Clostridium: Botulism and Tetanus Neurotoxins

• Clostridia produce neurotoxins, leading to diseases like botulism and tetanus.
• Botulism and tetanus are caused by exotoxins released by Clostridium botulinum and Clostridium tetani, respectively.

Botulinum Neurotoxin

• There are several types of botulinum toxins (A-G), but human diseases are typically caused by types A, B, or E.
• Botulinum toxin has an activity domain (A domain) and a binding domain (B domain).
• Classical botulism is acquired through food poisoning; infant botulism is common in the US; wound botulism is rare.
• Infant botulism is contracted through infant foods contaminated with Clostridium botulinum spores.
• The toxin is absorbed from the gut, enters the bloodstream, and reaches peripheral nerve synapses.
• Botulinum toxins mechanism of action occurs at the neuromuscular junction, where acetylcholine is released.
• An action potential triggers acetylcholine-containing vesicles to fuse and release acetylcholine into the synaptic cleft.
• Acetylcholine binds to the postsynaptic muscle membrane, initiating muscular contraction
• Synaptic fusion requires a synaptic fusion complex made of snare proteins.
• Synaptobrevin (VAMP) is located on the acetylcholine vesicle, while SNAP-25 and syntaxin are on the neuronal membrane.
• SNARE complex formation releases energy required for membrane fusion.
• Botulinum toxins target the SNARE core complex.
• If SNARE proteins are damaged, acetylcholine vesicles cannot fuse, preventing acetylcholine release.
• Botulinum toxin type B's heavy chain binds to synaptotagmin; the light chain enters the vesicle via endocytosis.
• The light chain cleaves synaptobrevin, preventing acetylcholine vesicles from fusing, causing chemo-denervation
• Chemo-denervation inhibits synaptic transmission, ceasing muscle contraction
• Smaller, unmyelinated nerve endings (peripheral sprouts) form to restore neurotransmission.
• Light chains degrade within the affected nerve terminal, allowing normal neurotransmission to be re-established and the nerve endings to retract.
• Peripheral sprouting starts around 28 days with normal nerve transmission re-established in approximately three months post-injection.
• Symptoms include drooping eyelids, difficulty swallowing, dry mouth, facial weakness, trouble breathing, nausea, vomiting, and flaccid paralysis.

Clostridium Tetani Neurotoxin

• Clostridium tetani spores release this neurotoxin after entering wounds (even small ones) via contaminated soil.
• This disease is commonly seen in older individuals.
• Tetanospasmin is an extremely potent toxin.
• The toxin travels from the infection site through retrograde neuronal flow or blood.
• The metro toxin has two domains, A and B, held together by a disulfide bond.
• Tetanus is caused by a toxin from Clostridium tetani that attacks the central nervous system, causing muscle spasms.
• Symptoms include lockjaw, stiffness of limbs, and arching of the neck and spine.
• Spasms are painful and can cause bone fractures, tendon ruptures, and dislocations.
• Death often results from respiratory failure or cardiac arrest.
• In newborns, infection can enter via the umbilical stump.
• Unhygienic conditions or deep puncture wounds (e.g., stepping on a nail) can cause tetanus
• It cannot spread from person to person.
• Clostridium tetani spores germinate in low-oxygen conditions within deep wounds.
• The spores release tetanospasmin.
• Skeletal muscles are controlled by motor neurons.
• An electrical message goes down the axon to the motor neuron and stimulates nerotransmitters.
• Chemical neurotransmitters are released to cause muscle contractions.
• Inhibitory interneurons prevent motor neurons from constantly firing.
• Tetanospasmin interferes with inhibitory interneurons, preventing the release of inhibitory neurotransmitters.
• The interneuron can no longer control the motor neuron, so the motor neuron fires constantly.
• Many motor neurons that have lost control and are constantly firing.
• The loss of inhibitory control leads to continuous release of neurotransmitters, causing repeated muscle contractions and spasms.