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MICR3330 > 20 - Bacterial Toxins > Flashcards

20 - Bacterial Toxins Flashcards

1
Q

Toxin

A
  • A microbial product or component that injures another cell or organism
  • Uses in vaccines (toxoids), botox, and tools in cell biology
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2
Q

How are toxins classified

A

Endotoxin or exotoxin

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3
Q

Endotoxin

A

Heat-stable lipid A portion of the LPS of Gram-negative bacteria, within the outer membrane

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4
Q

Exotoxin

A

Heat labile protein that is usually released from cell

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5
Q

Cytotoxin

A

Attacks a variety of cell types

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6
Q

Neurotoxin

A

Attacks nerve tissue

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7
Q

Leukotoxin

A

Attacks leukocytes

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8
Q

Hepatotoxin

A

Attacks liver cells

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9
Q

Naming of toxins

A
  • Based on host cell types they attack
  • Species that produce them
  • Disease associated with the toxin
  • Based on enzymatic activity
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10
Q

Enzymatic actviity of toxins

A
  • Adenylate cyclase (Cell loses ability to control flow of ions and respiratory problems follow)
  • Lecithinase or phospholipase C (Hydrolyses lecithin in mammalian cell membranes, expanding zone of dead tissue results
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11
Q

Example of bacteria that secrete adenylate cyclase toxin

A

Bordetella pertussis (whooping cough)

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12
Q

Example of bacteria that secrete lecithinase or phospholipase C toxin

A

Clostridium perfringens (gas gangrene)

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13
Q

Toxin classification based on toxin mechanism of action

A

Type 1, 2 and 3

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14
Q

Type 1 toxins

A
  • Bind to a host cell surface but do not enter host cell, act extracellularly
  • Superantigens
  • Secreted proteins lead to massive, non specific inflammatory response
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15
Q

Examples of type 1 toxins

A
  • Staphylococcus aureus (toxic shock, food poisoning)
  • Streptococcus pyogenes (Streptococcal toxic shock syndrome, necrotising fasciitis)
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16
Q

Type 2 toxins

A
  • Act extracellularly on eukaryotic cell membranes and destroy their integrity
  • Two types (pore forming cytotoxins and phospholipase enzymes that damage cell membranes)
  • Many are also haemolysins
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17
Q

Pore forming cytotoxins

A
  • Toxin proteins bind to cholesterol on mammalian cell membrane
  • Proteins then polymerize to form
    large pores or channels
  • Cell membrane becomes permeable
    leading to cell death
  • E.g. Streptolysin O
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18
Q

Phospholipase enzymes that damage cell membranes

A
  • Toxin removes the charged polar head groups from the phospholipid part of the host cell membrane
  • Destabilises membrane causing lysis
  • E.g. Lecithinase/phospholipase C of C. perfringens
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19
Q

Type 3 toxins

A
  • Proteins with A-B structure (two polypeptides)
  • Binding region B of toxin recognises specific receptor
  • Translocation region in B subunit of toxin introduces A subunit into host cytoplasm
  • Active (enzymatic) A subunits of toxin acts on an intracellular target
20
Q

Simple A-B toxin

A
  • Synthesized as a single chain which
    is cleaved by a protease yielding
    B and A components, then
    linked by disulphide bond
  • E.g. Diphtheria toxin
21
Q

Compound A-B toxin

A
  • Multiple B subunits linked noncovalently to 1 or more A subunits
  • E.g. Cholera toxin
22
Q

Diphtheria toxin

A
  • an A1 -B1 exotoxin that inhibits protein synthesis
  • Induces leukocyte response, tissue necrosis and cell death
  • Systemic effects on heart and nerve cells may occur
23
Q

Corynebacterium diphtheriae

A
  • Gram positive aerobic rod with distinctive club-shape
  • Diphtheria is a respiratory disease mainly of children, can be fatal
  • Vaccine is inactivated form of diphtheria toxin (toxoid)
  • Disease starts with colonization of throat, grayish “pseudomembrane” forms in throat consisting of bacteria, fibrin and inflammatory cells: due to action of toxin
24
Q

Mode of action of diphtheria toxin

A
  • B domain binds receptor
  • Whole toxin enters cell by receptor-mediated endocytosis, in a vacuole
  • Endosome vacuole acidifies causing
    unfolding of toxin
  • B chain contains T translocation domain
  • The A chain catalyses ADP-ribosylation of EF-2, an essential factor in host cell protein synthesis, causing inhibition of protein synthesis
25
Q

How does T translocation domain of Diphtheria toxin enable A chain to enter cell

A

As pH in endosome drops, hydrophobic residues of T are exposed and it can insert into membrane forming a pore through which A chain translocates to cell cytoplasm

26
Q

Bacterial toxins that target Translation factor EF-2

A
  • Corynebacterium diphtheriae
  • Pseudomonas aeruginosa
27
Q

Bacterial toxins that target Adenylate cyclase regulatory Gi proteins

A

Bordetella pertussis

28
Q

Bacterial toxins that target Adenylate cyclase regulatory Gs proteins

A
  • ETEC
  • Vibrio cholerae
29
Q

Bacterial toxins that target G actin

A

Clostridium difficile

30
Q

Pertussis toxin

A
  • An A1B5 toxin that deregulates adenylate cyclase
  • Accelerates mucin secretion and alters water transport, kills ciliated cells, inhibiting removal of bacteria and mucous
  • 5 binding domain (S2, S3, 2xS4, S5) that binds to cell surface receptor
  • S1 is enzymatic subunit that ribosylates a host cell Gi protein and inactivates it
31
Q

Bordetella pertussis

A
  • Gram negative coccobacillus
  • Causes whooping cough (pertussis)
  • Mild cough developing into prolonged and paroxysmal cough that ends in a gasp or whoop
  • Death by apnea
32
Q

Role of Gi in host cell

A
  • Host adenylate cyclase makes cAMP in the cell.
  • The role of the regulatory protein Gi is to inactivate adenylate cyclase once there is enough cAMP in the cell (i = inhibitory)
  • Thus when Gi is destroyed by pertussis toxin, cAMP is uncontrolled, cell loses ability to control ion flow, one result is increased mucous production
33
Q

Cholera toxin

A
  • A1B5
  • B= Pentameric ring, binds GM1 receptor on surface of intestinal cells
  • A = A1 + A2 disulphide bond
34
Q

Mode of action of cholera toxin

A
  • A1 (active component) enters cell: ADP-ribosylates a G protein (Gs)
  • Gs normally regulates host adenylate cyclase which synthesises cAMP (s = stimulatory)
  • ADP ribosylation of Gs → permanently activates Gs and stimulates adenylate cyclase.
  • The resulting increased cAMP levels affect activity of CFTR ion channels
  • Leads to massive diarrhoea, shock and death
35
Q

ADP - Ribosylating toxins

A
  • > 35 known ADP ribosylating toxins
  • Found in Gram +ve and Gram –ve
  • Common eukaryotic substrates are EF2, G proteins, G-actin
  • Proteins with A1B1, A1B5 or A3B7 structure
  • Not all A-B toxins are ADP-ribosylating toxins
36
Q

Botulinum toxin

A
  • Proteolytic A1B1 exotoxin
  • Blocks neurotransmitter acetylcholine release, prevents muscle from contracting, causes flaccid paralysis
37
Q

Botulism

A
  • Clostridium botulinum is a Gram-positive spore forming anaerobe
  • Botulism is an intoxication (the bacteria do not colonise the body, symptoms caused by ingestion of
    botulinum toxin BT)
  • Many cases due to home-canned foods: temps not high enough to kill spores which then germinate and produce BT
38
Q

Tetanus toxin

A
  • Proteolytic A1B1 exotoxin
  • Neurotoxin responsible for spastic paralysis (muscles contract and cause death)
  • TT binds to neuronal cells, and prevents neurons from signalling relaxation after muscle contraction (acetylcholine continually released)
39
Q

Tetanus

A
  • Clostridium tetani is a Gram-positive sporeforming anaerobe found in soil, faeces
  • Bacteria colonise deep (anoxic) puncture wound
  • Fatal neurological disease, sometimes called lockjaw (inability to open jaws
    due to muscle spasm)
40
Q

Similarities between Botulinum toxin and Tetanus toxin

A
  • Both neurotoxins, but have quite different effects on the body
  • Share considerable sequence homology
  • Both are zinc-requiring proteases that cleave a set of proteins called SNARE proteins that are needed for release of neurotransmitters
41
Q

With these similarities, why do the two toxins cause such different effects

A
  • TT cleaves SNARE protein synaptobrevin, when cleaved, inhibitory neurotransmitters cannot be released,
    thus acetylcholine continually released
  • BT toxin cleaves SNARE protein SNAP-25, prevents release of acetylcholine
  • BT targets receptors found on peripheral neurons; TT enters blood stream and targets central nervous system, binds different neuronal receptors
42
Q

How can BT be good for you

A
  • BT is used to treat painful, disabling muscle spasms
  • Injection of small amount of BT in affected area prevents transmission of nerve impulses and relieves spasms
  • Use in cerebral palsy and Parkinson’s disease patients to control limb movements
43
Q

Effects of endotoxin on host

A
  • Inflammation, tissue damage (localised infections)
  • Fever, widespread tissue damage, septic shock (systemic infections)
    → death
44
Q

Mechanism of action of endotoxin

A

Overstimulation of immune system during systemic infection

45
Q

Other endotoxins that are released when bacteria lyse or turn over their cell walls

A
  • Lipoteichoic acid of Gram positive pathogens
  • Peptidoglycan fragments of the cell wall
  • Tracheal cytotoxin (TCT) of B. pertussis

MICR3330 (29 decks)

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