Identification and functional analysis of two toxin–antitoxin systems in <i>Campylobacter jejuni</i>

Shen, Zhangqi; Patil, Rocky; Şahin, Orhan; Wu, Zhongliang; Pu, Xiaoying; Dai, Lei; Plummer, Paul J.; Yaeger, Michael J.; Zhang, Qijing

doi:10.1111/mmi.13431

Cited by 17 publications

(11 citation statements)

References 53 publications

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“…Our large genome analysis revealed that this physical genomic link between TA pairs and CRISPR arrays can be extended to the majority of sequenced C. difficile strains. Initially, TA systems were shown to be important for maintenance of plasmids through a post-segregation killing mechanism ( 20 , 21 , 84 ). The role of numerous chromosomal TA systems remains largely enigmatic, even though their possible implication in stabilization of chromosomal regions has been emphasized.…”

Section: Discussionmentioning

confidence: 99%

Discovery of new type I toxin–antitoxin systems adjacent to CRISPR arrays in Clostridium difficile

Maikova

Peltier

Boudry

et al. 2018

Nucleic Acids Research

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Clostridium difficile, a major human enteropathogen, must cope with foreign DNA invaders and multiple stress factors inside the host. We have recently provided an experimental evidence of defensive function of the C. difficile CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) system important for its survival within phage-rich gut communities. Here, we describe the identification of type I toxin–antitoxin (TA) systems with the first functional antisense RNAs in this pathogen. Through the analysis of deep-sequencing data, we demonstrate the general co-localization with CRISPR arrays for the majority of sequenced C. difficile strains. We provide a detailed characterization of the overlapping convergent transcripts for three selected TA pairs. The toxic nature of small membrane proteins is demonstrated by the growth arrest induced by their overexpression. The co-expression of antisense RNA acting as an antitoxin prevented this growth defect. Co-regulation of CRISPR-Cas and type I TA genes by the general stress response Sigma B and biofilm-related factors further suggests a possible link between these systems with a role in recurrent C. difficile infections. Our results provide the first description of genomic links between CRISPR and type I TA systems within defense islands in line with recently emerged concept of functional coupling of immunity and cell dormancy systems in prokaryotes.

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Section: Discussionmentioning

confidence: 99%

Discovery of new type I toxin–antitoxin systems adjacent to CRISPR arrays in Clostridium difficile

Maikova

Peltier

Boudry

et al. 2018

Nucleic Acids Research

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“…CjrA/CjpT (type I) and VirA/VirT (type II) TA systems were identified in Campylobacter spp. (377). These systems were encoded by the pVir plasmid, which is involved in virulence and natural transformation.…”

Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

“…These systems were encoded by the pVir plasmid, which is involved in virulence and natural transformation. VirT belongs to the RelE family, one of the best-studied TA systems (374,377).…”

Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

et al. 2018

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SUMMARYPathogens that infect the gastrointestinal and respiratory tracts are subjected to intense pressure due to the environmental conditions of the surroundings. This pressure has led to the development of mechanisms of bacterial tolerance or persistence which enable microorganisms to survive in these locations. In this review, we analyze the general stress response (RpoS mediated), reactive oxygen species (ROS) tolerance, energy metabolism, drug efflux pumps, SOS response, quorum sensing (QS) bacterial communication, (p)ppGpp signaling, and toxin-antitoxin (TA) systems of pathogens, such as , spp., spp., spp., , spp., spp., spp., and , all of which inhabit the gastrointestinal tract. The following respiratory tract pathogens are also considered:, ,, , and Knowledge of the molecular mechanisms regulating the bacterial tolerance and persistence phenotypes is essential in the fight against multiresistant pathogens, as it will enable the identification of new targets for developing innovative anti-infective treatments.

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“…Campylobacter genomes generally lack homologs of prototypical TA systems ( Shao et al, 2011 ). To date, only two TA systems (both located on a plasmid in C. jejuni ) have been described ( Shen et al, 2016 ). Given the general importance of TA systems in bacteria we asked whether the multiple fic genes in C. fetus fulfill this important role.…”

Section: Introductionmentioning

confidence: 99%

Fic Proteins of Campylobacter fetus subsp. venerealis Form a Network of Functional Toxin–Antitoxin Systems

et al. 2017

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Enzymes containing the FIC (filamentation induced by cyclic AMP) domain catalyze post-translational modifications of target proteins. In bacteria the activity of some Fic proteins resembles classical toxin–antitoxin (TA) systems. An excess of toxin over neutralizing antitoxin can enable bacteria to survive some stress conditions by slowing metabolic processes and promoting dormancy. The cell can return to normal growth when sufficient antitoxin is present to block toxin activity. Fic genes of the human and animal pathogen Campylobacter fetus are significantly associated with just one subspecies, which is specifically adapted to the urogenital tract. Here, we demonstrate that the fic genes of virulent isolate C. fetus subsp. venerealis 84-112 form multiple TA systems. Expression of the toxins in Escherichia coli caused filamentation and growth inhibition phenotypes reversible by concomitant antitoxin expression. Key active site residues involved in adenylylation by Fic proteins are conserved in Fic1, Fic3 and Fic4, but degenerated in Fic2. We show that both Fic3 and the non-canonical Fic2 disrupt assembly and function of E. coli ribosomes when expressed independently of a trans-acting antitoxin. Toxicity of the Fic proteins is controlled by different mechanisms. The first involves intramolecular regulation by an inhibitory helix typical for Fic proteins. The second is an unusual neutralization by heterologous Fic–Fic protein interactions. Moreover, a small interacting antitoxin called Fic inhibitory protein 3, which appears unrelated to known Fic antitoxins, has the novel capacity to bind and neutralize Fic toxins encoded in cis and at distant sites. These findings reveal a remarkable system of functional crosstalk occurring between Fic proteins expressed from chromosomal and extrachromosomal modules. Conservation of fic genes in other bacteria that either inhabit or establish pathology in the urogenital tract of humans and animals underscores the significance of these factors for niche-specific adaptation and virulence.

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Identification and functional analysis of two toxin–antitoxin systems in Campylobacter jejuni

Cited by 17 publications

References 53 publications

Discovery of new type I toxin–antitoxin systems adjacent to CRISPR arrays in Clostridium difficile

Discovery of new type I toxin–antitoxin systems adjacent to CRISPR arrays in Clostridium difficile

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

Fic Proteins of Campylobacter fetus subsp. venerealis Form a Network of Functional Toxin–Antitoxin Systems

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