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The genus Clostridium comprises a number of spore forming Gram positive, rod shaped bacilli. They are found in the intestines of numerous mammalian species including domestic animals, horses, chickens, and humans. They are also widely distributed in the soil and in marine and freshwater sediments. Many clostridial species produce medically important toxins but the species of neurological interest (Clostridium tetani and Clostridium botulinum) produce neurotoxins. The toxins responsible for these neurotoxic syndromes are tetanus toxin (sometimes known as tetanospasmin) and the botulinum toxins.
THE TOXINS
Tetanus and botulinum toxins share several important features: they are produced as a single polypeptide of 75 kb which undergoes post-translational cleavage to form a heavy (H) chain and a lighter (L) chain of 100 kDa and 50 kDa, respectively, linked by a single disulfide bond. The H chain facilitates binding to gangliosides on the plasma membrane of peripheral nerve terminals before internalisation via receptor mediated endocytosis. Protonation of the endosome results in the reduction of the disulfide bond. The H chain forms a transmembrane pore across the endosome and the L chain then enters the nerve terminal cytosol. The L chains of both tetanus and botulinum toxins are zinc activated proteases. Their targets are a number of specific proteins involved in synaptic vesicle docking—synaptobrevin (also know as VAMP), SNAP-25, and syntaxin.1
The toxins selectively target individual proteins (table 1), but the result is always the same—the hydrolysis of the target protein, blockade of transmitter release, and a resultant flaccid paralysis. While the botulinum toxins remain in the nerve terminal the tetanus toxin is transported by retrograde axonal transport into the cell body and then by transynaptic exchange into the terminals of inhibitory neurones in the spinal cord and brain stem. The resultant inhibition of inhibitory transmission by the tetanus toxin results in the dominant clinical …