L4 Tetanus Toxin & BoTox Flashcards by Amy Ahern

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)

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True or False: Clostridium tetani itself causes tetanus

False - the toxin it produces causes tetanus

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True or False: Clostridia is a very diverse genus

True

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Are all Clostridia pathogenic?

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What is the vaccine against tetanus?

A toxoid - toxin is taken and purified → inactivated using chemicals → vaccine injected into kids → Abs produced against tetanus toxin

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What bacterium produces the toxin that causes tetanus?

Clostridium tetani

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What bacterium produces the toxin that causes botulism?

Clostridium botulinum

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Describe Clostridium tetani & Clostridium botulinum

Gram positive, spore formers, strictly anaerobic (absolutely cannot grow in the presence of oxygen)

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Where is the botulinum toxin commonly found?

Toxin produced in food (or wound), often canned foods, foods with areas of anaerobiosis

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What is a bulged can of food an indication of?

That bacteria is growing

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How common is botulism? What is the fatality rate?

Rare - about 25 cases per year in US. Around 10% fatality

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Who are particularly susceptible to botulism?

Infants

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Botulism symptoms?

Flaccid paralysis, blurred vision, inability to swallow, difficultly speaking, descending weakness of skeletal muscles & respiratory paralysis

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How common is tetanus? What is the fatality rate?

750,000-1,000,000 cases per year, around 50-70% fatality

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How do most cases of tetanus arise?

From small puncture wounds or lacerations which become contaminated with C. tetani spores that germinate & produce toxin

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True or False: A large amount of C. tetani spores are needed for severe reaction

False - only a small amount are needed

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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 synpatic fusion

Clostridium tetani toxin mechanism?

Tetanus toxin prevents release of inhibitory NTs (e.g. GABA) → overstimulation → hypertonia with no control → spasmic contraction
- Tetanus toxin works in CNS

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)
Botulinum 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?

1. 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 AA seq of B. B subunit ensures 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 ensures that the endosome containing toxin undergoes retrograde transport along 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 it 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