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PubMed2003

Identifying and modulating disulfide formation in the biopharmaceutical production of a recombinant protein vaccine candidate.

Structural conversion of the serotype A recombinant botulinum neurotoxin heavy chain fragment (rBoNTA(Hc)) produced intracellularly in Pichia pastoris yeast was observed and characterized during purification development efforts. A pH screening study captured the transformation stages of the original recovered species into its derived counterpart and a number of analytical tools such as peptide mapping by LC/MS confirmed the formation of a disulfide bond, especially in samples of neutral to basic pH. A cation exchange chromatographic method proved useful in following the incidence of the reaction in various rBoNTA(Hc) samples. The disulfide formation kinetics were characterized using a one-quarter quadratic factorial design, following the investigation and development of controlled oxidation conditions using cysteine and cystamine as the redox pair. Temperature, pH and concentration of the redox pair had a significant effect on the yield and rate of the disulfide formation. This controlled reaction was eventually introduced as a functional unit operation in the purification process. The summation of preliminary scale-up and potency data showed scalability and robustness in the production of an active disulfide-bonded form of a recombinant botulism vaccine candidate. The presence of the disulfide bond did not effect the vaccine potency and it enhanced the molecule's thermal stability.

Amino Acid Sequence↗
PubMed1996

Mapping of protective and cross-reactive domains of the type A neurotoxin of Clostridium botulinum.

The purpose of this study was to identify the location of domains within the serotype A neurotoxin of Clostridium botulinum (BoNT/A) that conferred protection against botulism. The BoNT/A gene was subcloned into a series of 10 overlapping fragments that were expressed in Escherichia coli. The expressed proteins were partially purified and used to immunize mice. The resulting antisera were screened by immunoblotting analysis for the presence of BoNT/A-specific antibody. All fragments, except one, elicited antibody that recognized BoNT/A in an immunoblot. Serological screening identified several fragment-specific cross-reactive epitopes that were shared by heterologous serotypes of BoNT. Most of these epitopes immunoreactive by enzyme-linked immunosorbent assay, but not by immunoblot. Only two fragments were shown to confer protection against BoNT/A intoxication. Both of these proteins were derived from segments of the heavy chain and encoded amino acid residues H455-661 and H1150-1289 of BoNT/A.

Animals↗
PubMed2003

The basic science of botulinum toxin.

Understanding the basic science of botulinum toxin should serve as a fundamental first step for clinical therapy. This article endeavors to cover many aspects of basic research that also have clinical import. The two principal toxins of the clostridial family, Clostridium tetani and C botulinum, are described in detail. The five clinical manifestations of botulism poisoning are also outlined, and structural aspects and the mechanism of action of botulinum toxin are then presented. Finally, the immunologic and pharmacologic principles that define the various serotypes of botulinum toxin are set forth.

Animals↗
PubMed1995

Structure and function of tetanus and botulinum neurotoxins.

Tetanus and botulinum neurotoxins are produced by Clostridia and cause the neuroparalytic syndromes of tetanus and botulism. Tetanus neurotoxin acts mainly at the CNS synapse, while the seven botulinum neurotoxins act peripherally. Clostridial neurotoxins share a similar mechanism of cell intoxication: they block the release of neurotransmitters. They are composed of two disulfide-linked polypeptide chains. The larger subunit is responsible for neurospecific binding and cell penetration. Reduction releases the smaller chain in the neuronal cytosol, where it displays its zinc-endopeptidase activity specific for protein components of the neuroexocytosis apparatus. Tetanus neurotoxin and botulinum neurotoxins B, D, F and G recognize specifically VAMP/ synaptobrevin. This integral protein of the synaptic vesicle membrane is cleaved at single peptide bonds, which differ for each neurotoxin. Botulinum A, and E neurotoxins recognize and cleave specifically SNAP-25, a protein of the presynaptic membrane, at two different sites within the carboxyl-terminus. Botulinum neurotoxin type C cleaves syntaxin, another protein of the nerve plasmalemma. These results indicate that VAMP, SNAP-25 and syntaxin play a central role in neuroexocytosis. These three proteins are conserved from yeast to humans and are essential in a variety of docking and fusion events in every cell. Tetanus and botulinum neurotoxins form a new group of zinc-endopeptidases with characteristic sequence, mode of zinc coordination, mechanism of activation and target recognition. They will be of great value in the unravelling of the mechanisms of exocytosis and endocytosis, as they are in the clinical treatment of dystonias.

Amino Acid Sequence↗
PubMed1994

The production of Clostridium botulinum type A, B and D toxin in rotting carcasses.

Carrion is a major source of botulinal toxin for animals. A type D strain of Clostridium botulinum differed from type A and B strains in producing (1) much higher concentrations of toxin in putrefying mouse carcasses at several different temperatures over a period of 35 days, (2) toxicity that sometimes persisted in mouse carcasses for at least a year, and (3) mouse carcasses with exceptionally high oral toxicity. Fish carcasses were much less favourable than mouse carcasses for type D toxigenesis. The study, together with earlier studies on types C and E, indicated that carrion contaminated with C. botulinum type C or D is likely to be particularly dangerous for animals that may ingest it. This accords with the observation that carrion-transmitted botulism in animals is usually caused by type C or D.

Animals↗
PubMed1995

Expression and purification of the light chain of botulinum neurotoxin A: a single mutation abolishes its cleavage of SNAP-25 and neurotoxicity after reconstitution with the heavy chain.

Botulinum neurotoxin type A (BoNT/A) selectively and irreversibly inhibits acetylcholine release from peripheral nerve endings. While the toxin's heavy (H) chain contributes to neuronal binding and internalization, its light (L) chain is a Zn(2+)-dependent endoprotease that intracellularly cleaves synaptosomal-associated protein of M(r) = 25 kDa (SNAP-25). For research and clinical exploitation of this uniquely-acting neurotoxin, recombinant wild-type L chain was produced together with a mutant in which His227 in the Zn(2+)-binding motif was substituted by Tyr. The PCR-amplified wild-type and mutant L chain genes were cloned, fused to the gene for maltose-binding protein, and expressed at high levels in Escherichia coli. The soluble fusion proteins were purified using amylose affinity chromatography, and, after factor Xa cleavage, the free L chains were isolated. The wild-type was shown to proteolyze SNAP-25 at a rate approaching that of the native chain while the mutant was inactive. Reconstitution of the pure wild-type L chain with native homogeneous H chain yielded a disulfide-linked dichain form that inhibited neuromuscular transmission in vitro and produced the symptoms of botulism in vivo. After reconstitution with the H chain, the Tyr227 mutant L chain failed to show any neuroparalytic activity in either of these assays. This methodology allows, for the first time, routine preparation of recombinant forms of the L chain that are needed to decipher the molecular details of its interaction with substrate and, thereby, assist the design of effective inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP-Binding Cassette Transporters↗
PubMed2006

The use of small molecules to investigate molecular mechanisms and therapeutic targets for treatment of botulinum neurotoxin A intoxication.

Botulinum neurotoxins (BoNTs) are agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and subsequent flaccid paralysis. The potent paralytic ability of these toxins has resulted in their use as a therapeutic; however, BoNTs are also classified by the Centers for Disease Control and Prevention as one of the six highest-risk threat agents of bioterrorism. Consequently, a thorough understanding of the molecular mechanism of BoNT toxicity is crucial before effective inhibitors and, ultimately, an approved drug can be developed. In this article, we systematically detail BoNT intoxication by examining each of the discrete steps in this process. Additionally, rationally designed strategies for combating the toxicity of the most potent BoNT serotype are evaluated.

Animals↗
PubMed2006

Identification of a potent botulinum neurotoxin a protease inhibitor using in situ lead identification chemistry.

[reaction: see text] Botulinum neurotoxins (BoNTs), etiological agents of the deadly food poisoning disease botulism, are the most toxic proteins currently known. By using in situ lead identification chemistry, we have uncovered the first class of inhibitors that displays nanomolar potency. From a 15 microM lead compound, structure-activity relationship studies were performed granting the most potent BoNT/A inhibitor reported to date that displays an inhibition constant of 300 nM.

Botulinum Toxins, Type A↗
PubMed2005

Neurological syndromes among horses in The Netherlands. A 5 year retrospective survey (1999-2004).

The presence of toxins or infectious agents combined with environmental factors in combination with a susceptible host can be the cause for neurological disease in groups of horses. During a 5 year observational period outbreaks of neurological diseases among horses were evaluated. Causes of occurring neurological diseases were equine botulism, lolitrem intoxications, equine herpesvirus type 1-associated myelo(encephalo)pathy, and encephalitis caused by (disseminated) Streptococcus equi subspecies equi infection. This article focuses on the first three syndromes because of their predominant influence on locomotion. The pathogenesis of each disease is presented, followed by a description of a general presentation of the diseases as encountered under Dutch circumstances.

Animals↗
PubMed2003

Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells.

Botulinum neurotoxins (BoNTs) cause botulism by entering neurons and cleaving proteins that mediate neurotransmitter release; disruption of exocytosis results in paralysis and death. The receptors for BoNTs are thought to be composed of both proteins and gangliosides; however, protein components that mediate toxin entry have not been identified. Using gain-of-function and loss-of-function approaches, we report here that the secretory vesicle proteins, synaptotagmins (syts) I and II, mediate the entry of BoNT/B (but not BoNT/A or E) into PC12 cells. Further, we demonstrate that BoNT/B entry into PC12 cells and rat diaphragm motor nerve terminals was activity dependent and can be blocked using fragments of syt II that contain the BoNT/B-binding domain. Finally, we show that syt II fragments, in conjunction with gangliosides, neutralized BoNT/B in intact mice. These findings establish that syts I and II can function as protein receptors for BoNT/B.

Amino Acid Sequence↗
PubMed2003

Bioterrorism web site resources for infectious disease clinicians and epidemiologists.

Finding bioterrorism-related information on the World Wide Web can be laborious. We hope to help readers find such information more easily by summarizing essential information in a consistent framework. A panel of 7 Centers for Disease Control and Prevention reviewers identified Web sites and evaluated them for sponsorship, mission, content usefulness, online ease of use, and adherence to commonly accepted quality criteria. Of >100 potential sites identified, 81 were chosen for target content of interest, and 43 were selected for inclusion. The results were classified into general purpose/portal sites; biological agent information; laboratory, infection control, epidemiology, and mental health information; and emergency contact sources, news and updates, event preparedness resources, information for first-responder settings, clinical and public education materials, and research resources. Agents covered included anthrax, smallpox, plague, botulism, tularemia, and viral hemorrhagic fever.

Anthrax↗
PubMed1997

Update on Pan-American research on anaerobes: the situation in Argentina.

The study of anaerobic bacteria became important in Argentina when the first outbreak of botulism was reported in Mendoza in 1922. In the 1970s, the emphasis was on the development of methods to obtain suitable samples for isolation and identification of anaerobic bacteria. In 1985, a working group belonging to the Argentine Association of Microbiology was organized to study anaerobic bacteria and infections. Last year, I became involved with the immunologic, microbiological, and epidemiological features of periodontitis. Other investigators in our country are studying Clostridium difficile, Campylobacter species, and Helicobacter species as well as lactobacilli, Propionibacterium species (as probiotics to protect the gastrointestinal tracts of children), anaerobic veterinary infections, food contamination by anaerobes, and biotechnological applications of anaerobes.

Argentina↗
PubMed1981

Isolation of Clostridium botulinum type G and identification of type G botulinal toxin in humans: report of five sudden unexpected deaths.

Clostridium botulinum type G has not been identified until now from humans or animals; it has been isolated only twice, from soil samples in Argentina. Type G organisms were isolated from necropsy specimens in four adults and an 18-week-old infant. Type G botulinal toxin was demonstrated in the serum of three of these individuals. The toxic dose in mice ranged from 2 to 7 50% lethal doses/ml. These persons died suddenly and unexpectedly at home, without any pathologic evidence to account for the cause of death in four cases. Symptoms in two individuals were similar to those observed in food-borne botulism. Thus, a prompt postmortem search for toxin and organisms of C. Botulinum in blood and feces may be worthwhile in determining the etiology of unexplained deaths. More microbiologic, physiologic, and toxicologic data are needed to clarify the role of C. botulinum in the pathogenesis of sudden unexpected death in infants and adults.

Adult↗
PubMed2006

Transport of bacterial toxins into target cells: pathways followed by cholera toxin and botulinum progenitor toxin.

A number of bacterial toxins have sophisticated mechanisms for reaching their specific targets in mammalian cells, to exert their toxicity. This review focuses on the transport mechanisms of cholera toxin and botulinum neurotoxin complex. Cholera toxin is an ADP-ribosyltransferase toxin, and the covalent modification of heterotrimeric Gs protein in the cytosol leads to the activation of adenylyl cyclase and a sequence of events culminating in massive diarrheal disease. Here, we describe the structural features of this toxin and the transport pathway followed by this toxin from the plasma membrane to the cytosol of intestinal epithelial cells. Botulinum neurotoxin is a metalloprotease toxin that enters neurons, where it cleaves core proteins of the neuroexocytosis apparatus and elicits the inhibition of neurotransmitter release. The food-borne botulism is manifested when the neurotoxin is absorbed from the digestive tract, enters the blood stream, and reaches the cytosol of the peripheral nerves. We overview the structural organization and the long journey followed by this toxin.

Botulinum Toxins↗
PubMed2005

Bioterrorism and smallpox: policies, practices, and implications for social work.

Terrorist acts and the fear of terrorism have become a part of everyday life in the early 21st century. Among the threats most feared is bioterrorism, including the intentional release of smallpox. With the invasion of Iraq and toppling of the Saddam Hussein regime, acute bioterrorism fears have abated; however, an ongoing threat remains.This article addresses the need for knowledge and rational policies in dealing with potential bioterrorism attacks. It presents information on four of the most likely bioterrorism agents: smallpox, anthrax, botulism, and plague. It illustrates the importance of accurate knowledge and rational decision making in addressing the threat of terrorism through the intentional release of biological weapons such as smallpox. Finally, it provides information essential for social workers to make informed practice decisions, to educate clients and the public, and to advocate for sound public policy.

Anthrax↗
PubMed1976

Anaerobic infections: diagnosis and treatment.

Anaerobic bacteria outnumber aerobic bacteria in normal flora in the oropharynx and gastrointestinal tract. They are important and frequent causes of infection, although they often go unrecognized except in the classic and very distincitve clostridial infections and intoxications-gas gangrene, botulism, and tetanus. Although anaerobic infections often originate close to a muscosal surface where anaerobes are part of the normal flora, they may occur anywhere in the body via direct of hematogenous spread. Clues to diagnosis include a foul-smelling discharge, gas, necrotic tissue, abscess formation, the unique morphology of certain anaerobes on Gram's Stain, and failure to obtain growth on aerobic culture despite the presence of organisms on Gram-stained direct smear. Predisposing conditions include aspiration, vascular insufficiency, trauma, malignancy, and previous antimicrobial therapy. Clinical suspicion requires confirmation of diagnosis by appropriate collecting, transport and culturing of specimens while excluding contamination with anaerobes from the normal flora. Treatment usually requires a combination of surgical and medical measures. Penicillin G is the drug of choice for virtually all anaerobic infections except those caused by Bacteroides fragilis, which require chloramphenicol or clindamycin. Investigational agents also appear promising in the treatment of anaerobic infections.

Anaerobiosis↗
PubMed1981

Differential diagnosis of acute weakness.

Muscle weakness evolving rapidly over hours to days demands prompt diagnosis and proper treatment to prevent life-threatening respiratory insufficiency. Such weakness usually results from disease affecting some portion of the motor unit, such as poliomyelitis, Guillain-Barré syndrome, botulism, and dyskalemic myopathy. The differential diagnosis of these processes is discussed.

Botulism↗
PubMed1982

Hypotonia in infants and children.

Many diseases in the pediatric population present with hypotonia and/or weakness. In order to ensure proper diagnosis and facilitate appropriate treatment, the nurse must be familial with those diseases which produce motor unit dysfunction in infants and children; among these conditions are infantile botulism and Guillain-Barré Syndrome. An understanding of the particular features which distinguish central from peripheral hypotonia is essential for the nurse. It is also important to obtain detailed histories and to ensure thorough physical examination. The nurse should also be aware of those laboratory studies that evaluate hypotonia and weakness, including the EMG, PNCT, muscle biopsy, and lumbar puncture.

Botulism↗