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== Background == | == Background == | ||
Botulinum Toxin (BTX) is produced by three species of obligate anaerobe bacterium, primarily ''Clostridium botulism'', but ''Clostridium baratii'' and ''Clostridium butyricum'' also produce the protein. <ref name="Hall"> PMID: 3988908</ref> <ref name="Aureli"> PMID: 3722863</ref> <ref name="Arnon"> PMID: 11209178</ref> ''Clostridium botulism'' is commonly found in soil, marine sediments, and the gut of grazing animals. <ref name="Ward"> PMID: 5340653</ref> <ref name="Smith"> PMID: 355208</ref> <ref>Sugiyama H. Clostridium botulinum neurotoxin. Microbiol Rev. 1980;44:419–448. 28. Dodds KL. Clostridium botulinum in the environment. In: Hauschild AHW </ref> <ref>Dodds KL, eds. Clostridium botulinum—Ecology and Control in Foods. New York, NY: Marcel Dekker, Inc; 1992: 21–51. 29. </ref> <ref name="Popoff"> PMID: 8542750</ref> BTX is only produced by these bacteria under anaerobic conditions that induce spore germination. Once produced, the protein can have toxic effects on animals and humans by causing botulism, a potentially fatal illness | Botulinum Toxin (BTX) is produced by three species of obligate anaerobe bacterium, primarily ''Clostridium botulism'', but ''Clostridium baratii'' and ''Clostridium butyricum'' also produce the protein. <ref name="Hall"> PMID: 3988908</ref> <ref name="Aureli"> PMID: 3722863</ref> <ref name="Arnon"> PMID: 11209178</ref> ''Clostridium botulism'' is commonly found in soil, marine sediments, and the gut of grazing animals. <ref name="Ward"> PMID: 5340653</ref> <ref name="Smith"> PMID: 355208</ref> <ref>Sugiyama H. Clostridium botulinum neurotoxin. Microbiol Rev. 1980;44:419–448. 28. Dodds KL. Clostridium botulinum in the environment. In: Hauschild AHW </ref> <ref>Dodds KL, eds. Clostridium botulinum—Ecology and Control in Foods. New York, NY: Marcel Dekker, Inc; 1992: 21–51. 29. </ref> <ref name="Popoff"> PMID: 8542750</ref> BTX is only produced by these bacteria under anaerobic conditions that induce spore germination. Once produced, the protein can have toxic effects on animals and humans by causing botulism, a potentially fatal illness. | ||
<Structure load='3BTA' size='350' frame='true' align='right' caption='Botulinum Toxin Neurotoxin Serotype A' scene='Insert optional scene name here' /> | <Structure load='3BTA' size='350' frame='true' align='right' caption='Botulinum Toxin Neurotoxin Serotype A' scene='Insert optional scene name here' /> | ||
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The light chain contains the <scene name='69/696299/Consensus_sequence_heilh/1'>consensus sequence HELIH</scene> that codes for the binding of zinc, which subsequently regulates the endopeptidase activity of the light chain. | The light chain contains the <scene name='69/696299/Consensus_sequence_heilh/1'>consensus sequence HELIH</scene> that codes for the binding of zinc, which subsequently regulates the endopeptidase activity of the light chain. | ||
BTX also has two auxiliary proteins that compromise a multimeric complex: hemagglutinins (HA) and nontoxic-nonhemagglutinin (NTNH). HA and NTNH do not directly play a role in the toxic effect of BTX, but have an indirect role during ingestion of the protein by making the BTX more resistant to low pH environments and proteolytic enzymes found in the gut. | BTX also has two auxiliary proteins that compromise a multimeric complex: hemagglutinins (HA) and nontoxic-nonhemagglutinin (NTNH). HA and NTNH do not directly play a role in the toxic effect of BTX, but have an indirect role during ingestion of the protein by making the BTX more resistant to low pH environments and proteolytic enzymes found in the gut. <ref name="Simpson"> PMID: 14744243</ref> | ||
== Function == | == Function == | ||
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Of the seven serotypes of BTX, the forms that most often cause botulism in humans are A, B, and E. <ref name="Arnon" /> Humans can be exposed to the neurotoxin through inhalation, ingestion, or surface wounds. The lethal doses for a human weighing 70 kg is 0.09-0.15 μg when administered intravenously or intramuscularly, 0.70 - 0.90 μg through inhalation, and 70 μg orally. <ref> Franz DR, Pitt LM, Clayton MA, Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. In: DasGupta BR, ed. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects. New York, NY: Plenum Press; 1993:473-476. </ref> <ref name="Herrero"> PMID: 4960839</ref> Within 12 to 72 hours of exposure to BTX, the inhibition of acetylcholine signaling at nerve synapses creates symptoms of vomiting, nausea, diarrhea, blurred vision, ptosis, dysarthria and dysphagia, and finally weakness of muscles beginning with the head and moving down to the lower extremities. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> If not treated, BTX can cause death due to respiratory failure or due to complications when on prolonged medical ventilation. | Of the seven serotypes of BTX, the forms that most often cause botulism in humans are A, B, and E. <ref name="Arnon" /> Humans can be exposed to the neurotoxin through inhalation, ingestion, or surface wounds. The lethal doses for a human weighing 70 kg is 0.09-0.15 μg when administered intravenously or intramuscularly, 0.70 - 0.90 μg through inhalation, and 70 μg orally. <ref> Franz DR, Pitt LM, Clayton MA, Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. In: DasGupta BR, ed. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects. New York, NY: Plenum Press; 1993:473-476. </ref> <ref name="Herrero"> PMID: 4960839</ref> Within 12 to 72 hours of exposure to BTX, the inhibition of acetylcholine signaling at nerve synapses creates symptoms of vomiting, nausea, diarrhea, blurred vision, ptosis, dysarthria and dysphagia, and finally weakness of muscles beginning with the head and moving down to the lower extremities. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> If not treated, BTX can cause death due to respiratory failure or due to complications when on prolonged medical ventilation. | ||
The treatment for human exposure to BTX is an antitoxin developed from horse plasma. Horses are exposed naturally to ''Clostridium botulism'' in their gut and therefore produce antibodies against ''Clostridium botulism'' to prevent the bacteria population from growing to an extreme. Antitoxins have been developed by isolating this antibody from horses, and in some cases, removing the Fc from the immunoglobulin and leaving the F(ab')2 fragment. By removing the Fc fragment, the incidence of hypersensitivity and anaphylaxis are reduced. There are divalent, trivalent, and heptavalent antitoxins available that treat botulinum serotypes A and B (divalent), serotypes A, B, and C (trivalent), and all seven serotypes (heptavalent). An antitoxin, botulism immune globulin (BabyBIG) has also been developed that can be used in infantile cases of botulism. BabyBIG is produced by using the human antibodies produced when a person is injected with pentavalent botulinum toxoid vaccine. By using human antibodies, there is less of a risk of anaphylactic shock and hypersensitivity to equine antigens. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> | The treatment for human exposure to BTX is an antitoxin developed from horse plasma. Horses are exposed naturally to ''Clostridium botulism'' in their gut and therefore produce antibodies against ''Clostridium botulism'' to prevent the bacteria population from growing to an extreme. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> Antitoxins have been developed by isolating this antibody from horses, and in some cases, removing the Fc from the immunoglobulin and leaving the F(ab')2 fragment. <ref>Franz DR, Pitt LM, Clayton MA, Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. In: DasGupta BR, ed. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects. New York, NY: Plenum Press; 1993:473-476.</ref> By removing the Fc fragment, the incidence of hypersensitivity and anaphylaxis are reduced. There are divalent, trivalent, and heptavalent antitoxins available that treat botulinum serotypes A and B (divalent), serotypes A, B, and C (trivalent), and all seven serotypes (heptavalent). An antitoxin, botulism immune globulin (BabyBIG) has also been developed that can be used in infantile cases of botulism. <ref>Lewis GE Jr. Approaches to the prophylaxis, immunotherapy,and chemotherapy of botulism. In: Lewis GE Jr, ed. Biomedical Aspects of Botulism. New York, NY: Academic Press; 1981: 261–270</ref> BabyBIG is produced by using the human antibodies produced when a person is injected with pentavalent botulinum toxoid vaccine. By using human antibodies, there is less of a risk of anaphylactic shock and hypersensitivity to equine antigens. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> | ||
The antitoxins cannot stop BTX from inhibiting acetylcholine signaling once it has started in parts of the body, but it can stop the progression of paralysis. Thus, treatment can decrease fatalities to 5-10% if administered within 24 hours of exposure. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> | The antitoxins cannot stop BTX from inhibiting acetylcholine signaling once it has started in parts of the body, but it can stop the progression of paralysis. Thus, treatment can decrease fatalities to 5-10% if administered within 24 hours of exposure. <ref> Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.</ref> | ||
