3. Tetanus Toxin & BoTox Flashcards
What are toxinoses (intoxications)? Give examples
Disease caused by toxin (little or no colonisation)
E.g.
- Botulism/tetanus - Clostridium botulinum/tetani (A-B toxin)
- Food poisoning - Clostridium perfringens (pore-forming toxin)
- Toxic shock - Staphylococcus aureus (superantigen)
True or False: Clostridium tetani itself causes tetanus
False - the toxin it produces causes tetanus
True or False: Clostridia is a very diverse genus
True
Are all Clostridia pathogenic?
No
What is the vaccine against tetanus?
A toxoid - toxin is taken and purified → inactivated using chemicals → vaccine injected into kids → Antobodies produced against tetanus toxin
What bacterium produces the toxin that causes tetanus?
Clostridium tetani
What bacterium produces the toxin that causes botulism?
Clostridium botulinum
Describe Clostridium tetani & Clostridium botulinum
Gram positive, spore formers, strictly anaerobic (absolutely cannot grow in the presence of oxygen)
Where is the botulinum toxin commonly found?
Toxin produced in food (or wound), often canned foods, foods with areas of anaerobiosis
What is a bulged can of food an indication of?
That bacteria is growing
How common is botulism? What is the fatality rate?
Rare - about 25 cases per year in US. Around 10% fatality
Who are particularly susceptible to botulism?
Infants
Botulism symptoms?
Flaccid paralysis, blurred vision, inability to swallow, difficulty speaking, descending weakness of skeletal muscles & respiratory paralysis
How common is tetanus? What is the fatality rate?
750,000-1,000,000 cases per year, around 50-70% fatality
How do most cases of tetanus arise?
From small puncture wounds or lacerations which become contaminated with C. tetani spores that germinate & produce toxin
True or False: A large amount of C. tetani spores are needed for severe reaction
False - only a small amount are needed
What is the main symptom of tetanus?
Spasmic contraction of muscles (in contrast to botulism) - ‘lockjaw’
How does Clostridia spread?
It will not grow & replicate - not colonisation. The spores will germinate
What are the 3 most poisonous substances known to man?
Botulinum toxin, tetanus toxin, diphtheria toxin (all are A-B toxins)
LD50 for BoNT and TeNT?
1 ng/kg
C. botulinum can produce a family of bot toxins. What are they?
Toxin types A, B, C, D, E, F, G
Toxin types A & B are more commonly assoc. with humans in US & UK
Toxin type E - fish in Japan & Middle East
What is the A subunit of Clostridia?
Zinc binding metalloprotease - specifically cleaves proteins involved in synaptic fusion
Clostridium tetani toxin mechanism?
- Synaptosome (lipid enclosed vacuole) contains NT
- Synapse fuses with neuron wall → NTs released into synpatic cleft → NTs bind → muscle contracts
- C. tet toxin prevents release of inhibitory NTs (e.g. GABA) → overstimulation → hypertonia with no control → spasmic contraction
- Tetanus toxin works in CNS and functions to block release of inhibitory NTs
Clostridium botulinum toxin mechanism?
- Toxin binds neuron, tropism dictated by B subunit
- After endocytosis, B subunit transfers A subunit across membrane & into cytoplasm
- Active A subunit (zinc metalloprotease) cleaves target protein
- Different botulinum toxins attack different proteins (SNAP, VAMP, synaptobrevin)
- C. bot toxin prevents fusion of synaptosome with neuron surface → no contraction → paralysis
- Treatment: tri- or hepta-valent antitoxin; BIG-IV (BabyBIG)
Which is more fatal: botulism or tetanus?
Tetanus
What are the 2 roles that the B subunit plays in toxin delivery?
- It has to bind to target cell
2. It has to translocate A subunit into target cell
What does tetanus toxin attack?
Synaptobrevin II
What is botulinum toxin specific for?
Peripheral nerve endings - it blocks the release of NTs like ACh, leading to flaccid paralysis
What is blepharospasm?
Uncontrolled blinking - generally affects older people. Can be treated by injecting BoTox into eyelids
Tetanus toxin (Tetanospasmin) is specific for?
Presynaptic inhibitory nerve endings (found in CNS) (e.g. GABA)
Similarities between Tetanus toxin & BoTox?
Both zinc metalloproteases, both simple A-B toxins, both target neurons (are neurotoxins)
Even tho BoTox has a simpler journey throughout the body, both toxins are controlled by the amino acid sequence of its B subunit.
Differences between Tetanus toxin & BoTox?
Different tropisms - different routes into & through the body
Different targets in nervous system - tetanus toxin has to travel into CNS, whereas BoTox targets peripheral nerves (quite accessible)
Normal tetanus exposure is through a puncture wound. How does it get from the muscle to the CNS?
Long journey controlled by amino acid sequence of B subunit. B subunit makes sure toxin gets from muscle into blood, across endothelial barrier into body cavity, to a nerve, and then binds to end of nerve (in the periphery). B subunit makes sure that the endosome containing tetanus toxin undergoes retrograde transport back up through entire length of nerve axon into CNS. It then has to travel effectively & efficiently to inhibitory neural synapses.
What is the only virulence factor in Botulism?
Toxin production (simple A-B toxin)
Who make up the majority of tetanus cases?
Neonates
Although tetanus toxin is incapable of overcoming host defences, what is one virulence factor that is could practice?
Evasion
Why shouldn’t you give very young children honey?
Because it is a common place to find C. bot spores
What does C. tetani use to overcome host defences?
The wound
What are mobile genetic elements?
Plasmids/ transposons/ bacteriophages - pieces of DNA that can move between organisms
What gene can only be found on large plasmids in C. tetani?
TetX gene
Can toxin genes be unstable?
Yes
Why can’t all strains of C. bot cause botulism?
Because they need to have the toxin genes
