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MB3001 > L6 Diphtheria > Flashcards

L6 Diphtheria Flashcards

1
Q

What bacterium causes Diphtheria?

A

Corynebacterium diphtheriae - colonisation, A-B toxin

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2
Q

What does the 6 in 1 vaccine prevent against?

A

Diphtheria, tetanus, whooping cough (pertussis), Hib (Haemophilus influenzae B), polio, Hepatitis B

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3
Q

Features of Corynebacterium diphtheriae?

A
  • G+ve
  • Non spore-forming
  • Non-motile
  • Aerobic rod
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4
Q

Diphtheria is primarily a disease of…

A

Children

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5
Q

True or False: Diphtheria has a high fatality rate if left untreated

A

True

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6
Q

What does the 4 in 1 vaccine prevent against?

A

Diphtheria, tetanus, whooping cough, polio

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7
Q

Symptoms of diphtheria

A

Initially - malaise, sore throat, fever
Progresses to - irregular heartbeat, difficulty swallowing, coma, death
Bull neck is common

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8
Q

What happens when Corynebacterium diphtheria colonises the throat?

A

A pseudomembrane forms - can progress to lungs

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9
Q

What type of toxin is diphtheria toxin?

A

Simple A-B toxin - enters bloodstream, no invasion

Highly potent

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10
Q

What does the transmembrane domain do?

A

Delivers A subunit across membrane of endosome into cytoplasm

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11
Q

What is the natural response of the intoxicated cell?

A

To undergo endocytosis

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12
Q

What are the 3 functions in a simple A-B toxin?

A

A domain (light chain, catalytic domain) has the toxic activity (in this case, an ADP ribosylase). B domain (heavy chain) has 2 distinct structural domains that correlate with 2 distinct functions - receptor binding domain & transmembrane domain

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13
Q

What is the A subunit in the diphtheria toxin?

A

An ADP-ribosylase

- Attaches to an ADP-ribose on elongation factor-2 at a modified histidine residue → protein synthesis ceases

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14
Q

What is a source of ADP-ribose?

A

NAD

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15
Q

How does the diphtheria toxin target cardiac cells & cause heart problems?

A

Receptor for B (heparin binding epidermal growth factor [HB-EGF]-like receptor) found mainly on cardiac cells
(serious symptom)

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16
Q

Process of diphtheria toxin:

A
  1. Toxin circulates in blood
  2. Cleavage of A-B toxin by surface associated host protease e.g. furin
  3. A and B domains separate but A domain still connected to transmembrane subdomain by disulphide bridge
  4. Endocytosis occurs & toxin taken up into endosome
  5. Aqueous lumen of endosome contains toxin now
  6. Endosome undergoes maturation process - acidification
  7. Decrease in pH (critical) - T domain conformational change
  8. T domain inserts into membrane & delivers A subunit across membrane into cytoplasm
  9. Cytoplasm’s reducing environment breaks disulphide bridge - releases A subunit into cytoplasm
  10. Toxin activated
  11. Disrupts cellular biochemistry
17
Q

What is an important step in effective toxin delivery?

A

Endosome undergoing maturation process → acidification (transmembrane domain can now undergo a conformational change and insert into endosomal membrane)

18
Q

Where is the toxin gene for Corynebacterium diphtheriae located?

A

On a temperate (lysogenic) bacteriophage

19
Q

The bacterial regulator of diphtheria toxins (DtxR) is sensitive to what?

A

Iron levels

20
Q

When there is high iron, DtxR-Fe binds to what?

A

DNA, and then no toxin is produced

21
Q

What happens to DtxR when there is low iron (as in body)?

A

DtxR does not bind to DNA, and then the toxin is produced

22
Q

Are you vaccinated against intoxication by Diphtheria toxin, or infection by Corynebacterium diphtheriae?

A

Intoxication

23
Q

How is Diphtheria treated?

A

Toxin accounts for all symptoms so patient is dosed with equine antitoxin to bind free toxin (speed essential). Followed by a course of powerful antibiotics

24
Q

What is used as the vaccine (toxoid)?

A

Formalin treated toxin

25
Q

What other form of diphtheria can you get?

A

Cutaneous diphtheria - skin infection (ulceration & necrosis)

26
Q

Therapeutic applications of diphtheria toxin?

A
  1. Replace binding domain with another binding domain which recognises a new target cell (e.g. one infected with AIDS or cancer cell). Will direct the toxic A fragment to the target e.g. Tf-CRM107, fusion between transferrin & derivative of diphtheria toxin with increased toxicity
    or
  2. Use non-toxic derivative (inactive) of diphtheria toxin (CRM197) to increase immunogenicity of pneumococcal vaccine (PCV)

MB3001 (15 decks)

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