic elements. Although in plasmids TA systems have a clear role in their vertical inheritance by selectively killing plasmid-free daughter cells (postsegregational killing or addiction phenomenon), the physiological role of chromosomally encoded ones remains under debate. The assumption that chromosomally encoded TA systems are part of stress response networks and/or programmed cell death machinery has been called into question recently by the observation that none of the five canonical chromosomally encoded TA systems in the Escherichia coli chromosome seem to confer any selective advantage under stressful conditions (V. Tsilibaris, G. Maenhaut-Michel, N. Mine, and L. Van Melderen, J. Bacteriol. 189:6101-6108, 2007). Their prevalence in bacterial chromosomes indicates that they might have been acquired through horizontal gene transfer. Once integrated in chromosomes, they might in turn interfere with their homologues encoded by mobile genetic elements. In this work, we show that the chromosomally encoded Erwinia chrysanthemi ccd (control of cell death) (ccdEch) system indeed protects the cell against postsegregational killing mediated by its F-plasmid ccd (ccdF) homologue. Moreover, competition experiments have shown that this system confers a fitness advantage under postsegregational conditions mediated by the ccdF system. We propose that ccdEch acts as an antiaddiction module and, more generally, that the integration of TA systems in bacterial chromosomes could drive the evolution of plasmid-encoded ones and select toxins that are no longer recognized by the antiaddiction module

Occurrence of toxin homologues in seven <i>E. coli</i> chromosomes.

<p>Homologues of the nine toxins were identified by Psi-Blast <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Altschul1" target="_blank">[59]</a> in the chromosomes of seven <i>E. coli</i> isolates. Homologues are either present in one copy (+), in two copies (+(2)) or absent (−).</p

The nine toxin families.

<p>The targets and the types of activities of the nine toxins as well as the cellular processes that are affected by the expression of the toxins are shown. This table is adapted from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Gerdes2" target="_blank">[7]</a> except where indicated. ND, not determined.</p>1<p>The CcdB toxin does not generate double-strand breaks by itself. Overexpression of CcdB inhibits the re-ligation step of the DNA gyrase, a type II topoisomerase, which leads to the generation of double-strand breaks.</p>2<p>Overexpression of RelE induces cleavage of mRNAs at the ribosome A-site.</p>3,4<p>ParE was shown to poison DNA gyrase and to generate double-strand breaks in vitro.</p>5<p>As CcdB, it induces inhibition of cell division and therefore, it is assumed that it inhibits replication.</p>6<p>Overproduction of the Doc toxin activates the <i>relBE</i> TA system and indirectly causes mRNA cleavage <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-GarciaPino1" target="_blank">[53]</a>.</p>7<p>Doc inhibits translation elongation by association with the 30S ribosomal subunit <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Liu1" target="_blank">[54]</a>.</p>8<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Daines1" target="_blank">[55]</a>. Although VapC shows an endoribonucleolytic activity, it has not been reported whether or not VapC is able to inhibit translation.</p>9<p>The ζ toxin is part of a three-component TA system (ω−ε−ζ) in which the antitoxin and autoregulation properties are encoded by separate polypeptides.</p>10<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Meinhart1" target="_blank">[56]</a>.</p>11<p>At a high overexpression level, the ζ toxin inhibits replication, transcription, and translation, eventually leading to cell death <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Lioy1" target="_blank">[57]</a>. However, the specific target(s) is (are) unknown.</p>12<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Schumacher1" target="_blank">[34]</a>.</p>13<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Correia1" target="_blank">[33]</a>.</p>14<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Korch2" target="_blank">[32]</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Correia1" target="_blank">[33]</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Schumacher1" target="_blank">[34]</a>.</p>15<p>The genetic organisation of the <i>higBA</i> system is unusual; the toxin gene is upstream of the antitoxin gene in the operon.</p>16,17<p>See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-ChristensenDalsgaard1" target="_blank">[40]</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000437#pgen.1000437-Budde1" target="_blank">[58]</a>.</p