Botulism
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Botulism is a severe neuroparalytic disease caused by exposure to botulinum neurotoxins produced by the bacterium Clostridium botulinum. There are several forms of human botulism depending on transmission, including food-borne, wound, infant, and adult botulism. The botulinum neurotoxin blocks the release of acetylcholine at neuromuscular junctions, causing descending flaccid paralysis that can progress to respiratory failure. Diagnosis involves demonstrating the toxin or bacteria in samples, and treatment focuses on supportive care, antitoxin therapy, and antibiotics for wound infections. Prevention emphasizes proper food handling and hygiene.
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Botulism
- 1. Botulism
- 2. Introduction ▪ A severe neuroparalytic bacterial disease ▪ Affects humans, all warm-blooded animals, and fishes ▪ Is caused by exposure to botulinum neurotoxins (BoNTs) ▪ Latin word “BOTULUS”: “SAUSAGE” ▪ Botulism refers to the poisoning caused due to consumption of sausages
- 3. Etiology ▪ BoNT-producing Clostridia ▪ Clostridium botulinum ▪ Ubiquitously found in soil & aquatic sediments ▪ Found in GIT fish, birds & mammals, and the gills & viscera of shellfish ▪ In presence of warmth and moisture, multiplies fast & produce toxin.
- 4. Etiology - Classifiction ▪ Based on their genotypic, phenotypic, and biochemical characteristics: ▪ Divided into six groups: C. botulinum (I-IV), C. butyricum, & C. baratii ▪ Groups I & II, C. butyricum, & C. baratii: Human botulism ▪ Group III: Animal botulism ▪ Group IV:Wound botulism
- 5. Botulinum NeuroToxin (BoNT) ▪ Produces seven immunologically distinct toxins (A-G) ▪ Most strains produce only one toxin type ▪ All produce a clinically similar syndrome ▪ The genes for encoding BoNTs found in the chromosome or on extrachromosomal elements, such as plasmids or bacteriophages
- 6. Botulinum NeuroToxin (BoNT) ▪ Human cases: Mostly toxin types A, B, E, & (rarely) F ▪ Exact lethal dose has not been quantized ▪ For a 70-kg man ▪ 0.09–0.15 µg: I.V. ▪ 0.80–0.90 µg: inhalation ▪ 70 µg: orally
- 7. Botulinum NeuroToxin (BoNT) ▪ Are zinc endopeptidases ▪ Produced as single-chain proteins of 150 kDa polypeptides ▪ Released after bacterial lysis then cleaved by proteolytic nicking by bacterial or tissue proteases to give the active toxin
- 10. BoNT- Mechanism of Action
- 11. BoNT-Therapeutic & cosmetic use Therapeutic Dystonia & spasticity Achalasia Cosmetic use Diminishing the appearance of facial lines
- 12. BoNT-Therapeutic & cosmetic use
- 13. Transmission ▪ Ingestion ▪ An anaerobic milieu ▪ pH <4.5 ▪ Low salt & sugar content ▪ Temperature of 40C–1210C ▪ Wound infection with spore ▪ Contamination of a wound with spores from the environment
- 14. Transmission ▪ Colonization of the intestines of certain infants aged <1year ▪ Normal bowel florae not fully established ▪ Inhalation ▪ Dissemination of BoNT by aerosol (Bioterrorism) ▪ Iatrogenic ▪ Injection of BoNT for cosmetic or therapeutic purpose
- 15. Incubation Period ▪ Depends on the rate and amount of toxin absorbed ▪ In general, the clinical signs occur within 24 hours up to 17 days.
- 16. Forms of Human Botulism
- 17. Pathogenesis Active toxin absorbed in the small intestine Bind to the receptors on the apical surface of gut epithelial cells Released into the systemic circulation Reach all peripheral cholinergic nerve endings Toxin binds to specific receptors Internalized into the cytosol of the nerve terminus Blocks the release of acetylcholine Flaccid paralysis
- 18. Clinical Sign ▪ Is highly distinctive ▪ Symmetrical cranial nerve palsies ▪ Blurry vision or frank diplopia ▪ Ptosis ▪ Expressionless facies ▪ Dysphagia ▪ GI symptoms (food-borne botulism only) ▪ Nausea, vomiting, abdominal pain, diarrhea or constipation ▪ Symmetrical descending flaccid paralysis that may progress to respiratory arrest
- 19. Laboratory Diagnosis ▪ Demonstration of the toxin ▪ Serum ▪ Gastric secretions ▪ Stool ▪ Food sample ▪ Demonstration of C. botulinum ▪ Stools ▪ Wound material Satisfactory for diagnosis of adult botulism & definitive for diagnosis of infant botulism
- 20. Laboratory Diagnosis ▪ Bioassay for BoNT (Mouse protection test /Toxin neutralization test ) ▪ Involves intraperitoneal injection of toxin into mice and observation of the development of botulism-specific symptoms.Toxin type is determined by injecting a panel of mice with mixtures of test sample & a monoclonal type specific antitoxin & by observing which antitoxin confers protection on the mice
- 21. Treatment ▪ Supportive intensive care ▪ Monitoring of vitals & institution of mechanical ventilation if required • Paralysis due to botulism is protracted, lasting weeks to months Anti-toxin therapy Should be given early in the course of illness, ideally <24 h after onset of symptoms Antibiotic administration & debridement forWound infection
- 22. Prevention ▪ Hygienic food ▪ Avoid canned food ▪ Vaccines ▪ 2 doses ant an interval of 10weeks followed by booster dose a year later
Editor's Notes
- Based on their genotypic, phenotypic, and biochemical characteristics, these strains of microorganism can be divided into six groups: C. botulinum (groups’ I-IV), C. butyricum, and C. baratii
- Most clostridial strains produce only one toxin type. All of the botulinum toxins cause the same clinical signs but different in severity of the disease. Knowing the type of toxin is important in selecting an antiserum for treatment because antiserum produced against one type is not effective for others
- The C-terminal domain of the HC (HC) is responsible for binding to the target receptor of the neuronal cell membrane and internalising the toxin molecules by endocytosis. The N terminal domain of the HC (HN) is responsible for translocating the toxin from the endosomal vesicle into the neural cell, allowing the LC — which is the zinc-dependent endopeptidase catalytic domain — to transfer into the cytosol where it will reach its target. The active di-chain molecule consists of a light chain (LC) of 50 kDa and a heavy chain (HC) of 100 kDa that are linked by a disulphide bond.
- Action potential arriving at the presynaptic terminal causes voltage gated Ca++ channel to open.
- Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin. After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell.
- Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release. Botulinum toxins types B, D, F, and G cleave synaptobrevin; types A, C, and E cleave SNAP-25; type C also cleaves syntaxin. Without acetylcholine release, the muscle is unable to contract
- The main route of transmission of botulism is by oral ingestion and wound infection with spore
- Colonization is believed to occur because normal bowel florae that could compete with C. botulinum have not been fully established.
- Intoxination due to consumption of food contaminated with botulism toxin is responsible for the majority of human botulism outbreaks. Toxico-infection occurs in young children by ingestion of C. botulinum spores that will produce the toxin in-vivo. Wound botulism is mainly seen among drug addict.
- Colonization is believed to occur because normal bowel florae that could compete with C. botulinum have not been fully established.