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Flashcards in Neurotoxins and other toxins Deck (28):
1

what causes Tetanus?

Clostridium tetani, Gram positive, anaerobic

2

how does Tetanus cause death?

• Spores enter wounds, germinate at low oxygen tension
• Toxin synthesised at approach to stationary phase
i.e. toxico-infection
• Death from exhaustion, respiratory failure

3

what are the Clinical symptoms of tetanus?

muscular spasms, fluctuation in blood pressure, irregular heartbeat, sweating dehydration

4

describe the Tetanus toxin

• Synthesised as a 150-kDa pro-toxin, protease cleaved to give:
- 50-kDa light chain
- 100-kDa heavy chain - disulphide bond
• Heavy chain mediates binding to GT1 gangliosides on peripheral nerve endings
• Conformational changes allow internalisation into nerve cells
• Retrograde axonal transport

5

whats the Action of tetanus toxin

• Normally signals across synapses are controlled by excitatory and inhibitory neurotransmitters
• Tetanustoxin blocks release of inhibitory neurotransmitters (e.g. glycine, g-amino-butyric acid)
• Continuous stimulation - SPASTIC PARALYSIS

6

what causes Botulism

Clostridium botulinum, Gram positive, anaerobic, spore forming

7

how does botulism cause infection?

• Spores present in food, germinate in anaerobic conditions
• Toxin released into food
• If not destroyed by heating, toxin is ingested, absorbed in gut, enters bloodstream
i.e. intoxication

8

what are the symptoms of botulism

vomiting, headaches, slurred speech, generalised flaccid paralysis, progressive weakness of muscles, impaired organ functions, death

9

describe the movement of the toxin

1. PROGENITOR TOXIN- ingested, passes through stomach,
subunits dissociate in small intestine
2. DERIVATIVE TOXIN- proteolytically cleaved in small intestine
3. ACTIVE TOXIN- enters blood, targets peripheral neurones and enters synaptic vesicles

10

what happens after the botulism toxin is activated?

- Toxin binds ganglioside receptors on neurone surface via C-terminus of large subunit
• pH changes at cell surface enhance toxin hydrophobicity, penetrates membrane
• N-terminus of large subunit inserts into membrane of synaptic vesicle, forms pores
• pH changes disrupt disulphide bond
• small (toxic) subunit passes into synaptic vesicle

11

describe the Action of botulinum toxin?

• Normally stimuli cause release of stimulatory neurotransmitter acetylcholine (A)
• Acetylcholine crosses synaptic space,
interacts withreceptors, trans-stimulus to neurones or to muscle
• Botulinum toxin prevents release of acetylcholine
• Inhibits stimulatory activity - FLACCID PARALYSIS

12

what is the Botulinum toxin used for?

• Used to treat disorders that involve muscle hyperactivity
- e.g. laryngeal dystonia, tremors, facial tics
- induces paralysis of target hyperactive muscle
• Cosmetic use - reduce deep wrinkles caused by contraction of facial muscles (Botox)

13

what are the similarities between Tetanus and botulinum toxins?

Both are ‘zinc endopeptidases’ and cleave synaptobrevins (vesicle- associated membrane proteins, VAMPS), inhibiting release of neurotransmitters

14

why are Tetanus and botulinum toxins Effects different?

- tetanus toxin acts at nerve junctions
- botulinum toxin acts at junctions between nerves and muscles

15

name an enzyme toxin

• Clostridium perfringens a-toxin - phospholipase C
• Cleaves phospholipids at phosphodisester linkage - phosphatidylcholine to phosphorylcholine + a diglyceride
- sphingomyelin to phosphorylcholine + ceramide
• Causes localised cell and tissue destruction  gas gangrene
• Bacteria enter bloodstream, release more toxin (toxaemia)
• Only treatment is radical surgery

16

explain the action of Hyaluronidase enzyme toxin?

- produced by Group A streptococci, Bacteroides gingivalis, staphylococci
• Catalyses breakdown of hyaluronic acid, a component of connective tissue
• Sub-epidermal injection of cell free hyaluronidase causes a diffuse area of tissue damage
• Called ‘spreading factor’ – allows pathogens greater access to colonise tissues

17

what is the enzyme toxin of Pseudomonas aeruginosa?

- causes lung infections in immunocompromised patients, particular problem in cystic fibrosis
• Produces elastase, a protease specific for elastin, major component of connective tissue - disrupts ciliary function of respiratory epithelium and hence clearance of mucus/bacteria

18

whats the enzyme toxin associated with Streptococcus pneumoniae

- produces proteases specific for secretory IgA
• Degrade antibodies, prevent recognition by macrophages, so reducing phagocytosis

19

what are the 4 types of Membrane damaging toxins

1. Non-enzymatic proteins cause lysis of erythrocytes and other cell types
2. Immunologically cross-reactive, similar structures
3. Toxins bind to cholesterol in target cell membranes,
insert as rings of oligomers forming pores
4. Efflux of small molecules, breakdown of membrane electrical potential

20

name 2 Non-enzymatic proteins cause lysis of erythrocytes

- pneumolysin of Streptococcus pneumonia
- streptolysin of Streptococcus pyogenes

21

describe the action of a-hemolysin (HlyA) of E. coli

• One of the first pore-forming toxins described
• Synthesised as pro-toxin acylated (i.e. attachment of fatty acids) and secreted (107-kDa)
• Inserts into eukaryotic membranes of erythrocytes, leukocytes, lymphocytes, epithelial and endothelial cells
• Small amounts induce cytokine production and inflammatory response
• Large amounts cause cell lysis

22

what happens at Low HlyA

Interaction with host proteins
e.g. GTPase RhoA
Changes Ca2+ levels
Causes cytokine induction (IL-1, TNF)

23

what happens at High HlyA

Pore formation
Alters osmotic balance Causes cell lysis

24

what are the Functions of HlyA

+ In UTI isolates work in combination with cytotoxic necrotizing factor 1 to cause sloughing of uroepithlium, bladder hemorrhage and inflammation
+ May enhance spread by disrupting epithelial cells in gut lining, providing nutrients and inactivating immune effector cells

25

what is Streptococcus pyogenes

• Human pathogen
• Mild diseases - pharyngitis and impetigo
• Severe, life-threatening diseases - necrotizing fasciitis
• Post-infection sequelae - glomerulonephritis and rheumatic fever
• Rheumatic fever is often associated with heart disease and is a hypersensitive reaction mediated by cross-reactive antibodies

26

what are S. pyogenes virulence factors

• M-protein – fibronectin-binding protein for
adhesion and inhibition of phagocytosis
• Hyaluronic acid capsule – inhibits phagocytosis
• Streptokinase, steptodornase, hyaluronidase and streptolysins – invasion, tissue damage and spread
• Pyrogenic toxin – causes scarlet fever rash and toxic shock

27

what is the role of Streptolysin O and SPN in Virulence

1. SLO induces pro-inflammatory cytokines (IL1b, IL6 and IL8)
2. the absence of SPN helps to resolve the infection.
3. double-mutant lacks mitigating effect is more virulent.
4. In wt, the combination of both genes results in strong pathogenic effect.

28

summarise Neurotoxins and other toxins

1. Neurotoxins cause tetanus and botulisum, two component molecules, inhibit release of neurological signalling molecules
2. Enzymatic toxins disrupt host tissues facilitating spread or inhibiting clearance
3. Membrane-damaging (pore forming) toxins perturb host immune responses influencing clearance, competition and transmission