Botulinum neurotoxin | Botulinum neurotoxin types and Therapy

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Botulinum Neurotoxin Context

In the XIX th century, the doctor Württemberg Justinus Kerner (1786-1862) described a mala-specific die of the campaign. Which was caused by the ingestion of raw or poorly prepared cold meats Reese.

This disease was called botulism poisoning (from the Latin botulus = gut, sausage). Those affected had symptoms of mild to severe muscle paralysis. Which can lead to death from asphyxiation (respiratory paralysis). Learn more about botulinum neurotoxin.

At the end of the XIX th century. The Belgian Emile van Ermengem identified after a devastating poisoning caused by raw ham. The microorganism responsible for the disease and the toxin it producesduit. Van Ermengem called this infectious agent Bacillus botulinus (which was later renamed Clostridium botulinum ). The condition caused by the toxin was later called botulism. Learn more about botulinum neurotoxin.

Clostridium Botulinum

Botulinum neurotoxin is usually derived from a species of Gram-positive bacteria, the Clos-tridium botulinum . It has also been found that a few rare strains of Clostridium speciesbaratii and Clostridium butyricum also produce botulinum neurotoxin. Learn more about botulinum neurotoxin.

C  botulinum is an exclusively anaerobic microorganism. But the spores it produces can also survive in an aerobic environment. And are found in soil all over the planet and especially in sediments freshwater and seawater. As C. botulinum spores colonize many places, contamination of the food is easy since a simple contact is enough.

Due to lack of hygiene, sporesor C. botulinum vegetative cells can also contaminate food vs botulinum also develops. When the food preservation process is incomplete and that the latter are also hermetically packaged. The resulting toxins spreadtooth in the environment and thus reach edible foodstuffs. The consumption, even small amounts of contaminated food can trigger symptoms of poisoningso-called botulism. Learn more about botulinum neurotoxin.

Botulism Botulinum Neurotoxin

The first symptoms of poisoning may appear only a few hours after the consumption of contaminated food. Typically, increasing paralysis disorders begincent in eye and mouth muscle training, such as double vision, numb tongue and speech difficulties.

The peripheral muscles of the limbs follow: flaccid paralysis arms and legs. The paralysis then progresses inside the body where it affects ultimately the diaphragm, causing respiratory paralysis, circulatory arrest and death. Unlike bacterial or viral diseases, such poisoning is not contagious. Learn more about botulinum neurotoxin.

The bacillus is transmitted only by eating spoiled food or by contact with a source of contamination. Infant botulism or infant botulism is distinguished from classical botulism due to the multiplica-tion of C. botulinum. And the continued production of neurotoxins in the baby’s digestive system.

It affects children under 12 months of age and immunocompromised adults. A third type of business fection is injury botulism, originating from (open) wounds infected with C. botulinum. And by continuous secretion of neurotoxins. This botulism mainly concerns drug addicts doing intravenous injection. Learn more about botulinum neurotoxin.

 

Therapy Of Botulinum Neurotoxin

There is no medicine for botulism, because the toxins that have entered the neurons can no longer be disabled. But it is possible to block their action by the administra-tion of an antitoxin (antibody) as long as they are in the bloodstream. Learn more about botulinum neurotoxin.

In case severe poisoning and advanced paralysis. Artificial respiration may be necessary during for a period of up to 6 months. While waiting for the affected neurons to have reconstituted new synapses. In the past, laboratory personnel working on botulinum neurotoxin were inoculated with a vaccine consisting of inactivated toxin.

This practice is not recommended nowadays, due to a possible resistance to possible subsequent clinical treatment with this neurotoxin. Learn more about botulinum neurotoxin.

Composition / Structure Of Botulinum Neurotoxin

Botulinum neurotoxin is a protein genic toxin. C. botulinum synthesizes it asisolated peptide chain, which splits in two in the cytoplasm. The heavy chain (HC =Heavy Chain) with a molecular weight of approx. 100 kDa and the light chain (LC = Light Chain) of approx.50 kDa, linked to each other by a disulfide bridge (Fig. 1). Learn more about botulinum neurotoxin.

The heavy chain has two domains. They agree particular required at the level of the motor end plate of cholinergic neurons. And translocation of the toxin into the cell read them. The light chain is a zinc end protease that selectively cleaves, in the neuron. The SNARE proteins of motor endplates and inhibits the transmission of nerve impulses to muscles. There are 7 botulinum neurotoxin serotypes, named alphabetically types A to G. Learn more about botulinum neurotoxin.

In addition, each serotype is subdivided into several subtypes such as eg. A1to A4. These serotypes and their subtypes are secreted by different strains of C. botulinum .The serotypes are distinguished both by their amino acid sequence (level up to approx.30%) than by their action.

Human Botulism

Thus, types A and E cleave the SNARE SNAP-25 protein, typesB, D, F and G synaptobrevin, also called VAMP and type C1 syntaxin and SNAP-25. The amino acid sequence of the subtypes can also vary greatly (up to about 16%).Types A, B, E and F are the cause of human botulism. Learn more about botulinum neurotoxin.

In the majority of cases, intoxication comes from the toxin secreted by type A. At the same time as the toxin, it also forms NAPs (neurotoxin associated Proteins). The complex resulting from the association with these proteins increases the stability, both thermal. And acidic environment, toxin, which is not without consequences during gastrointestinal transit. Learn more about botulinum neurotoxin.

We also suppose that the protein complex intervenes during the passage of the digestive system in the bloodstream. These NAPs give the toxin complex a molecular weight of650 to 900 kDa.

Action mechanism Of Botulinum Neurotoxin

During the digestion of contaminated food, botulinum neurotoxin enters the intestines into the bloodstream. And then in cholinergic neurons which regulate the transmission of nerve impulse to muscle cells.

At the level of the motor end plate synapses. The toxin binds to two specific surface receptors through the domain of heavy chain binding. And then enters the cytoplasm by endocytosis under the action of heavy chain translocation domain. Learn more about botulinum neurotoxin.

The end protease domain of the light chain de-increases its activity at this stage. And specifically fractionates proteins of the SNARE complex. That inhibits the fusion of synaptic vesicles, containing the neurotransmitter acetylcholine, with the Plasma membrane of the motor end plate.

The transmission of nerve impulses between the neuron and muscle cell is thus interrupted. Because the neurotransmitter is not more liberated in the intersynaptic space (Fig 2).

Toxicity

Botulinum neurotoxin is considered to be the strongest poison found in nature. Its toxi-oral city of approx. 1μg / person is a thousand times greater than that of vegetable ricin and clearly larger than that of VX combat gas.

Its toxicity in case of inhalation is much higher Again. As the toxin is more stable in the form of a complex, the latter is deemed to be more toxic; by ail-Their toxicity also varies depending on the serotype or subtype.

Detection

The demonstration of poisoning is carried out as standard by the lethal test in mice (DIN10’102). Botulism is diagnosed in clinical samples (serum or stool) after neutralization of toxicity by addition of antitoxin.

The samples are diluted in apon phosphate-gelatin and injected into mice (approx. 20 g) at doses of 100 to 1000 μl in order to observe the possible appearance of symptoms characterizing the presence of botulinum neurotoxinlique.

For botulinum neurotoxicant type A for example, LD 501 is located at approx. from 5 to20pg / mouse. Immunological tests or other functional tests, such as measuring end protein activity of the light chain by detection of the final product (by means of mass spectrometry by example) are other standard methods of highlighting.

Botulinum neurotoxin used as a biological combat agent

Iraq and the former Soviet Union in particular have been major producers of botulinum neurotoxin. Some terrorist groups such as the Aum sect have also attempted to gain possession of this biological agent.

But its massive use has never happened yet. However, botulinum neurotoxin remains a formidable substance in the event of attacks biological terrorists. In the first place, there is a fear of botulinum toxin contamination of the food supplies.

Some minor incidents have already been recorded, although no link with aterrorist group has not been established. It is generally difficult to acquire and cultivate a strain of C. botulinum, and the production of its toxin is just as much.

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