Tetanus is caused by a powerful neurotoxin, tetanus toxin (TeNT) or tetanospasmin, produced by the anaerobic bacterium Clostridium tetani. This toxin targets the nervous system, leading to characteristic symptoms. The bacterium’s spores can survive in various environments and typically enter the body through contaminated wounds.
The Tetanus Toxin: Structure and Journey
Tetanus toxin is a protein of about 150 kilodaltons (kDa). It consists of two distinct polypeptide chains: a heavy chain (H) of about 100 kDa and a lighter chain (L) of approximately 50 kDa, linked by a disulfide bond. The heavy chain binds the toxin to nerve cells and facilitates entry, while the light chain is the active enzymatic part.
The toxin typically enters through deep puncture wounds contaminated with Clostridium tetani spores, where anaerobic conditions allow bacterial growth and toxin production. Once released, the toxin binds to receptors on peripheral motor neurons. It is then internalized and transported in a retrograde fashion, meaning it travels backward along the axon, to the cell body in the spinal cord or brainstem, reaching the central nervous system where it exerts its effects.
Targeting the Nervous System: Neuronal Entry
In the spinal cord or brainstem, tetanus toxin is released from motor neurons and taken up by inhibitory interneurons. These inhibitory neurons, which primarily use neurotransmitters like GABA (gamma-aminobutyric acid) and glycine, are the toxin’s specific targets. The heavy chain facilitates this targeting by binding to receptors like polysialylated gangliosides and synaptic vesicle glycoprotein 2 (SV2) on the neuron surface.
After binding, the toxin is internalized into inhibitory neurons via endocytosis. This process forms vesicles (endosomes) that encapsulate the toxin and bring it into the neuronal cytoplasm. Acidification within these endosomes triggers a conformational change in the toxin, allowing the light chain to translocate into the neuronal cytosol for its destructive enzymatic activity.
Disrupting Synaptic Communication: The Core Mechanism
Inside the inhibitory neuron cytoplasm, the tetanus toxin light chain acts as a zinc-dependent protease. This means it requires a zinc atom to function as an enzyme. It targets and cleaves VAMP2 (synaptobrevin-2), a protein on the membrane of synaptic vesicles that store neurotransmitters.
VAMP2 is part of the SNARE complex, proteins essential for synaptic vesicle fusion with the presynaptic membrane, which releases neurotransmitters into the synaptic cleft. By cleaving VAMP2, the toxin prevents correct SNARE complex formation. This blocks the fusion of synaptic vesicles containing inhibitory neurotransmitters (GABA and glycine) with the presynaptic membrane, preventing their release. The result is a significant loss of inhibitory signals in the central nervous system, leading to unchecked neuronal excitation.
From Cellular Disruption to Clinical Symptoms
Blocked inhibitory neurotransmitter release in the spinal cord and brainstem leads to uncontrolled motor neuron excitation. Normally, inhibitory signals regulate muscle contractions, allowing muscles to relax after contracting. Without this inhibition, motor neurons become overactive, causing continuous muscle contraction and the characteristic symptoms of tetanus.
This disinhibition manifests as generalized muscle rigidity and painful, involuntary spasms. Common symptoms include trismus (lockjaw), where jaw muscles tighten, making it difficult to open the mouth. Opisthotonos, an arching of the back due to severe spasms of back and neck muscles, can also occur. Spasms of respiratory and laryngeal muscles can cause difficulty swallowing and breathing, potentially leading to respiratory failure, which is a common cause of death in severe cases. The painful spasms can be triggered by external stimuli like noise or touch and may persist for several weeks.