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(please type) Explain the pathogenic mechanism of Tetanus. Be sure to include the importance of inhibitory...

(please type) Explain the pathogenic mechanism of Tetanus. Be sure to include the importance of inhibitory neurons, neurotransmitters and lockjaw.

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Tetanus is also known as lockjaw. It is a bacterial infection. It is characterized by muscle spasms and most commonly, the spasms begin in the jaw and then progress to the rest of the body. Tetanus is caused by an infection with the bacterium Clostridium tetani, which is commonly found in soil, saliva, dust and manure. It enters through a break in the skin such as a cut or puncture wound by a contaminated object. They produce toxins that interfere with normal muscle contractions. The disease does not spread between people.

Mechanism-

1.Neurospecific binding

The toxin travels from the wound site to the neuromuscular junction through the blood stream where it binds to the presynaptic membrane of a motor neuron. The heavy chain C-terminal domain aids in the binding to the correct site recognizing and binding to the correct glycoproteins and glycolipids in the presynaptic membrane. The toxin binds to a site that will be taken into the neuron as an endocytic vesicle that will travel all the way down the axon, past the cell body, and down the dendrites to the dendritic terminal at the spine and CNS. Here it will be released into the synaptic cleft and allowed to bind with the presynaptic membrane of inhibitory neurons in a similar manner seen with the binding to the motor neuron.

2. Internalization

Tetanus toxin is then internalized again via endocytosis , this time in an acidic vesicle. Depolarization caused by the firing of the inhibitory neuron causes the toxin to be pulled into the neuron inside vesicles.

3. Membrane translocation

The toxin then needs a way to get out of the vesicle and into the neuron cytosol in order for it to act on its target. The low pH of the vesicle lumen causes a confirmational change in the toxin shifting it from a water soluble form to a hydrophobic form. With the hydrophobic patches exposed, the toxin is able to slide into the vesicle membrane. The toxin forms an ion channel in the membrane that is non specific for Na+, K+, Ba2+,Cl- ions. This new channel is involved in the translocation for the toxin's light chain from the inside of the vesicle to the neuron cytosol. It has been proposed that the channel could allow the light chain to leave through the toxin pore, or that the pore could alter the electrochemical gradient enough, by letting in or out ions, to cause osmotic lysis of the vesicle, spilling the vesicle's contents.

4. Enzymatic target cleavage

The light chain of the tetanus toxin is a zinc-dependent protease. It shares a common zinc protease motif ( His-Glu-Xaa-His ) that researchers hypothesized was essential for target cleavage until this was more recently confirmed by experiment: when all zinc was removed from the neuron with heavy metal chelators, the toxin was inhibited, only to be reactivated when the zinc was added back in. The light chain binds to VAMP and cleaves it between Gln76 and Phe77. Without VAMP, vesicles holding the neurotransmitters needed for motor neuron regulation (GABA and Glycine) cannot be released, causing deregulation of motor neurons and muscle tension.

Tetanus often begins with mild spasms in the jaw muscles- known as lockjaw or trismus. The spasms can also affect the facial muscles resulting in appearance called risus sardonicus.

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