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At least 73 records · Page 4Linked to original sources
PubMed2003

New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system.

BACKGROUND: Several prokaryotic plasmids maintain themselves in their hosts by means of diverse post-segregational cell killing systems. Recent findings suggest that chromosomally encoded copies of toxins and antitoxins of post-segregational cell killing systems - such as the RelE system - might function as regulatory switches under stress conditions. The RelE toxin cleaves ribosome-associated transcripts, whereas another post-segregational cell killing toxin, ParE, functions as a gyrase inhibitor. RESULTS: Using sequence profile analysis we were able unify the RelE- and ParE-type toxins with several families of small, uncharacterized proteins from diverse bacteria and archaea into a single superfamily. Gene neighborhood analysis showed that the majority of these proteins were encoded by genes in characteristic neighborhoods, in which genes encoding toxins always co-occurred with genes encoding transcription factors that are also antitoxins. The transcription factors accompanying the RelE/ParE superfamily may belong to unrelated or distantly related superfamilies, however. We used this conserved neighborhood template to transitively search genomes and identify novel post-segregational cell killing-related systems. One of these novel systems, observed in several prokaryotes, contained a predicted toxin with a PilT-N terminal (PIN) domain, which is also found in proteins of the eukaryotic nonsense-mediated RNA decay system. These searches also identified novel transcription factors (antitoxins) in post-segregational cell killing systems. Furthermore, the toxin Doc defines a potential metalloenzyme superfamily, with novel representatives in bacteria, archaea and eukaryotes, that probably acts on nucleic acids. CONCLUSIONS: The tightly maintained gene neighborhoods of post-segregational cell killing-related systems appear to have evolved by in situ displacement of genes for toxins or antitoxins by functionally equivalent but evolutionarily unrelated genes. We predict that the novel post-segregational cell killing-related systems containing a PilT-N terminal domain toxin and the eukaryotic nonsense-mediated RNA decay system are likely to function via a common mechanism, in which the PilT-N terminal domain cleaves ribosome-associated transcripts. The core of the eukaryotic nonsense-mediated RNA decay system has probably evolved from a post-segregational cell killing-related system.

Adenosine Triphosphatases↗
PubMed1993

Comparative studies of the in vivo toxin neutralization and the in vitro Vero cell assay methods for use in potency testing of diphtheria component in combined vaccines/toxoids. 1: Standardization of a modified Vero cell assay for toxin-antitoxin titration of immunized guinea-pig sera.

The in vivo Toxin Neutralization (TN) test is currently used as an antibody limit test for regulatory control testing of diphtheria potency in combined vaccines/toxoids. This test requires the use of guinea-pigs for estimating diphtheria antitoxin titre in immunized sera. The acceptability criteria (minimum requirement) for adsorbed pediatric vaccines/toxoids in the TN test are the production of at least 2.0 IU/ml of antitoxin in the serum pool of immunized animals. The feasibility of employing the in vitro Vero cell assay as an alternative limit test to the TN test was investigated. Parallel titration of serum samples from guinea-pigs immunized with DPT (ads) vaccine (pediatric use) showed that although the in vitro antitoxin titre paralleled the in vivo values, a direct correlation between the two methods could not be established. The mean in vitro titres were lower (in terms of IU/ml) than those obtained by the in vivo TN test. This could possibly be explained by the differences between reference serum which is a hyperimmune horse serum and the test sera which are from guinea-pigs which have been immunized only once. The in vitro/in vivo ratio of the antitoxin titre ranged from 0.1 to 0.24 IU/ml with a mean value of 0.17 (SD, 0.06). Hence, for pediatric vaccines, a tentative in vitro limit of 0.3 IU/ml, which would correspond to the currently required limit of 2.0 IU/ml in the in vivo TN test, could be accepted as the minimum requirement for the antitoxin titre in the Vero cell assay.

Animals↗
PubMed2004

Identification and characterization of a nontypeable Haemophilus influenzae putative toxin-antitoxin locus.

BACKGROUND: Certain strains of an obligate parasite of the human upper respiratory tract, nontypeable Haemophilus influenzae (NTHi), can cause invasive diseases such as septicemia and meningitis, as well as chronic mucosal infections such as otitis media. To do this, the organism must invade and survive within both epithelial and endothelial cells. We have identified a facilitator of NTHi survival inside human cells, virulence-associated protein D (vapDHi, encoded by gene HI0450). Both vapDHi and a flanking gene, HI0451, exhibit the genetic and physical characteristics of a toxin/antitoxin (TA) locus, with VapDHi serving as the toxin moiety and HI0451 as the antitoxin. We propose the name VapXHi for the HI0451 antitoxin protein. Originally identified on plasmids, TA loci have been found on the chromosomes of a number of bacterial pathogens, and have been implicated in the control of translation during stressful conditions. Translation arrest would enhance survival within human cells and facilitate persistent or chronic mucosal infections. RESULTS: Isogenic mutants in vapDHi were attenuated for survival inside human respiratory epithelial cells (NCI-H292) and human brain microvascular endothelial cells (HBMEC), the in vitro models of mucosal infection and the blood-brain barrier, respectively. Transcomplementation with a vapDHi allele restored wild-type NTHi survival within both cell lines. A PCR survey of 59 H. influenzae strains isolated from various anatomical sites determined the presence of a vapDHiallele in 100% of strains. Two isoforms of the gene were identified in this population; one that was 91 residues in length, and another that was truncated to 45 amino acids due to an in-frame deletion. The truncated allele failed to transcomplement the NTHi vapDHi survival defect in HBMEC. Subunits of full-length VapDHi homodimerized, but subunits of the truncated protein did not. However, truncated protein subunits did interact with full-length subunits, and this interaction resulted in a dominant-negative phenotype. Although Escherichia coli does not contain a homologue of either vapDHi or vapXHi, overexpression of the VapDHi toxin in trans resulted in E. coli cell growth arrest. This arrest could be rescued by providing the VapXHi antitoxin on a compatible plasmid. CONCLUSION: We conclude that vapDHi and vapXHi may constitute a H. influenzae TA locus that functions to enhance NTHi survival within human epithelial and endothelial cells.

Alleles↗
PubMed1984

Toxin-antitoxin selection for isolating somatic cell fusion products between any cell types.

A selective system was developed that permits the isolation of heterokaryons and cell hybrids between any cell types without the use of selectable genetic markers. Antibodies were introduced into two populations of non-transformed normal diploid human fibroblasts by the osmotic lysis of pinosomes containing hypertonic antibody solutions. Heterokaryons formed by fusing antiricin-injected cells to antidiphtheria toxin-injected cells survived an overnight treatment in both ricin and diphtheria toxin. This approach should have general applicability to a variety of investigations such as the complementation analysis of human genetic syndromes, heterokaryon studies of cell differentiation, tumorigenesis and growth control, cell reconstruction experiments, and the production of hybridoma cells.

Antibodies, Monoclonal↗
PubMed1998

Standardization of acellular pertussis vaccine by assay of serum neutralizing antibodies to pertussis toxin (antitoxin): analogy with diphtheria toxoid.

Immunity conferred by vaccination with cellular pertussis vaccines and pertussis wanes so that adults are now the main reservoir of B. pertussis. Similar to diphtheria toxoid, acellular pertussis vaccines are suitable for vaccination of adults and it is probable that addition of pertussis toxoid to DT will be recommended for this age group. If this can be achieved, it is easy to predict that pertussis will be eliminated and the possibility of eradicating B. pertussis will become feasible. We propose that, despite the relative inaccuracy of correlating levels of antitoxin with individual immunity, a standardized assay and reference antiserum for pertussis toxoid will control acellular pertussis vaccines as was achieved with diphtheria toxoid.

Adult↗
PubMed2006

Expression of the F plasmid ccd toxin-antitoxin system in Escherichia coli cells under nutritional stress.

The ccd system of the F plasmid encodes CcdB, a protein toxic to DNA-gyrase, and CcdA, its antitoxin. The function attributed to this system is to contribute to plasmid stability by killing bacteria that lose the plasmid during cell division. However, the function of ccd in resting bacteria is not clear. Results presented show that ccd transcription increases as bacteria enter stationary phase and that the amount of the Ccd proteins is higher in bacteria under nutritional stress than in growing bacteria. Moreover, an increase in the frequency of Lac+ "adaptive" mutations was observed in stationary-phase bacteria that over-express the Ccd proteins.

Bacterial Proteins↗
PubMed1974

Evaluation of type A botulinal toxin assays that use antitoxin to crystalline toxin.

The type A botulinal toxin assay by the reverse passive hemagglutination procedure which uses antitoxin to crystalline toxin was examined for specificity. The analysis was based on the fact that crystalline type A toxin is a complex of neurotoxic protein (Aalpha) and a nontoxic protein (Abeta). By using these components, obtained in essentially pure forms, it was shown that the antitoxin to crystalline toxin has a significantly higher titer to Abeta than to Aalpha. When Formalin-treated red blood cells were sensitized with this antitoxin, the antibodies coupled to the cells were, for practical results, only anti-Abeta. When the suspension is reacted with dilutions of type A toxic solutions, the limiting dilutions are determined by Abeta and not by the neurotoxin, which should be the determinant if the assay is to measure toxicity. These observations may be pertinent to the development of serological assays for other botulinal toxin types.

Animals↗
PubMed1979

Prevention of clindamycin-induced colitis in hamsters by Clostridium sordellii antitoxin.

Toxins produced by Clostridium difficile have been implicated in the etiology of antibiotic-induced colitis. Clostridium difficile antitoxin is not available, but recent studies have shown that toxins present in the feces of patients with this disease are neutralized by Clostridium sordellii antitoxin. We found that C. sordellii antitoxin neutralized toxins produced in broth cultures of either C. sordellii or C. difficile and that passive immunization with C. sordellii antitoxin before challenge with clindamycin prevented colitis in hamsters. Significantly fewer antitoxin-treated animals than unimmunized controls developed diarrhea and died with hemorrhagic colitis. Administration of 300 U of antitoxin parenterally either on the day of challenge with clindamycin or 24 hr later provided significant protection (25% mortality vs. 100% mortality in controls, P less than 0.01). None of eight animals given antitoxin (300 U) both on the day of challenge and 24 hr later died. Filtrates prepared from cecal contents of dead or killed hamsters were tested for toxicity by intraperitoneal injection into hamsters and by addition to monolayers of monkey kidney cells. Fecal filtrates from antitoxin-protected animals were not toxic in these assays, but filtrates from control animals were uniformly toxic. Passive immunization against clostridial toxins was protective against clindamycin-associated colitis in this model. This finding further substantiates the importance of these toxins in the pathogenesis of antibiotic-induced colitis.

Animals↗