Toxins

The vegetative forms of C. tetani release two exotoxins: tetanolysin, which is of little clinical importance, and tetanospasmin, also known as tetanus toxin, which is responsible for all the manifestations of tetanus.

The genetic information for tetanospasmin is encoded on a single plasmid. Infections with strains of C. tetani lacking this plasmid do not result in tetanus. It is synthesized as a single polypeptide chain, and post-translational changes (disulfide bridge formation and strand cleavage) produce one heavy chain (100 kDa) and one light chain (50 kDa). Hematogenous spread is followed by uptake at neuromuscular junctions mediated by the heavy chain of tetanospasmin. Retrograde transportation to the cell body and across the synaptic cleft into the presynaptic neuron then occurs. Once within the presynaptic neuron, the light chain of tetanospasmin mediates inhibition of transmitter release.

The release of neurotransmitter in response to neuronal depolarization requires docking of synaptic vesicles with the presynaptic membrane. Calcium-mediated fusion of vesicle and membrane then occurs, releasing neurotransmitter into the synaptic cleft. Because the light chain of tetanospasmin is a zinc-dependent endoprotease, it is thought to cleave one of the docking proteins, specifically vesicle-associated membrane protein, also known as synaptobrevin ( Fried.1995). This explains the finding that 'intoxicated' presynaptic terminals contain normal amounts of neurotransmitter but release subnormal quantities when stimulated. Angiotensin-converting enzyme is also a zinc-dependent endoprotease. Tetanospasmin-mediated production of angiotensin II may contribute to hypertension in tetanus. Treatment of tetanospasmin-inhibited neurons with angiotensin-converting enzyme inhibitors or zinc chelators has restored neurotransmitter release ( Dayanithi etal 1994). The importance of these findings still has to be tested clinically.

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