Bacterial Pathogens and Diseases I - Exotoxins Flashcards

1
Q

What is a pathogen?

A

β†’ A microorganism capable of causing disease

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2
Q

What is pathogenicity?

A

β†’ The ability of an infectious agent to cause disease

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3
Q

What is virulence?

A

β†’ The quantitative ability of an agent to cause disease

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4
Q

What is toxigenicity?

A

β†’ The ability of a microorganism to produce a toxin that contributes to development of disease

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5
Q

what are 4 virulence mechanisms?

A

β†’ Adherence factors
β†’ biofilms
β†’ invasion of host cells
β†’ toxins

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6
Q

What are endotoxins?

A

β†’ a heterogenous group of proteins produced and secreted by living bacterial cells

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7
Q

What types of bacteria produce endotoxins?

A

β†’ gram negative and gram positive

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8
Q

What selective advantages do exotoxins give to the bacteria?

A

β†’ they cause disease that may help transmission

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9
Q

What are the 4 other actions of toxins?

A

β†’ Evade immune response
β†’ Enable biofilm formation
β†’ Enable attachment to host cells
β†’ Escape from phagosomes

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10
Q

What do toxins allow for?

A

β†’ Colonisation

β†’ Niche establishment and carriage

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11
Q

What are the two proteins S.Aureus uses to cause disease?

A

β†’ Haemolytic toxins

β†’ Phenol soluble modulins (PSM)

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12
Q

What are the 7 haemolytic toxins of S.Aureus?

A
β†’ Alpha
β†’ beta
β†’ delta
β†’ Panton valentine leukocidin (PVL) 
β†’ LukAB
β†’ LukED
β†’ LukMF
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13
Q

What is the effect of haemolytic toxins?

A

β†’ cause cells to lyse by forming pores

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14
Q

What is the function of phenol soluble modulins?

A

β†’ aggregate the lipid bilayer of host cells

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15
Q

Where is the majority of S.Aureus?

A

β†’ asymptomatic carriage in the nose

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16
Q

How does S.aureus remain alive in the cell?

A

β†’ alpha toxin and PSM prevent the attachment of the lysosome to the phagosome so the bacteria can remain alive in the cell

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17
Q

What does PSM allow S.aureus to do?

A

β†’ allows S. aureus to slide across surfaces

β†’ because S.aureus is not motile

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18
Q

What toxin enables the attachment of a biofilm?

A

β†’ Alpha toxin

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19
Q

What toxins enable the growth of a biofilm?

A

β†’ beta toxin and PSM

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20
Q

What effect does PSM have on the biofilm?

A

β†’ Allows it to detach and spread

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21
Q

What can toxins be encoded by?

A

β†’ chromosomal genes
β†’ extrachromosomal genes
β†’ plasmids
β†’lysogenic bacteriophage

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22
Q

What bacteria have toxins encoded for by plasmids?

A

β†’ Anthtrax

β†’ tetanus

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23
Q

What are the three classifications of exotoxins?

A

β†’ Membrane acting toxins - type I
β†’ membrane damaging toxins - type II
β†’ intracellular toxins - type III

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24
Q

What is the main issue with the classification of exotoxins?

A

β†’ many toxins have more than one type of activity

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25
Q

What are 4 targets of membrane acting toxins (type 1) ?

A

β†’ guanylyl cyclase
β†’ adenylyl cyclase
β†’ Rho proteins
β†’ Ras proteins

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26
Q

Describe how the E.Coli heat stable toxin works and how it causes diarrhoea?

A

β†’ Binds to a specific receptor (GC - C)
β†’ causes the intracellular domain to produce cGMP
β†’ cGMP acts on a pump inside the cell membrane (CFTR)
β†’ the CFTR normally pumps Cl- and HCO3- ions out of the cell
β†’ by stimulating CFTR it pumps out more
β†’ it produces cAMP that inhibits a pump that brings in Na+ and pumps out H+
β†’ Na+ and Cl- ions are salt so when they move out of the cell water follows them
β†’ Diarrhoea occurs

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27
Q

What type of toxin is the E.Coli heat stable toxin?

A

β†’ Type I exotoxin

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28
Q

What do type 1 toxins interfere with?

A

β†’ Host cell signaling by inappropriate cell activation of host cell receptors

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29
Q

What are the two effects of Type II (membrane damaging) toxins?

A

β†’ Inserting channels into the host cell membrane

β†’ enzymatic damage

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30
Q

Describe how alpha toxin works?

A

β†’ binds to a receptor called ADAM10
β†’ it polymerises to form channels
β†’this allows cells to be damaged
β†’intracellular components move out

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31
Q

What is the structure of intracellular toxins?

A

β†’ usually have two components (A and B)

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32
Q

What do the components of intracellular toxins do?

A

β†’A - toxigenic

β†’ B - receptor binding and translocation

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33
Q

What is the structure of the cholera toxins?

A

β­’ AB5

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34
Q

What are 5 examples of intracellular toxins?

A
β­’ ADP 
β­’ Glucosyltransferases
β­’ Deamidate
β­’ Protease
β­’ Adenylyl cyclase
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35
Q

What is an example of a deamidate toxin (type III) ?

A

β­’ Dermonecrotic toxin of bordetella pertussis

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36
Q

What is an example of a protease toxin (type III)?

A

β­’ Clostridial neurotoxins : botulism and tetanus

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37
Q

What is an example of an adenylyl cyclase toxin (type III)?

A

β­’ EF toxin of bacillus anthracis

38
Q

What is an example of a glucosyltransferase toxin (type III)?

A

β­’ TcdA and TcdB of C.diff

39
Q

What is an example of ADP toxin (type III)?

A

β­’ Ribosyl transferases of Pseudomonas aeruginosa & pertussis toxin

40
Q

What is an example of a type III secretion and toxin injection?

A

β­’ YopE in yersinia

41
Q

What is an example of a type IV secretion and toxin injection?

A

β­’ CagA in helicobacter pylori

42
Q

What can exotoxins induce?

A

β­’ Inflammatory cytokine release

43
Q

What cytokines are released due to exotoxins?

A
β­’ IL1 
β­’ IL11 
β­’ TNF 
β­’ IL6 
β­’ delta interferon 
β­’ IL18
44
Q

Describe the superantigen mechanism?

A

β­’ Non-specific bridging of the MHC Class II and T cell receptor leading to cytokine production
β­’ via activation of the different inflammasome leading to release of IL1 beta and IL18

45
Q

Give 2 examples of a superantigen?

A

β­’ Staphylococcal exfoliative toxin A

β­’ toxic shock syndrome toxin 1

46
Q

What are the two ways in which toxoids can be inactivated?

A

β­’ Formaldehyde

β­’ Glutaraldehyde

47
Q

What are toxoids?

A

β­’ Inactive proteins that are still highly immunogenic

48
Q

What do toxoids form the basis of?

A

β­’ Vaccines

49
Q

Name 3 vaccines that use toxoids?

A

β­’ Tetanus vaccine
β­’ Diphtheria
β­’ Pertussis

50
Q

How can you treat toxin mediated disease?

A

β­’ Administering preformed antibodies to the toxin

51
Q

What antibodies are used for Diphtheria and Botulism toxin?

A

β­’ horse antibodies

52
Q

What antibodies are used for tetanus toxin?

A

β­’ pooled human immunoglobulin

53
Q

What type of a bacterium is C.diff?

A

β­’ Gram +ve bacillus

β­’ anaerobic

54
Q

How can C.diff be carried?

A

β­’ Asymptomatically in the gut

55
Q

How is C.diff spread?

A

β­’ ingestion of spores

56
Q

What are the risk factors of getting C.diff?

A

β­’ Antibiotic use
β­’ age
β­’ antacids
β­’ prolonged hospital stay

57
Q

How do antibiotics act?

A

β­’ Disrupting the microbial ecosystem

58
Q

Why do antibiotics facilitate C.diff?

A

β­’ Provide a competitive advantage to spore forming anaerobes

59
Q

What are the 4 antibiotics likely to cause C.Diff infection?

A

β­’ Quinolones & clindamycin

β­’ 2nd and 3rd generation cephalosporins

60
Q

What are the 3 antibiotics that make it less likely for C.diff to colonise?

A

β­’ Aminoglycosides
β­’ Trimethoprim
β­’ Vancomycin

61
Q

What are the 4 components of C. difficile?

A

β­’ Cytotoxin A
β­’ Cytotoxin B
β­’ Binary toxin
β­’ TcdA and TcdB

62
Q

Describe how C.diff induces cell death?

A

β­’ The toxin binds to the receptor
β­’ It is phagocytised and forms an endosome
β­’ the endosome becomes acidified
β­’ this allows the glucosyltransferase domain to escape into the cytoplasm
β­’ this domain targets Rho GTPases and inactivates them
β­’ this stops the growth of the cytoskeleton and breaks it down
β­’ this causes cytotoxic damage
β­’ It stimulates the inflammasome and cell death is induced

63
Q

What are the three cytopathic effects of C.Diff?

A

β­’ Patchy necrosis with neutrophil infiltration
β­’ Epithelial ulcers
β­’ Pseudomembranes

64
Q

What are the ranges of disease of C.diff?

A
β­’ Asymptomatic
β­’ Watery diarrhoea
β­’ Dysentery 
β­’ Pseudomembranous colitis 
β­’ toxic megacolon
β­’peritonitis
65
Q

What are the clinical signs of C.diff infection?

A

β­’ Raised white cell count

β­’ Detection of organisms and toxins in the stool

66
Q

What is the 2 phase test for a C.diff infection?

A

1) Glutamate dehydrogenase detects if C.diff organism is present
2) toxin enzyme linked immunosorbent assay (ELISA) for TcdA and TcdB toxins

67
Q

How do you detect TcdA and TcdB genes in C.diff?

A

β­’ PCR

68
Q

Why is detecting genes during C.diff not a good representation of whether you have the disease?

A

β­’ Genes can be present without the toxin

69
Q

How do you check for pseudomembranous colitis?

A

β­’ Colonoscopy

70
Q

What is surgical treatment for C.diff?

A

β­’ Partial or total colectomy

71
Q

What is a treatment for recurrent C.diff?

A

β­’ Fecal transplant

72
Q

What are the 3 antibiotics used for a C.diff infection?

A

β­’ Vancomycin
β­’ metronidazole
β­’ Fidaxomicin

73
Q

What is VTEC ecoli?

A

β­’ verocytotoxin E.coli

74
Q

What is STEC E.coli?

A

β­’ shiga toxin E coli

75
Q

How do you identify E.coli?

A

β­’ Growth on sorbitol

β­’ E.coli does not ferment sorbitol and hence is clear

76
Q

How is E.coli transmitted?

A

β­’ Contaminated food and water
β­’ person to person
β­’ animal to person

77
Q

Where is E.coli normally found?

A

β­’ Naturally colonises the GI tracts of cattle who are generally asymptomatic

78
Q

What are the three types of pathogenic toxin in E.coli?

A

β­’ SLT - shiga- like toxin
β­’ STX - shiga toxin
β­’ VTEC - verocytotoxin

79
Q

What are the 8 types of toxin variation in E.coli?

A
β­’ Stx
β­’ Stx1 
β­’ Stx1a 
β­’ 1c
β­’ 1d
β­’2c 
β­’ 2d
80
Q

What type of an exotoxin is E.coli?

A

β­’ AB5

β­’ Type III exotoxin

81
Q

What is the enzymatic component of the E.coli toxin and what does it do?

A

β­’ N-glycosidase

β­’ Damages RNA in ribosomes and inhibits protein synthesis

82
Q

What is the mechanism of the E.coli toxin?

A

β­’ Binds to a receptor globotriaosylceramide Gb3 or Gb4 on the host cell membrane
β­’ Bound toxin is internalised by receptor mediated endocytosis
β­’ Carried by retrograde trafficking via the Golgi apparatus to the ER
β­’ The A subunits is cleaved off by membrane bound proteases
β­’ Once in the cytoplasm A1 and A2 dissociate
β­’ A1 binds to 28S RNA subunit and blocks protein synthesis

83
Q

Where does STEC adhere to and what is this due to?

A

β­’ Epithelial cells of the gut mucosa

β­’ Due to the B binding domain

84
Q

How can Stx get transported from the intestine to the kidney?

A

β­’ Polymorphonuclear neutrophils

85
Q

Where does the Stx preferntially bind to ?

A

β­’ Binds to glomerular endothelial cells of the kidney, cardiovascular and central nervous system

86
Q

Why are the kidneys most affected by Stx?

A

β­’ very high levels of Gb3 in the kidney so the kidneys are the most affected

87
Q

What is the effect of Stx?

A

β­’ Favours inflammation

β­’ Results in microvascular thrombosis and inhibition of fibrinolysis

88
Q

Who has the greatest risk of STEC disease?

A

β­’ Children <5 years

89
Q

What happens in Haemolytic uraemic syndrome?

A

β­’ Anaemia
β­’ Renal failure
β­’thrombocytopenia

90
Q

What are the neurological symptoms of Haemolytic uraemic syndrome?

A

β­’ Lethargy
β­’ Severe headache
β­’ Convulsions
β­’ Encephalopathy

91
Q

What are the 4 ways of diagnosis STEC disease?

A

β­’ Clinical signs and symptoms
β­’ Haematological and biochemical evidence
β­’ stool culture
β­’ PCR for Stx genes

92
Q

What is the treatment for STEC disease?

A

β­’ Supportive including renal dialysis and blood product transfusion