The cytolethal distending toxin family

Pickett, Carol L.; Whitehouse, Chris A.

doi:10.1016/s0966-842x(99)01537-1

Cited by 207 publications

(196 citation statements)

References 26 publications

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“…In APSE-1, the corresponding genomic region instead contains a distinct gene set including a homolog of stx, encoding Shiga toxin (7); we detected a similar stx homolog in H. defensa originating from a different insect species. Both of these toxins are deployed by a variety of human pathogens, and their cellular activities have been well characterized: CdtB is a nuclease that interferes with DNA replication during the G 2 phase of the eukaryotic cell cycle (42,43), and Shiga toxin inhibits protein synthesis by disrupting 28S ribosomal RNA (44).…”

Section: Discussionmentioning

confidence: 99%

The players in a mutualistic symbiosis: Insects, bacteria, viruses, and virulence genes

Moran

Degnan

Santos

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

289

271

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Aphids maintain mutualistic symbioses involving consortia of coinherited organisms. All possess a primary endosymbiont, Buchnera, which compensates for dietary deficiencies; many also contain secondary symbionts, such as Hamiltonella defensa, which confers defense against natural enemies. Genome sequences of uncultivable secondary symbionts have been refractory to analysis due to the difficulties of isolating adequate DNA samples. By amplifying DNA from hemolymph of infected pea aphids, we obtained a set of genomic sequences of H. defensa and an associated bacteriophage. H. defensa harbors two type III secretion systems, related to those that mediate host cell entry by enteric pathogens. The phage, called APSE-2, is a close relative of the previously sequenced APSE-1 but contains intact homologs of the gene encoding cytolethal distending toxin (cdtB), which interrupts the eukaryotic cell cycle and which is known from a variety of mammalian pathogens. The cdtB homolog is highly expressed, and its genomic position corresponds to that of a homolog of stx (encoding Shiga-toxin) within APSE-1. APSE-2 genomes were consistently abundant in infected pea aphids, and related phages were found in all tested isolates of H. defensa, from numerous insect species. Based on their ubiquity and abundance, these phages appear to be an obligate component of the H. defensa life cycle. We propose that, in these mutualistic symbionts, phage-borne toxin genes provide defense to the aphid host and are a basis for the observed protection against eukaryotic parasites.Acrythosiphon pisum ͉ Hamiltonella defensa ͉ lamboid phage ͉ aphid ͉ Enterobacteriaceae

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Section: Discussionmentioning

confidence: 99%

The players in a mutualistic symbiosis: Insects, bacteria, viruses, and virulence genes

Moran

Degnan

Santos

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

289

271

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“…The H. ducreyi cytolethal distending toxin (HdCDT) has been shown to inhibit proliferation, induce cell enlargement and cause death of a number of human cells and cell lines, e.g., HEp-2, HeLa, HaCaT, T cells, B cells and human ®broblasts [7±13]. It has been shown to induce a cell cycle arrest not only in the G2/M phase, but also in the G1 phase [14,15]. cdt genes have also been identi®ed in strains of Escherichia coli [16±18], some Shigella [19], Campylobacter [20±22] and Helicobacter [23] species and in the oral pathogen Actinobacillus actinomycetemcomitans [24±26].…”

Section: Introductionmentioning

confidence: 99%

“…cdt genes have also been identi®ed in strains of Escherichia coli [16±18], some Shigella [19], Campylobacter [20±22] and Helicobacter [23] species and in the oral pathogen Actinobacillus actinomycetemcomitans [24±26]. All these toxins are encoded by an operon consisting of three genes (cdtABC), the products of which have molecular masses of c. 25, 30 and 20 kDa, respectively [10,14]. H. ducreyi cdtABC genes encode proteins that closely resemble those comprising the CDT of A. actinomycetemcomitans, which also belongs to the family Pasteurellaceae and is involved in the pathogenesis of human periodontal disease.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of cdtABC genes encoding cytolethal distending toxin among Haemophilus ducreyi and Actinobacillus actinomycetemcomitans strains

Ahmed

Svensson

Cope

et al. 2001

Journal of Medical Microbiology

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The aim of this study was to investigate the presence of the three cdtABC genes responsible for production of cytolethal distending toxin (CDT) in Haemophilus ducreyi and Actinobacillus actinomycetemcomitans strains. Of 100 H. ducreyi strains from the culture collection of the University of Go Èteborg (CCUG), 27 strains with low or intermediate cytotoxic titre (<1 in 10 4 ) and 23 of the remaining isolates with a high cytotoxic titre (>1 in 10 4 ) were selected. Twenty-nine strains of H. ducreyi were isolated recently from patients with chancroid and 50 A. actinomycetemcomitans strains from patients with periodontitis. The cytotoxic activity on HEp-2 cells and the presence of cdtABC genes were studied by cytotoxicity assay of bacterial sonicates and PCR with primers speci®c for individual cdtA, B, and C genes of H. ducreyi in bacterial DNA preparations, respectively. All strains that manifested a cytotoxic titre in sonicate >1 in 100 possessed all the three cdt genes. Eighteen of the 50 strains selected from the culture collection were negative and 32 positive for cdt genes. As all strains with a high cytotoxic titre gave positive PCR results, it can be assumed that the remaining 50 strains, which have high cytotoxic titre, would have been positive as well. Thus, it can be estimated that 82% of the culture collection strains had cdtABC genes. Similarly, 24 (83%) of 29 recent H. ducreyi isolates expressed the CDT activity and displayed all cdtABC genes. Forty-three (86%) of 50 strains of the closely related A. actinomycetemcomitans, expressing a cytotoxic activity >1 in 100, also possessed all three genes. Furthermore, the nucleotide sequence of the cdtABC genes was highly conserved among H. ducreyi strains from different geographic areas. These results indicate that the majority of pathogenic H. ducreyi and A. actinomycetemcomitans strains express a CDT activity encoded by all three cdtABC.

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“…The cytolethal distending toxins (CDTs) 1 are newly discovered bacterial protein toxins with the unique ability to induce cell cycle arrest, thereby inhibiting cell proliferation. CDTs are produced by a number of bacterial pathogens, including Escherichia coli, Haemophilus ducreyi, Campylobacter sp., Actinobacillus actinomycetemcomitans, Shigella dysenteriae, and Helicobacter hepaticus.…”

mentioning

confidence: 99%

“…Coexpression of all three components is required to confer toxicity (reviewed in Ref. 1), but the functions of the individual gene products are still not known. It was reported that purified cdtB from A. actinomycetemcomitans could induce cell cycle arrest in human T lymphocytes and HeLa cells (2,3).…”

mentioning

confidence: 99%

The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

Cortes-Bratti¹,

Karlsson²,

Lagergård³

et al. 2001

Journal of Biological Chemistry

147

173

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The cytolethal distending toxins (CDTs) induce cell cycle arrest by a mechanism still not well characterized. We demonstrate that the effect of the Haemophilus ducreyi CDT (HdCDT) is cell type-specific: B cell lines underwent apoptosis, epithelial cells and keratinocytes arrested exclusively in G 2 , whereas normal fibroblasts arrested both in G 1 and G 2 . We studied normal keratinocytes and fibroblasts, which are relevant for understanding the pathogenicity of H. ducreyi. The response to HdCDT resembles the checkpoint response activated by ionizing radiation. Both responses were characterized by an early induction of the p53 gene and the cyclindependent kinase inhibitor p21 in fibroblasts, and activation of the chk2 kinase in epithelial cells. In the Ataxia Telangiectasia-mutated gene (ATM)-deficient lymphoblastoid cell lines, intoxication was significantly delayed compared with ATM wild type cells, and was associated with a slower kinetic of p53 stabilization, suggesting that the early response to HdCDT is ATM-dependent. Activation of ATM-dependent pathways was further confirmed by the ability of caffeine to partially override the HdCDT-mediated cell cycle arrest. Our data shed new light on the mechanism of action of this novel family of bacterial toxins, limiting the target candidates to DNA or molecules directly involved in activation of checkpoint responses.

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The cytolethal distending toxin family

Cited by 207 publications

References 26 publications

The players in a mutualistic symbiosis: Insects, bacteria, viruses, and virulence genes

The players in a mutualistic symbiosis: Insects, bacteria, viruses, and virulence genes

Prevalence of cdtABC genes encoding cytolethal distending toxin among Haemophilus ducreyi and Actinobacillus actinomycetemcomitans strains

The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

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