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Human Microbial Diseases Block 1 > Bacterial Toxins > Flashcards

Bacterial Toxins Flashcards

1
Q

What are the stages of infectious disease?

A
  • Transmission
  • Evasion of primary host defences
  • Adherence to mucous membranes
  • Colonisation
  • Damage and symptoms
  • Host responses
  • Progression or resolution of the disease
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2
Q

Who discovered toxins?

A

Charrin and Ruffer

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3
Q

Name some examples of toxin mediated disease

A
  • Tetanus
  • Diphtheria
  • Gas gangrene
  • Cholera
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4
Q

What bacteria causes diphtheria?

A

Corynebacterium diphtheriae

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5
Q

What bacteria causes gas gangrene?

A

Clostridium perfringens

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6
Q

What type of toxin is gas gangrene mainly caused by?

A

Alpha-toxin

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7
Q

What activity does the alpha-toxin have?

A

Phospholipase C

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8
Q

What are endotoxins?

A

The lipid portions of lipopolysaccharides that are part of the outer membrane of the cell wall of gram negative bacteria

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9
Q

What is endotoxin also known as?

A

Lipid A

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10
Q

When are endotoxins liberated?

A

When the bacteria die and the cell wall breaks apart

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11
Q

What do endotoxins trigger?

A

Gram negative bacterial sepsis

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12
Q

What is the systemic inflammatory response in gram negative bacterial sepsis characterised by?

A
  • Pro-inflammatory cytokines
  • Nitric oxide
  • Fever
  • Hypotension
  • Intravascular coagulation
  • Organ failure
  • Culminates in septic shock
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13
Q

What does LPS affect on the bacteria?

A
  • Outer membrane permeability
  • Resistance to antibiotics
  • Recognition by the host immune system
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14
Q

What does LPS protect against?

A

Beta-lactam antibiotics

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15
Q

What do outer membrane vesicles contain?

A

LPS

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16
Q

What do outer membrane vesicles have a role in?

A
  • Cell stress response
  • Nutrient acquisition
  • Pathogenesis
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17
Q

What are exotoxins?

A

Proteins produced inside pathogenic bacteria as part of their growth and metabolism

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18
Q

What type of bacteria most commonly produce exotoxins?

A

Gram positive bacteria

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19
Q

When are exotoxins secreted?

A

During log phase

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20
Q

What are some actions of exotoxins?

A
  • Have direct mechanisms which affect target cells
  • Can facilitate the spread of bacteria through tissue
  • Can damage cell membranes/body structures
  • Can be immunomodulatory
  • Can inhibit protein synthesis
  • Can inhibit release of neurotransmitters
  • May be primarily responsible for disease or just another virulence factor
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21
Q

What exotoxin can facilitate the spread of bacteria through tissue?

A

Hyaluronidase

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22
Q

What exotoxin damages cell membranes/body structures?

A

Collagenase

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23
Q

What exotoxin is immunomodulatory?

A

IgA protease

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24
Q

What exotoxins inhibit protein synthesis?

A
  • Diphtheria toxin

- Shiga toxin

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25
Q

What exotoxin inhibits the release of neurotransmitters?

A

Botulinum toxin

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26
Q

What do endotoxins activate?

A

Mainly activate antigen presenting cells to produce cytokines

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27
Q

What do super antigens affect?

A
  • Affect antigen-presenting cells and T cells

- Induce both macrophages and T cells to produce cytokines

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28
Q

What are type I exotoxins?

A
  • Bind to surface receptors
  • Aren’t translocated into the host cell
  • Stimulate transmembrane signals
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29
Q

Give an example of a type I exotoxin?

A

Super antigens

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30
Q

What are type II exotoxins?

A

Act directly on cell membranes

31
Q

Give examples of type II exotoxins

A
  • Phospholipases

- Pore-forming toxins

32
Q

What are type III exotoxins?

A
  • AB toxins

- Translocate an active enzymatic component into the target cell which modifies an intracellular target molecule

33
Q

How do AB toxins work?

A
  • Part B binds specifically to the host cell
  • Several mechanisms exist by which the toxin can enter the cell -> e.g. endocytosis
  • The vacuole becomes acidified and the membrane breaks down
  • A and B dissociate from 1 another
  • A enters the cytoplasm to inflict its activity and everything else gets removed from the cell by exocytosis
34
Q

How many genes is an AB toxin the product of?

A

A single gene

35
Q

How is A linked to B in an AB toxin?

A

By a disulphide bond

36
Q

Give examples of AB toxins

A
  • Diphtheria toxin

- Tetanus toxin

37
Q

How are the subunits linked in an AB5 toxin?

A

Covalently linked

38
Q

Where does a 2A:7B toxin assemble?

A

On the cell surface

39
Q

What is ADP-ribosylation?

A

A post-translational modification

40
Q

What is ADP-ribosylation catalysed by?

A

ADP-ribosyltransferase

41
Q

What happens in ADP-ribosylation?

A

An ADP-ribose moiety is removed from NAD+ and transferred to a specific target molecule in the host cells resulting in activation or inactivation of the cell functions modulated by these proteins

42
Q

Give some examples of exotoxins with ADP-ribosylating action and name what they target

A
  • Cholera toxin -> Gs
  • E. coli LT toxin -> Gs
  • Pertussis toxin -> Gi
  • Diphtheria toxin -> EF2
  • Pseudomonas exotoxin A -> EF2
43
Q

How does Vibrio cholerae cause death?

A
  • Hypovolemic shock due to abnormally low volume of circulating fluid
  • Metabolic acidosis due to loss of bicarbonate and thus buffering capacity
44
Q

Describe the mechanism of V. cholerae virulence

A
  • V. cholerae ingested from contaminated water or food -> relatively high infectious dose
  • Passes through the stomach and adheres to and colonises the small intestine mucosa -> no invasion
  • Cholera toxin production
  • Toxin acts on mucosal cells and causes excessive water loss and illness
45
Q

What is the structure of the cholera toxin?

A

AB5 toxin

46
Q

What does the B unit of cholera toxin bind to?

A

GM1 ganglioside

47
Q

How is cholera toxin activated?

A
  • Produced in the inactive form

- Nicked by a bacterial endopeptidase in the body

48
Q

What is the mode of action of Cholera toxin?

A
  • V. cholerae attaches to intestinal epithelial cells and releases CTX
  • B subunit binds to GM1 gangliosides
  • A unit is transferred into the cell
  • A protein ribosylates the G protein making it permanently active -> adds an ADP-ribose molecule
  • G protein activates adenylate cyclase which converts ATP to cAMP -> levels rise 100 fold
  • cAMP is a mediator of a variety of mechanisms including ion balance
  • With a permanently active adenylate cyclase normal transport of Na from the lumen is blocked and Cl- and Na+ enter into the intestinal lumen
  • Results in a massive efflux of water by osmosis
49
Q

What is whooping cough caused by?

A

Bordetella pertussis

50
Q

What is the incubation period of whooping cough?

A

7-10 days

51
Q

What do children infected by Bordetella pertussis usually get?

A

Classical pertussis

52
Q

How long is the catarrhal stage of whooping cough?

A

1-2 weeks

53
Q

What are the symptoms in the catarrhal stage of whooping cough?

A
  • Fever

- Malaise with mild cough

54
Q

How long does the paroxysmal stage last in whooping cough?

A

1-6 weeks

55
Q

What are the symptoms of the paroxysmal stage of whooping cough?

A
  • 5-20 forceful coughs with no time for breathing
  • Whoop when air rushes back into the lungs
  • Vomiting
  • Exhaustion
  • Can lead to brain damage
56
Q

What do older children, adolescents and adults get when infected with Bordetella pertussis?

A

Disease can range from classical pertussis to mild illness to no cough

57
Q

Describe the mechanism of B. pertussis virulence

A
  • Inhalation of aerosols containing B. pertussis
  • Adherence to ciliated epithelial cells and colonisation of the upper respiratory tract
  • Toxins are produced
  • PTX damages mucosal cells
  • PTX and LPS act on neurons
  • Bacteria can adhere to phagocytes where they are ingested, which may lead to an intracellular phase explaining carriers
58
Q

How does pertussis toxin exert its effects?

A

Increases cAMP production

59
Q

Describe the structure of the pertussis toxin

A
  • AB5 structure
  • B is made up of S2-S5 subunits -> there are 2 S4 subunits
  • A is made up of a S1 subunit
60
Q

What is S1 of pertussis toxin activated by?

A
  • Host cell calmodulin

- Reduces the disulphide bridge

61
Q

What action does the active S1 subunit have?

A

Transfers ADP-ribose to G proteins

62
Q

What does the S2 subunit bind?

A

Lactosylceramide

63
Q

Where is lactosylceramide found?

A

On ciliated epithelial cells

64
Q

What does the S3 subunit bind?

A

Macrophages

65
Q

Describe the mechanism of pertussis toxin

A
  • Stimulates the production of cAMP
  • Disrupts tight junctions
  • Inhibits G{PCR to promote pulmonary hypertension
  • Inhibits lymphocyte homing to lymph nodes and extravasation
  • Reduces numbers and function of Tregs
  • Suppresses antibody responses
  • Inhibits early neutrophil recuitment
  • Induces chemokines and cytokines
66
Q

What is diphtheria caused by?

A

Corynebacterium diphtheria

67
Q

What is the incubation period of diphtheria?

A

2-6 days

68
Q

Describe the disease of diphtheria

A
  • Fever
  • Malaise
  • Sore throat
  • Low grade fever
  • Formation of pseudomembrane
  • Damage to mucosal cells
  • Damage to organs by diphtheria toxin
  • Breathing obstruction, cardiac arrhythmia and coma
  • Death
69
Q

Describe the mechanism of C. diphtheriae virulence

A
  • C. diphtheriae inhaled
  • Adherence to throat epithelial cells and colonisation -> no invasion
  • Elaboration of of diphtheria toxin and organ damage
  • Formation of a pseudomembrane
70
Q

What is the pseudomembrane made up of?

A
  • Fibrin
  • Bacteria
  • Dead cells
  • Lymphocytes
71
Q

How is diphtheria toxin activated?

A

Through nicking

72
Q

What is the mechanism of action of diphtheria toxin?

A
  • B binds to heparin-binding epidermal growth factor precursor
  • Complex is taken up by receptor mediated endocytosis
  • Acidification changes the conformation of the T-domain allowing it to insert into the membrane
  • A is translocated into the cytoplasm and becomes active
  • ADP ribosylates EF2
  • This stops translation and causes cell death
73
Q

How can toxins be used as therapy?

A
  • Bacterial protein toxins can be utilised as vaccine antigens
  • Vehicles for taking in heterologous proteins into the cell -> could be used in chemotherapy
  • Immunotoxins enable targeting of diseased cells
  • Potential targets for antimicrobial therapy or could be used as antibiotics
  • Botox has important medical uses for the treatment of neurological disorders

Human Microbial Diseases Block 1 (7 decks)

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