Page by Samantha Frawley
Introduction
Clostridium botulinum is a large, gram positive, rod-shaped bacteria
that forms endospores. C. botulinum flourishes in anaerobic conditions
and is killed when exposed to excessive amounts of oxygen. This bacteria
produces botulinum toxin, a neurotoxin which is responsible for the disease
known as botulism. The botulinum toxin is the most potent biological
toxin known to man. Clostridium botulinum can produce seven different
"types" of toxin; A, B, C, D, E, F, and G. Of these seven toxins,
types C, D, and G have not been linked to humans yet. Type A toxin
is the most lethal of the seven and is also the most common; 62 % of all
botulism cases are from type A. Clostridium botulinum is mostly found
in soil or water and is usually transferred to the food that it comes in
contact with. The most susceptible foods are low acid vegetables
grown in the affected soil or nourished with contaminated water.
High acid foods such as citrus fruits are not at risk because their low
pH kills off the bacteria and the bacteria's resistant endospores; clostridium
botulinum cannot grow at a pH of 4.5 of less. The most common way
people develop botulism is from the ingestion of improperly canned foods.
The endospores that clostridium botulinum produces are very resistant to
heat so extra care must be taken when people can food themselves.
If the foods are not heated properly or under enough pressure when canned,
then the endospores will not die and the bacteria can germinate.
The anaerobic conditions in the canned jar makes this scenario even worse
by setting the proper environment for clostridium botulinum to flourish.
In this day and age botulism is currently pretty obsolete (less than a
dozen cases reported in North America annually), however with the current
terrorism threat, biological warfare using C. botulinum is becoming much
more probable.
Picture of Clostridium Botulinum (Gram Stain)
History
The first case of botulism is believed to have occurred in 1735.
The next recorded case was not until 1793, when an epidemic of botulism
occurred in southern Germany. This epidemic claimed the lives of
half of the people who became infected. This outbreak was linked
to uncooked blood sausage that had been consumed by the victims.
It was not until 1897, however, that someone discovered what caused botulism.
Emile Pierre Marie van Ermengem found botulism to be caused from a toxin
produced by the bacteria C. botulinum. It was later discovered in
1949 that the pathogenesis of the botulinum toxin was from the blocking
of neuromuscular transmission. The research of botulinum toxin came
to the forefront in the late 1960's when Alan B. Scott, MD at Smith-Kettlewell
Eye Research Foundation and Edward J. Schantz , Ph.D and director of food
microbiology at the University of Wisconsin, worked together to use botulinum
toxin type A as a therapeutic agent. These men believed that type
A neurotoxin would be able to treat symptoms of neurological disorders.
Finally, it 1989, a research group was granted the rights to a form of
botulinum toxin type A, also known as BOTOX. BOTOX is currently being
administered to cases of strabismus (misalignment of the eyes) and blepharospasm
(involuntary blinking). These conditions are caused from dystonia,
a movement disorder which causes involuntary muscle contractions.
Work is also being done to approve this drug for the use of relieving migraines.
3-D representation of Botulinum Toxin Type A
What Botulinum toxin does to the body
The toxin binds to the presynaptic stimulatory terminals which then
blocks the release of acetylcholine, a neurotransmitter responsible for
muscle stimulation from the nerve. Through experimentation, it has
been found that this toxin has a preference for stimulatory motor neurons
at the neuromuscular junction, so it mainly affects the peripheral nerve
endings (peripheral nervous system). The bacterial toxin inhibits
the release of acetylcholine by cleaving synaptobrevins. Synaptobrevins
are responsible for releasing neurotransmitters and by cleaving these proteins
their function is lost. The actual mechanism on how the toxin cleaves
these synaptobrevins is not known but people believe the cleavage by the
toxin is zinc dependent (see ligand site in 3D representation of toxin).
Researchers have, however, determined what part of the toxin cleaves the
synaptobrevins. The actual toxin itself is not very potent.
The toxin is nicked by a protease, which produces two chains connected
together by a disulfide bond; a light chain (50 kDa) and a heavy chain
(100 kDa). Once the toxin is nicked, the activity of the toxin dramatically
increases. The way this toxin prevents the release of acetylcholine
happens in three steps; binding, internalization and inhibition of aceytlcholine.
The heavy chain is responsible for the binding activity and the light chain
is responsible for the inhibition (enzymatic activity). To watch
how the botulinum toxin works click here Animation
of Botulinum toxin (you must download Shockwave to view).
Human body effects from botulinum toxin
It usually takes anywhere from 18-36 hours (average) possibly even
as late an onset as eight days for there to be any signs of botulism.
Generally, the early warning signs of botulism are tiredness, dizziness,
difficulty swallowing or speaking, difficulty breathing, weakness of other
muscles, absence of a gag reflex and pupil dilation may occur as well.
Since the toxin prohibits the communication between the nerves and the
muscles by the lack of neurotransmitters, paralysis can begin to set in,
usually beginning with the eyes and the face and then progressively moving
downward to the extremities. If the person is left untreated, paralysis
of the diaphragm and the chest muscles occurs and the person becomes unable
to breath, which then leads to respiratory failure.
Treatments
The only way to combat this toxin is by the administration of tri-valent
antitoxin (anti A, B, and E) as soon as the victim has been diagnosed with
botulism. The antitoxin works by blocking the action of the toxin
circulating in the blood. Unfortunately, it does not have any affect
on any toxin already bound to the nerve endings. Once a synapse is
damaged it is no longer capable of functioning. Aother problem with
this antitoxin is that some people have shown an allergic response to the
treatment. Due to some sensitivity to the antitoxin, before it is
administered to the patient, they first must be tested for the allergy.
If they are allergic, desensitization is performed on the patient by giving
them small doses of the antitoxin. These extra steps taken also prolong
the patient from receiving treatment. Once the toxin is administered,
the patient can start on the road to recovery, unfortunatly this is not
complete until their body begins the formation of a new synapse which could
take a long time. In the advance stages of the disease, the patient
should be kept on a ventilator to assist their breathing. Even with
the antitoxin, there is a 20 % fatality rate. The patient's chances
depend on the amount of toxin in the body and the type of toxin the victim
consumed. After the patient has been checked out of the hospital,
months of intense physical therapy will follow. There is research
being done on a vaccine for the botulinum toxin, however it is only currently
avaliable to at-risk workers.
References
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