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M&I: Pathogens & Pathogenesis > Bacterial Pathogens And Disease 1 - Exotoxins > Flashcards

Bacterial Pathogens And Disease 1 - Exotoxins Flashcards

1
Q

Describe the function of antibodies (3)

A
  • opsonise bacteria
  • neutralise bacteria
  • activate complement
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2
Q

What is a pathogen?

A

Microorganism capable of causing disease

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3
Q

What is pathogenicity?

A

The ability of an infectious agent to cause disease

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4
Q

Define virulence?

A

Quantitative ability of an agent to cause disease

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5
Q

What is toxigenicity?

A

The ability of a microorganism to produce a toxin that contributes to the development of a disease

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6
Q

What are the mechanisms of virulence?

A
  • Adherence
  • Biofilms
  • Invasion of host cells and tissues
  • Toxins
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7
Q

What are exotoxins?

A

Heterogeneous group of proteins produced and secreted by living bacterial cells

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8
Q

What are exotoxins produced by?

A

Both gram-positive and gram-negative bacteria

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9
Q

What is the function of exotoxins?

A
  • They act via a variety of diverse mechanisms to cause tissue damage and result in disease symptoms in the host
  • However, with many toxins the disease-causing activity may not be the primary function
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10
Q

What are the selective advantages of exotoxins to bacteria?

A
  • evade immune responses
  • enable biofilm formation
  • enable attachment to host cells
  • escape from phagosomes
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11
Q

What do the advantages of exotoxins to bacteria allow for?

A
  • Colonisation
  • niche establishment
  • carriage
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12
Q

Describe the exotoxins produced by Staphyloccocus Aureus

A

Cause cells to lyse by forming pores

  • one type is called PSMs
  • also alpha toxin and beta toxins
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13
Q

How does alpha toxin help survival?

A
  • Alpha toxins block binding of the lysosome to the phagosome to form the phagolysosome
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14
Q

How does beta toxin help survival?

A

Beta toxin kills other bacteria to decrease competition

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15
Q

How do these staph Aureus toxins help survival?

A
  • PSMs (Phenyl soluble modulin) allow bacteria to escape from the phagosomes
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16
Q

What do haemolytic toxins do?

A

Cause cells to lyse by forming pores

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17
Q

How phenol soluable modulins (PSM) help survival?

A

Cause damage to cells by interfering with the membrane structure → cause the lipid membrane of cells to become disaggregated → lysis

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18
Q

Describe the general genetics of bacterial exotoxins - how are most exotoxins encoded?

A

By extrachromosomal genes such as

  • plasmids (baccilus toxin, tetanus toxin)
  • lysogenic bacteriophage (toxin in scarlet fever and also diptheria toxin)
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19
Q

How (3 ways) can we classify exotoxins?

A
  1. membrane acting toxins (type 1)
  2. membrane damaging toxins (typ 2)
  3. intracellular toxins (type 3)
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20
Q

Describe how type 1 toxins work

A

Act by interfering with host cell signalling by innapropriate activation of host cell receptors

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21
Q

Describe how E.coli stable heat toxin works - what kind of toxin is this?

A
  • Type 1
  • Will cause diarrhoea due to efflux of Na+ into the colon
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22
Q

Describe how type 2 toxins work

A
  • Insert channels into host membrane
    • Beta sheet toxins
    • Alpha sheet toxins (diptheria)
  • Enzymatical damage
  • Can be receptor mediated or receptor independent
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23
Q

What is meant by receptor mediated vs receptor independent type 2 toxins?

A

Receptor mediated meaning that they use a receptor to damage the membrane as opposed to binding directly to the membrane

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24
Q

Describe how type 3 toxins work

A

Are active within the cell - so must gain access

  • Usually has two components: A and B (AB toxins) may have multiple B components
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25
Q

What is the function of A vs B? (type 3 exotroxins?)

A

A - Toxigenic (enzymatic)

B - Receptor binding and translocation function

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26
Q

Name some different ways that the A subunit of type 3 exotoxins part can work

A
  • ADP-ribosyl transferases
  • Glucosyltransferases
  • Deaminade
  • Protease
  • Adenylylcylase
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27
Q

How can these type 3 toxins get onto the cell?

A

May be ‘injected’ in or there can be a type of pump (pump is type 4 secretion and injection is type 3???)

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28
Q

What is meant by a superantigen?

A

Superantigen: Non specific bridging of the MHC class 2 and T cell receptor leading to cytokine production

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29
Q

What is toxic shock syndrome?

A
  • Many different T cell clones are activated instead of just the one specific T cell that is specific to the pathogen
  • So there is a huge inflammatory response leading to cytokine storm/toxic shock syndrome
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30
Q

What is the inflammasome?

A

The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins.

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31
Q

How can toxins affect the inflammasome?

A

Toxins can activate the inflammasome leading to release of IL1 beta and IL18

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32
Q

Explain what toxoids are

A
  • Toxins can be inactivated by formaldehyde or glutaldehyde = toxoids
  • Toxoids are inactive but highly immunogenic so we can use it as a vaccine to diptheria, tetanus or petrussis
  • Made in horses
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33
Q

Describe some of the properties of Clostridium difficile

A
  • Normally carried asymptomatically in the gut
  • Is gram negative,
  • Anaerobic
  • Spore-forming and spread this way as it can be resistant to antibiotics
  • toxin producing - produces 3 toxins
  • Is often hospital acquired
  • in the gut of 5% of adults
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34
Q

Name a specific risk factor for C.difficile infection

A

Use of antibiotics

  • due to changes in microbiota where C.difficile is able to find a niche and colonise very well
  • Some antibiotics are worse than others for causing disease
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35
Q

Name some different toxins of C.difficile

A
  • TcdA encoded by tcdA
  • TcdB encoded by tcdB
  • Binary toxin
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36
Q

Describe the structure (different domains of TcdA/TcdB)

A
  • Is an AB toxin (type 3)
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37
Q

Explain and describe the mechanism of pathogenesis of TcdA/B

A

Contain domains that use UDP-glucose to glycosylate and inactivate host Rho GTPases resulting in cytoskeletal changes causing cell rounding and loss of integrity

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38
Q

What happens in the guts of patients with C.difficile?

A

Formation of plaques of necrotic tissue with neutrophil infiltration

  • epithelial ulcers
  • pseudomembranes (leucocytes, fibrin, mucus, cell debris)
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39
Q

What are the symptoms of C.difficile?

A

Symptoms:

  • watery diarrhoea
  • dysentry
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40
Q

What can C.difficile eventually cause?

A

Can cause:

  • pseudomembranous colitis
  • toxic megacolon
  • pritonitis
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41
Q

How can we find (diagnose) C.difficile?

A
  • Raised WBC
  • Detection of C.difficile by glutamate dehydrogenase (but may not be pathogenic - needs to release toxin)
  • Detection of toxin (TcdA or TcdB) by ELISA or by PCR
  • Colonoscopy looking for pseudomembranes
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42
Q

Describe our treatment options for C.difficile

A
  • Want to remove the antibiotic (but not always possible)
  • Surgery (partial or total colectomy)
  • Faecal transplant
43
Q

How can we usually identify VTEC?

A

Usually identified by growth on Sorbitol MacConkey agar (SMac) - it does not ferment on sorbitol and so it is clear

44
Q

Describe the epidemiology of VTEC - transmission etc.

A

Naturally colonises the GIT of cows who are normally asymptomatic

  • transmission by contaminated food or water
  • person to person in child day cares or farms
  • animal to person (petting etc.)

Has a very low infectious dose (amount needed for disease)

45
Q

What toxin does VTEC produce?

A

Shiga like toxin (SLT) = shigatoxin (Stx) = verocytotoxin (VTEC)

  • I think they are different? so VTEC produces veroctotoxin and STEC produces shiga
46
Q

Describe the shiga toxin and its structure - what type of toxin is it?

A

Type 3 exotoxin (AB5)

  • A component (enzymatic component) = N-Glycosidase
  • 5 B components
47
Q

How does Shiga toxin work (mechanism)?

A
  • Is an AB toxin (type 3 I think)
  • B subunit binds to Gb3 or Gb4 receptor on host cell membrane and toxin is internalised by receptor -mediated endocytosis
  • A subunit cleaved by membrane-bound proteases and then in the cytoplasm A1 and A2 dissociate
  • A1 binds to 28s RNA subunit on ribosome to block protein synthesis
48
Q

Describe the mechanism of pathogenesis of STEC

A
  • STEC closely adheres to the epithelial cells of the gut mucosa
  • The route by which Stx is transported from the intestine to the kidney and other tissues is debated, possibly polymorphonuclear neutrophils (PMNs)
  • Bind to glomerular endothelial cells of kidney, cardiovascular and central nervous system.
  • Very high levels of Gb3 in kidney so kidneys most
    affected.
  • Thought that Stx favours inflammation resulting
    in microvascular thrombosis and
    fibrinolysis.
49
Q

Describe the symptoms of STEC

A
  • Can be severe and life threatening
  • Children < 5 years greatest risk
  • Abdominal cramps, watery or bloody diarrhoea - may not be present
  • Haemolytic uraemic syndrome
    • Anaemia
    • Renal Failure
    • Thrombocytopaenia
  • Less common are neurological symptoms
    • Lethargy
    • Severe headache
    • convulsions
    • encephalopathy
50
Q

How can we diagnose STEC?

A
  • clinical signs and symptoms
  • haematological and biological evidence
  • stool culture (growth on SMac)
  • PCR for Stx genes
51
Q

How can we treat STEC?

A
  • renal dialysis and blood product transfusion
  • antibiotics have little to no role
52
Q

Pathogens have the ability to cause disease; what do we analyse when we want to quantify the extent to which that pathogen causes disease?

A

Virulence

53
Q

What toxins are encoded by plasmids?

A

Bacillus anthracis
Tetanus

54
Q

What toxins are encoded by lysogenic bacteriophages?

A

Scarlett fever and diphtheria

55
Q

What are type II toxins?

A

Membrane damaging

56
Q

What are the issues with classifying toxins by activity?

A

Many toxins have more than one type of activity
The better understood the mechanism, the less sense it makes

57
Q

Where do type I toxins act from?

A

Outside the cell

58
Q

How do type I toxins work?

A

Interfere with host cell signalling by inappropriate activation of host cell receptors

59
Q

What do target receptors include?

A
  • Guanylyl cyclase
  • Adenyl cyclase
  • Rho proteins
  • Ras proteins
60
Q

What does guanylyl cyclase do?

A

Increase intracellular cGMP

61
Q

What does adenyl cyclase do?

A

Increase intracellular cAMP

62
Q

What is the mechanism by which the E. Coli stable heat toxin works?

A
  • Increases cGMP
  • Increases chloride and bicarbonate transporters
  • Inhibits sodium reuptake
  • More water out of cells
  • Diarrhoea
63
Q

How do type II toxins work?

A

Insert channels into the host cell membrane

64
Q

What are some examples of beta sheet toxins?

A
  • S. Aureus alpha toxin
  • gamma toxin
  • PVL
65
Q

What are some examples of alpha helix toxins?

A

Diphtheria

66
Q

What are some examples of type II enzymal damage toxins?

A
  • S. Aureus
  • beta haemolysin
  • PSM
67
Q

What are the two types of type II toxins?

A
  • Receptor mediated
  • Receptor independant
68
Q

What are the two components of type III toxins?

A

A and B

69
Q

What are the B components of toxins responsible for?

A

Receptor binding and translocation

70
Q

What are the A components of type III toxins?

A

The toxigenic (enzymatic) bit

71
Q

What are type III membrane acting toxins?

A

Intracellular

72
Q

What do type III toxins act like?

A

A needle

73
Q

What do type IV intracellular toxins act like?

A

A pump of toxins in the cell

74
Q

What are exotoxins able to induce?

A

Inflammatory cytokine release

75
Q

What are some examples of inflammatory cytokine release?

A

IL1, IL1 beta, TNF, IL6, interferon gamma and IL18

76
Q

How do superantigens cause non-specific bridging of MHCs?

A

Activation of the different inflammasome leading to IL1 beta and IL18 release

77
Q

What are examples of different inflammasomes?

A
  • S. Aureus toxin A
  • PVL
78
Q

How do superantigens work?

A

Antigen presenting cells -> lymph node -> T cell that processes the antigen that forms the specific antibody

79
Q

What are toxins inactivated by?

A
  • Heat, formaldehyde or gluteraldehyde
80
Q

What is an inactivated toxin called?

A

Toxoid

81
Q

What is a toxoid?

A

Inactive proteins that are still highly immunogenic

82
Q

What vaccines are based on toxoids?

A
  • Tetanus
  • diphtheria
  • pertussis
83
Q

What illnesses are treated by administering preformed antibodies?

A

Diphtheria cuboxin (horse antibodies)
Tetanus (pooled human Ig)
Botulism (human antibodies)

84
Q

How many toxins does clostridium difficile produce?

A

3

85
Q

Where do you tend to get clostridium difficile?

A

Hospitals

86
Q

How is clostridium difficile spread?

A

Ingestion of spores that remain dormant in the environment

87
Q

What are the risk factors for clostridium difficile?

A

Antibiotic use
Age
Antacids
Prolonged hospital stay

88
Q

What is the relevance for antibiotics with clostridium difficile?

A

Disrupt the microbial ecosystem in the gut which allows clostridium difficile overgrowth causing disease

89
Q

What do antibiotics provide a competitive advantage to?

A

Spore forming macrobes over non-spore forming macrobes

90
Q

What antibiotics are especially bad at disrupting the microbial ecosystem?

A
  • Quinolones
  • Clindamycin
  • Cephalosporins
91
Q

What are the steps in Clostridium Difficile colonisation?

A
  1. Toxins bind to specific host cell receptors, gets into cell are internalised
  2. Endosome acidification allows for inc CPD activity
  3. Pore formation in the endosome
  4. GTD release from the endosome to the host cell cytoplasm
  5. Rho GTPase inactivation by glucosylated
92
Q

What are the downstream cytopathic effects of Clostridium Difficile colonisation?

A
  • Cytoskeleton breakdown
  • Loss of cell-cell contacts
  • Increased epithelial permeability
93
Q

What are the downstream cytotoxic effects of Clostridium Difficile colonisation?

A
  • Activation of inflammasome
  • Increase in reactive oxygen species levels
  • Induction of programmed cell death
94
Q

How do you treat recurrent Clostridium Difficile disease?

A

Faecal transplant

95
Q

What causes VTEC disease?

A

Shigatoxin

96
Q

How do you identify shigatoxin?

A

Growth on a sorbitol macconkey agar (SMAC) - doesnt ferment sorbitol so its clear

97
Q

Where does VTEC come from?

A

Cows

98
Q

Where is the VTEC gene carried?

A

On the lysogenic virus

99
Q

What are all the variations of the VTEC toxin?

A

Stx, stx1, ta1c, 1d2a, 2c, 2d

100
Q

What type of toxin is the VTEC toxin?

A

Type III

101
Q

What is the mechanism for VTEC binding?

A

Bind to receptor globotriasylceramide Gb3 or globotetraosylceramide Gb4 on host cell membrane
Bound toxin internalised by endocytosis
Carried by retrograde trafficking via the Golgi apparatus-< endoplasmic reticulum
A subunit cleaved off by proteases

102
Q

What happens once VTEC gets into the cytoplasm?

A

A1 and A2 dissociate

103
Q

What does A2 do after it dissociates?

A

Binds to 285 RNA subunit - blocks protein synthesis

M&I: Pathogens & Pathogenesis (7 decks)

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