Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normally encountered. It is also called spasmogenic toxin, or TeNT. The LD50 of this toxin has been measured to be approximately 1 ng/kg, making it second only to Botulinum toxin H as the deadliest toxin in the world. However, these tests are conducted solely on mice which may react to the toxin differently from humans and other animals.
Tetanus toxin spreads through tissue spaces into the lymphatic and vascular systems. It enters the nervous system at the neuromuscular junctions and migrates through nerve trunks and into the central nervous system (CNS) by retrograde axonal transport by using dyneins.
The tetanus toxin protein has a molecular weight of 150kDa. It is translated from the TetX gene as one protein which is subsequently cleaved into two parts: a 100kDa heavy or B-chain and a 50kDa light or A-chain. The chains are connected by a disulfide bond.
- The B-chain binds to dissialogangliosides (GD2 and GD1b) on the neuronal membrane and contains a translocation domain which aids the movement of the protein across that membrane and into the neuron.
- The A-chain, a zinc endopeptidase, attacks the vesicle-associated membrane protein (VAMP).
The TetX gene encoding this protein is located on the PE88 plasmid.
Several structures of the binding domain and the peptidase domain have been solved by X-ray crystallography and deposited in the PDB. A summary of these structures is available using the UniPDB application at PDBe, for example or .
The action of the A-chain stops the affected neurons from releasing the inhibitory neurotransmitters GABA and glycine, but also excitatory transmitters, by degrading the protein synaptobrevin 2. The consequence of this is dangerous overactivity in the muscles from the smallest stimulus—the failure of inhibition of motor reflexes by sensory stimulation. This causes generalized contractions of the agonist and antagonist musculature, termed a tetanic spasm.
Tetanic spasms can occur in a distinctive form called opisthotonos and be sufficiently severe to fracture long bones. The shorter nerves are the first to be inhibited, which leads to the characteristic early symptoms in the face and jaw, risus sardonicus and lockjaw.
The toxin bind to the neurons is irreversible and nerve function can only be returned by the growth of new terminals and synapses.
Immunity and vaccination
Due to its extreme potency, even a lethal dose of tetanospasmin may be insufficient to provoke an immune response. Naturally-acquired tetanus infections thus do not usually provide immunity to subsequent infections. Immunization (which is impermanent and must be repeated periodically) instead utilizes the less deadly toxoid derived from the toxin, as in the tetanus vaccine and some combination vaccines such as DPT.
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