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At least 19 recordsLinked to original sources
PubMed1991

Anti-idiotype-based vaccines against biological toxins.

Biological toxins produced by living organisms represent one of the major sources of contamination of stored grain and agricultural products, and other food sources. The majority of these biological toxins are highly lethal, nonproteinaceous low-molecular-weight chemical compounds which exert their potent toxicity through a variety of mechanisms. Because of their small size, they generally do not induce a significantly high affinity protective antibody response upon toxin exposure, even when conjugated to large protein carriers which enhance their immunogenicity. Moreover, the very toxic nature of biological toxins precludes their use as immunogens in the induction of protective immunity. To circumvent this difficulty, an attempt was made to develop antibody (anti-idiotype)-based vaccines against a protein synthesis inhibitor, the trichothecene mycotoxin T-2, and the sodium channel blockers tetrodotoxin and saxitoxin. Protective monoclonal antitoxin antibodies were first generated and then used to induce specific monoclonal anti-idiotype antibodies. Specific anti-idiotype antibodies were assessed for their ability to induce in vivo protective immunity against toxicity.

Animals↗
PubMed2004

Medical aspects of biologic toxins.

Biologic toxins are molecules produced by living organisms that are poisonous to other species, such as humans. Some biologic toxins are so potent and relatively easy to produce that they have been classified as biothreat agents. These include the botulinum neurotoxins, ricin, staphylococcal enterotoxin B, and Clostridium perfringens epsilon toxin. This article focuses on these four biothreat toxins and their medical aspects. The majority of the article is spent on the botulinum neurotoxins, because these are the most poisonous substances known and are the only toxins classified as Category A threat agents-the highest level of threat agent. The remainder of the article is devoted to sections on the other three biothreat toxins: ricin, staphylococcal enterotoxin B, and C perfringens epsilon toxin.

Bacterial Toxins↗
PubMed1986

Structure-function relationship of islet-activating protein, pertussis toxin: biological activities of hybrid toxins reconstituted from native and methylated subunits.

Islet-activating protein (IAP), pertussis toxin, is a hexameric protein composed of an A protomer and a B oligomer, the residual pentamer having such a subunit assembly that two different dimers, dimer 1 and dimer 2, are connected with each other by means of the smallest C subunit. Incubation of IAP with formaldehyde and pyridine-borane produced the modified toxin in which most of the free amino groups were dimethylated. The methylated and nonmethylated (native) IAP were disintegrated into their respective constituent components, which were then cross combined to reconstitute hybrid toxins with the original hexameric structure. The binding of the B oligomer to the mammalian cell surface via dimer 2 was, but the binding via dimer 1 was not, seriously impaired by methylation of amino groups in the protein. The binding of the B oligomer allowed the A protomer to enter cells and to catalyze ADP-ribosylation of a membrane Mr 41 000 protein. The diverse biological activities of IAP occurring by this mechanism were mimicked by not only methylated IAP but also all hybrid toxins, indicating that the free amino groups in the protein were not essential for the enzyme activity of the A protomer and that the A protomer was able to enter cells if the B oligomer bound to cells "monovalently" via dimer 1. An additional effect of the B oligomer binding, i.e., the direct stimulation, without the transport of the A protomer, of cells leading to mitosis in lymphocytes in vitro or increases in circulating lymphocytes in vivo, was not mimicked by hybrid toxins containing methylated dimer 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate Ribose↗
PubMed1987

Detection of subunits of pertussis toxin in Tn5-induced Bordetella mutants deficient in toxin biological activity.

Monoclonal antibodies with specificity for pertussis toxin subunits S1, S2, and S4 were used in Western blots to show that the subunits were not secreted into culture medium from Tn5 insertion mutants. The mutants are deficient in toxin biological activities due to an insertion in the S3 subunit structural gene. The Western blots demonstrated that each of the respective subunits was exported in a wild-type strain. Anti-S1 and anti-S2 monoclonal antibodies were capable of detecting subunits in solubilized whole-cell material from a wild-type strain and from the Tn5 mutants lacking only in biologically active toxin (Tox-). Another Tn5 insertion mutant, lacking all known B. pertussis virulence factors (Vir-), did not produce any of the subunits either in whole cellular extracts or in culture supernatants. The data demonstrate that Tn5 Tox- insertion mutants, though defective in toxin activity, synthesize some toxin subunits. The presence of the S3 subunit is most likely a necessity for transport of the toxin from cells. Alternatively, a nonstructural gene coding for a protein involved in transport of the toxin across the membrane may be affected by the Tn5 mutation.

Antibodies, Monoclonal↗
PubMed2004

Other biologic toxin bioweapons: ricin, staphylococcal enterotoxin B, and trichothecene mycotoxins.

The ideal biologic warfare agent is lethal, easy, and inexpensive to produce in large quantities, stable in aerosol for/with the ability to be dispersed over wide areas, has no effective treatment or vaccine, and is communicable from person to person. With the exception of the last characteristic, the biologic toxins (ricin, staphylococcal enterotoxin B, T-2 mycotoxin, and botulinum) possess all the properties mentioned. This article will discuss the first three biologic toxins, with an emphasis on particular points of interest to the dermatologist. Botulinum toxin will be covered in another article.

Biological Warfare↗
PubMed2006

A liposome-PCR assay for the ultrasensitive detection of biological toxins.

We describe an ultrasensitive immunoassay for detecting biotoxins that uses liposomes with encapsulated DNA reporters, and ganglioside receptors embedded in the bilayer, as a detection reagent. After immobilization of the target biotoxin by a capture antibody and co-binding of the detection reagent, the liposomes are ruptured to release the reporters, which are quantified by real-time PCR. Assays for cholera and botulinum toxins are several orders of magnitude more sensitive than current detection methods.

Botulinum Toxins↗
PubMed1987

Effect of biological toxins on gap-junctional intercellular communication in Chinese hamster V79 cells.

Since chemical modulation of gap-junctional intercellular communication has been implicated in several toxicological endpoints, a study to examine the ability of several biological toxins to inhibit this process was undertaken. Eight biological toxins were tested for their ability to inhibit metabolic cooperation, a measure of gap-junctional intercellular communication, in the Chinese V79 cell system. Aplysiatoxin, anhydrodebromoaplysiatoxin and debromoaplysiatoxin showed the strongest ability to inhibit metabolic cooperation while T2-toxin and vomitoxin inhibited metabolic cooperation to a lesser degree. Aflatoxin B1, aflatoxin B2 and palytoxin were inactive in the Chinese V79 system. Palytoxin, which was extremely cytotoxic, might act as a tumor promoter if it induces compensatory hyperplasia in vivo.

Animals↗
PubMedDate not supplied

Therapy and prophylaxis of inhaled biological toxins.

This review highlights the current lack of therapeutic and prophylactic treatments for use against inhaled biological toxins, especially those considered as potential biological warfare (BW) or terrorist threats. Although vaccine development remains a priority, the use of rapidly deployable adjunctive therapeutic or prophylactic drugs could be life-saving in severe cases of intoxication or where vaccination has not been possible or immunity not established. The current lack of such drugs is due to many factors. Thus, methods involving molecular modelling are limited by the extent to which the cellular receptor sites and mode of action and structure of a toxin need to be known. There is also our general lack of knowledge of what effect individual toxins will have when inhaled into the lungs - whether and to what extent the action will be cell specific and cytotoxic or rather an acute inflammatory response requiring the use of immunomodulators. Possible sources of specific high-affinity toxin antagonists being investigated include monoclonal antibodies, selected oligonucleotides (aptamers) and derivatized dendritic polymers (dendrimers). The initial selection of suitable agents of these kinds can be made using cytotoxicity assays involving cultured normal human lung cells and a range of suitable indicators. The possibility that a mixture of selected antibody, aptamer or dendrimer-based materials for one or more toxins could be delivered simultaneously as injections or as inhaled aerosol sprays should be investigated.

Administration, Inhalation↗
PubMed2004

Aerosolized biologic toxins as agents of warfare and terrorism.

Incomplete participation in the 1972 Biological Weapons Convention treaty and noncompliance by several signatory nations makes the malicious use of aerosolized biologic toxins a continuing threat. Unfortunately,prompt diagnosis of toxin exposure may be confounded by a paucity of pathognomonic features and limited diagnostics, but the scenario of patients presenting en masse with a similar pulmonary syndrome should alert the clinician to the possibility of aerosolized toxin exposure. As knowledge of these agents increases, so too should the capabilities for detection,protection, diagnosis, and therapy. This improved understanding, coupled with ongoing public education and awareness and with detailed proactive planning will provide the framework for a prepared community.

Aerosols↗
PubMed2000

Determination of biological toxins using capillary electrokinetic chromatography with multiphoton-excited fluorescence.

We report a highly sensitive and rapid strategy for characterizing biological toxins based on capillary electrokinetic chromatography with multiphoton-excited fluorescence. In this approach, aflatoxins B1, B2, and G1 and the cholera toxin A-subunit are fractionated in approximately 80 s in a narrow-bore electrophoretic channel using the negatively charged pseudostationary phase, carboxymethyl-beta-cyclodextrin. The aflatoxins--highly mutagenic multiple-ringed heterocycles produced by Aspergillus fungi--are excited at the capillary outlet through the simultaneous absorption of two to three 750-nm photons to yield characteristic blue fluorescence; cholera toxin A-subunit, the catalytic domain of the bacterial protein toxin from Vibrio cholera, is excited through an unidentified multiphoton pathway that apparently includes photochemical transformation of an aromatic residue in the polypeptide. The anionic carboxymethyl-beta-cyclodextrin, used to chromatographically resolve the uncharged aflatoxins, enhances emission from these compounds without contributing substantially to the background. Detection limits for these toxins separated in 2.1-micron-i.d. capillaries range from 4.4 zmol (approximately 2700 molecules) for aflatoxin B2 to 3.4 amol for the cholera toxin A-subunit. Larger (16-micron-i.d.) separation capillaries provide concentration detection limits for aflatoxins in the 0.2-0.4 nM range, severalfold lower than achieved in 2.1-micron capillaries. These results represent an improvement of > 10(4) in mass detectability compared to previously published capillary separations of aflatoxins and demonstrate new possibilities for the analysis of proteins and peptides.

Bacterial Toxins↗
PubMed2001

RTX toxin structure and function: a story of numerous anomalies and few analogies in toxin biology.

It can be agreed that RTX toxins contribute to the pathogenesis of different diseases by causing dysfunction of the general cellular reactions of the immune response. The suggestion that RTX toxins induce cytokine production in nonimmune cells that would ultimately cause tissue damage is an expansion of their role in disease pathogenesis (Uhlen et al. 2000). Investigators in the RTX toxin field may not agree with me, but precise and satisfactory answers to the following questions are not yet available. How do RTX toxins mechanistically damage a cell? Do RTX toxins have receptors in the classic sense, in which there is a reversible ligand and receptor complex? What is responsible for the common Ca2+ ion influx in affected cells? The recent observation that an RTX toxin stimulates host-cell-mediated Ca2+ ion oscillation in part challenges the long held concept that these toxins damage cells by the direct formation of pores. Are the Ca2+ ion fluxes truly the noxious cellular insult? What is the final molecular structure of RTX toxins at the time they cause cellular death? How does the common requirement for acyl modification among RTX toxins fit into the toxin structure and mechanism of cellular killing, particularly when mixtures of unusual fatty acids are used by some toxins? There are a number of outstanding laboratories throughout the world that are seeking answers to these questions. We can reasonably expect that during the next decade research on the structure and function of RTX toxins will lead to new chemotherapeutic targets and reagents for basic cell biology and biotechnology.

Animals↗
PubMed1995

Lethal and dermonecrotic activities of Clostridium perfringens lota toxin: biological activities induced by cooperation of two nonlinked components.

The effect of separate injections of two components of Clostridium perfringens iota toxin, designated Ia and Ib components, on the biological activities of the toxin was investigated. The intravenous injection of one component within 120 min after the injection of the other component killed mice. The activity of iota toxin was abolished by anti-Ia or anti-Ib antiserum. On the other hand, when Ib component was intravenously administered to mice given anti-Ia antiserum within 120 min after the intravenous injection of Ia component, the lethal activity was completely neutralized, but when Ia component was injected into mice that were given anti-Ib antiserum over 5 min after the injection of Ib component, the activity was not neutralized. The separate injections of Ia and Ib components in skin of guinea pigs indicated dermonecrosis at the injection site of Ib components, but not at the site of Ia components. Furthermore, when one component was intradermally injected in guinea pigs and then the other intraperitoneally, the dermonecrotic activity of the toxin was observed at the intradermal injection site of Ib component, but not at that of Ia component. From the data, it appears that the lethal and dermonecrotic activities of iota toxin are initiated by the binding of Ib component to specific sites on tissues.

ADP Ribose Transferases↗
PubMed2000

Gangliosides as receptors for biological toxins: development of sensitive fluoroimmunoassays using ganglioside-bearing liposomes.

Gangliosides, glycosphingolipids present in the membranes of neuronal and other cells, are natural receptors for a number of bacterial toxins and viruses whose sensitive detection is of interest in clinical medicine as well as in biological warfare or terrorism incidents. Liposomes containing gangliosides mimic cells that are invaded by bacterial toxins and can be used as sensitive probes for detecting these toxins. We discuss detection of three bacterial toxins-tetanus, botulinum, and cholera toxins using ganglioside-bearing liposomes. Tetanus and botulinum toxins selectively bind gangliosides of the G1b series, namely, GT1b, GD1b, and GQ1b; and cholera toxin binds GM1 very specifically. Unilamellar liposomes containing GT1b or GM1 as one of the constituent lipids were prepared by extrusion through polycarbonate membranes. To impart signal generation capability to these liposomes, fluorophore-labeled lipids were incorporated in the bilayer of liposomes. The fluorescent liposomes, containing both a marker (rhodamine) and a receptor (GT1b or GM1) in the bilayer, were used in sandwich fluoroimmunoassays for tetanus, botulinum, and cholera toxins and as low as 1 nM of each toxin could be detected. The apparent dissociation constants of liposome-toxin complexes were in 10(-8) M range, indicating strong binding. This is the first report on detection of tetanus and botulinum toxins based on specific recognition by gangliosides. The fluorescent liposomes are attractive as immunoreagents for another reason as well--they provide enormous signal amplification for each binding event as each liposome contains up to 22,000 rhodamine molecules. The present approach using receptors incorporated in bilayers of liposomes offers a unique solution to employ water-insoluble receptors, such as glycolipids and membrane proteins, for sensitive detection of toxins and other clinically important biomolecules.

Bacterial Toxins↗
PubMed1984

Both cholera toxin-induced adenylate cyclase activation and cholera toxin biological activity are inhibited by antibodies against related synthetic peptides.

The immune response against six synthetic peptides corresponding to various segments of the B subunit of cholera toxin was evaluated. Conjugates in which the peptides were covalently linked to tetanus toxoid served for immunization of rabbits. As previously reported, four of these conjugates elicited antibodies cross-reactive with intact cholera toxin. We report here that antisera against two of these synthetic peptides inhibit the entire spectrum of activities of the intact cholera toxin. This is manifested both on the biochemical level (adenylate cyclase induction) and on the biological effect (intestinal fluid secretion). These results indicate that these peptides may serve as suitable candidates for preparation of a synthetic anticholera vaccine.

Adenylyl Cyclases↗
PubMed1991

Slow toxins, biologic markers, and long-latency neurodegenerative disease in the western Pacific region.

The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototypical neurodegenerative disorder found among inhabitants of Guam, New Guinea (Irian Jaya, Indonesia) and Japan (Kii Peninsula, Honshu). Nonviral environmental factors peculiar to the affected populations seem to play a prominent etiologic role. Although cause-effect relationships cannot be established by epidemiologic studies alone, we have shown in all three affected population groups that individuals develop the amyotrophic lateral sclerosis variant of this disorder after heavy exposure to the raw or incompletely detoxified seed of neurotoxic cycad plants. Since long periods may elapse between cycad exposure and the appearance of neurological disease in humans, cycads may harbor a "slow toxin" that causes the postmitotic neuron to undergo slow irreversible degeneration. Two cycad neurotoxins are recognized, one of which (cycasin) is known to have long-latency effects (tumorigenesis) on mitotic neurons and replicating cells in other tissues. This paper explores the possible relationship between tumorigenesis and long-latency neurotoxicity, and discusses possible biologic markers of cycad exposure and subclinical neurodegenerative disease.

Biomarkers↗