Shutoff of host transcription triggers a toxin-antitoxin system to cleave phage RNA and abort infection

Guegler, Chantal K.; Laub, Michael T.

doi:10.1016/j.molcel.2021.03.027

Cited by 87 publications

(96 citation statements)

References 48 publications

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“…Phenotypic heterogeneity in the expression of known phage resistance factors could also contribute to the observed phenotypic resistance to phage in structured environments and should be further investigated. For example, differential expression of toxin–antitoxin modules, such as MazEF and ToXI [ 74 , 75 ], or abortive infection systems, such as Rex, Lit, Rnl, or PrrC, could result in the inhibition of phage replication in some cells by inactivating the host transcription and translation machinery [ 56 , 76 ]. Such mechanisms could underlie the nongrowing phenotype we observe that resembles nondividing E .…”

Section: Discussionmentioning

confidence: 99%

Individual bacteria in structured environments rely on phenotypic resistance to phage

et al. 2021

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Bacteriophages represent an avenue to overcome the current antibiotic resistance crisis, but evolution of genetic resistance to phages remains a concern. In vitro, bacteria evolve genetic resistance, preventing phage adsorption or degrading phage DNA. In natural environments, evolved resistance is lower possibly because the spatial heterogeneity within biofilms, microcolonies, or wall populations favours phenotypic survival to lytic phages. However, it is also possible that the persistence of genetically sensitive bacteria is due to less efficient phage amplification in natural environments, the existence of refuges where bacteria can hide, and a reduced spread of resistant genotypes. Here, we monitor the interactions between individual planktonic bacteria in isolation in ephemeral refuges and bacteriophage by tracking the survival of individual cells. We find that in these transient spatial refuges, phenotypic resistance due to reduced expression of the phage receptor is a key determinant of bacterial survival. This survival strategy is in contrast with the emergence of genetic resistance in the absence of ephemeral refuges in well-mixed environments. Predictions generated via a mathematical modelling framework to track bacterial response to phages reveal that the presence of spatial refuges leads to fundamentally different population dynamics that should be considered in order to predict and manipulate the evolutionary and ecological dynamics of bacteria–phage interactions in naturally structured environments.

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Section: Discussionmentioning

confidence: 99%

Individual bacteria in structured environments rely on phenotypic resistance to phage

et al. 2021

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“…In the case of bacteria infected with bacteriophage, inhibiting the synthesis of new phage particles may enable populations of bacteria to slow or stop the spread of infection. Indeed, there is growing evidence that the endoribonuclease activity of toxin-antitoxin systems can both be activated by and defend against bacteriophage ( 13 , 14 ). Future exploration of the activation conditions of these toxins will shed light on their role in bacterial survival and stress response.…”

Section: Discussionmentioning

confidence: 99%

“…TA systems were also suggested to contribute to spontaneous persister cell formation, but at least for Escherichia coli , this has been refuted ( 9 , 11 ). Some TA systems are activated during phage infection, with the toxin leading to abortive infection, either by inhibiting host cell processes or by disrupting phage replication or maturation ( 12 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Global Analysis of the Specificities and Targets of Endoribonucleases from Escherichia coli Toxin-Antitoxin Systems

Culviner

Nocedal

Fortune

et al. 2021

mBio

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Toxin-antitoxin (TA) systems are widespread genetic modules found in almost all bacteria that can regulate their growth and may play prominent roles in phage defense. Escherichia coli encodes 11 TA systems in which the toxin is a known or predicted endoribonuclease. The targets and cleavage specificities of these endoribonucleases have remained largely uncharacterized, precluding an understanding of how each impacts cell growth and an assessment of whether they have distinct or overlapping targets.

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“…In the case of bacteria infected with bacteriophage, inhibiting the synthesis of new phage particles may enable populations of bacteria to slow or stop the spread of infection. Indeed, there is growing evidence showing the endoribonuclease activity of toxin-antitoxin systems can both be activated by and defend against bacteriophage 13, 14 . Future exploration of the activation conditions of these toxins will shed light on their role in bacterial survival and stress response.…”

Section: Discussionmentioning

confidence: 99%

“…TA systems were also suggested to contribute to spontaneous persister cell formation, but at least for E. coli, this has been refuted 9,11 . Some TA systems are activated during phage infection, with the toxin leading to abortive infection, either by inhibiting host cell processes or disrupting phage replication or maturation [12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Global analysis of the specificities and targets of endoribonucleases from E. coli toxin-antitoxin systems

Culviner

Nocedal

Fortune

et al. 2021

Preprint

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Toxin-antitoxin systems are widely distributed genetic modules typically featuring toxins that can inhibit bacterial growth and antitoxins that can reverse inhibition. Although Escherichia coli encodes 11 toxins with known or putative endoribonuclease activity, the target of most of these toxins remain poorly characterized. Using a new RNA-seq pipeline that enables the mapping and quantification of RNA cleavage with single-nucleotide resolution, we characterize the targets and specificities of 9 endoribonuclease toxins from E. coli. We find that these toxins use low-information cleavage motifs to cut a significant proportion of mRNAs in E. coli, but not tRNAs or the rRNAs from mature ribosomes. However, all the toxins, including those that are ribosome-dependent and cleave only translated RNA, inhibit ribosome biogenesis. This inhibition likely results from the cleavage of ribosomal protein transcripts, which disrupts the stoichiometry and biogenesis of new ribosomes and causes the accumulation of aberrant ribosome precursors. Collectively, our results provide a comprehensive, global analysis of endoribonuclease-based toxin-antitoxin systems in E. coli and support the conclusion that, despite their diversity, each disrupts translation and ribosome biogenesis.ImportanceToxin-antitoxin systems are widespread genetic modules found in almost all bacteria that can regulate their growth and may play prominent roles in phage defense. Escherichia coli encodes 11 TA systems in which the toxin is a known or predicted endoribonuclease. The targets and cleavage specificities of these endoribonucleases have remained largely uncharacerized, precluding an understanding of how each impacts cell growth and an assessment of whether they have distinct or overlapping targets. Using a new and broadly applicable RNA-seq pipeline, we present a global analysis of 9 endoribonulease toxins from E. coli. We find that each uses a relatively low-information cleavage motif to cut a large proportion of mRNAs in E. coli, but not tRNAs or mature rRNAs. Notably, although the precise set of targets varies, each toxin efficiently disrupts ribosome biogenesis, primarily by cleaving the mRNAs of ribosomal proteins. In sum, the analyses presented provide new, comprehensive insights into the cleavage specificities and targets of almost all endoribonuclease toxins in E. coli. Despite different specificities, our work reveals a striking commonality in function as each toxin disrupts ribosome biogenesis and translation.

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Shutoff of host transcription triggers a toxin-antitoxin system to cleave phage RNA and abort infection

Cited by 87 publications

References 48 publications

Individual bacteria in structured environments rely on phenotypic resistance to phage

Individual bacteria in structured environments rely on phenotypic resistance to phage

Global Analysis of the Specificities and Targets of Endoribonucleases from Escherichia coli Toxin-Antitoxin Systems

Global analysis of the specificities and targets of endoribonucleases from E. coli toxin-antitoxin systems

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