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Medical Microbiology > Bacterial Pathogens and Diseases I (Exotoxins) > Flashcards

Bacterial Pathogens and Diseases I (Exotoxins) Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
1
Q

What is a pathogen?

A

A microorganism capable of causing disease

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2
Q

What is pathogenicity?

A

The ability of an infectious agent to cause disease

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3
Q

What is virulence?

A

The quantitative ability of an agent to cause diseas

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4
Q

What is meant by toxigenicity?

A

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

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5
Q

What are the 4 virulence mechanisms?

A
  • Adherence Factors
  • Biofilms
  • Invasion of Host Cells + Tissues
  • Toxins; endotoxins + exotoxins
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6
Q

How are virulence mechanisms obtained?

A

These factors are genetically acquired in the bacterial genome allowing them to be virulent

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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 type of bacteria produces exotoxins?

A

Produced by both gram negative and gram positive bacteria

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9
Q

What is the effect of exotoxins on the human body?

A

Cause disease symptoms in hosts during disease by acting via a variety of diverse mechanisms

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10
Q

What are the selective advantages exotoxins provide for bacteria?

A

Ability to cause disease

However with many toxins the disease causing activity may not be the primary function

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11
Q

How do exotoxins enable bacteria to cause disease?

A

May help transmission of disease, however in severe disease the host may be a literal and evolutionary dead end

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12
Q

What are other exotoxin activities in bacteria?

A
  • Evade immune response
  • Enable biofilm formation
  • Enable attachment to host cells
  • Escape from phagosomes
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13
Q

What is the effect of exotoxins on bacterial survival?

A

All allowing for colonisation, niche establishment and carriage - Evolutionary advantage

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14
Q

How do haemolytic toxins cause S. aureus?

A

Haemolytic toxins cause cells to lyse by forming pores

Important cause of features of S. aureus disease

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15
Q

Name examples of haemolytic toxins leading to S. aureus

A
  • α,β,δ, toxins
  • Panton Valentine Leukocidin (PVL)
  • LukAB
  • LukED
  • LukMF
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16
Q

How do Phenol soluble modulins cause staphylococcus aureus?

A

PSM aggregate the lipid bilayer of host cells - lysis

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17
Q

How does S.aureus most commonly present in humans?

A

Majority of S. aureus in humans is asymptomatic carriage in the nose

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18
Q

How does S.aureus survive in the human body?

A

S.aureus colonises our nose in a biofilm

S.aureus’ toxins allow this commensalism biofilm to exist on our nasopharyngeal mucosal surfaces

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19
Q

Describe the structure of S.aureus biofilms in the nose

A

These biofilms are populations of bacteria that exist as complex structures that build up into layers and acquire different components

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20
Q

Outline how S.aureus infects

A
  1. Phagocytosis of invading bacteria
  2. Normally phagosome fusion to lysosome
    ⇒ bacteria destruction
  3. S. aureus α + PSM toxins inhibit lysosome fusing
  4. Enables bacteria to escape phagosome into cytoplasm
    ⇒ intracellular niche establishment + replication
  5. PSM toxins target cohabiting bacterial species within
    established niches, aiding competition for resources
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21
Q

Describe the genetics of exotoxins

A

Can be encoded by chromosomal or extra-chromosomal genes

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22
Q

Give examples of chromosomal genes encoding exotoxins

A
  • Shiga toxin in Shigella dysenteriae

- TcdA & TcdB in C. difficile

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23
Q

What extrachromosomal genes encode exotoxins?

A

Plasmids

  • Bacillus anthracis toxin
  • Tetanus toxin

Lysogenic bacteriophage

  • Streptococcal pyrogenic exotoxins in Scarlet Fever
  • Diphtheria toxin.
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24
Q

What is a plasmid?

A

Small circular DNA, separate from chromosomes that is passed on between bacteria through conjugation, transfection and transduction

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25
Q

What is a bacteriophage?

A

Virus that infects bacteria and takes up some of its genes to pass on to the next bacteria the virus infects via transduction

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26
Q

How do streptococcus strains lead to scarlet fever?

A

Streptococcus strains normally cause a sore throat or tonsillitis but certain toxigenic streptococcus strains that have been lysogenically converted now can cause scarlet fever

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27
Q

What is meant by lysogenic conversion of pathogens?

A

When bacteria is infected by a phage carrying a gene encoding a haemolytic toxin into the strain

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28
Q

What is the most common way of classifying exotoxins?

A

As a very diverse group of proteins and many ways to classify e.g. toxin activity

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29
Q

What are the 3 classifications of exotoxin activity?

A

Type I
- Membrane Acting Toxins

Type II
- Membrane Damaging Toxins

Type III
- Intracellular Toxins

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30
Q

What are the drawbacks of classifying exotoxins based on activity?

A

Many toxins may have more than one type activity

As mechanisms better understood this classification tends to break down

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31
Q

What type of toxin do Type I (membrane acting) bacteria produce?

A

These bacteria produce toxins that can bind to a signalling receptor on the cell

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32
Q

What is the effect of Membrane acting toxins?

A

As a result of ligand-receptor interaction, a wide range of intracellular signalling cascades are activated that cause damage to the intracellular metabolic processes occurring

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33
Q

Which receptors are targeted by Type I toxins?

A
  • Guanalyl cyclase
  • Adenyl cyclase
  • Rho protein
  • Ras protein
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34
Q

What is the normal efefct of guanalyl and adenyl cyclase?

A

Gunalyl and Adenyl cyclase are GTPase receptor molecules increase intracellular cGMP

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35
Q

What is the normal physiological role of Rho and Ras proteins?

A

Rho and Ras are smaller receptor proteins that are enzymes that generate cAMP to control actin and microtubule filaments

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36
Q

What is GC-C?

A

GC-C is a key receptor in regulating the electrolyte level and fluidity of intestinal content

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37
Q

What type of toxin does E.Coli contain?

A

Type I - E. Coli Stable Heat Toxin

38
Q

Outline how E.coli effects the GC-C receptor to cause diorrhoea

A
  1. Endogenous / exogenous ligand binds to ECD of GC-C
  2. Conformational change triggered in GC-C
  3. Catalytic domain activated and cGMP formation
  4. Signalling cascade initiated
  5. Results in electrolyte secretion into intestinal lumen
    accompanied by water release
39
Q

Why does the cholera toxin cause water loss?

A

Second messenger activity generates changes in pores of gut epithelial cell membranes

=> changes physiology of Cl- secretion pathway to increase Cl- secretion

Fluid follows osmotically causing dehydration via diarrhoea

40
Q

How do Type II membrane damaging toxins act?

A

Exotoxin type II toxins cause damage to the host cell membrane by forming pores in the membrane

41
Q

Outline the 2 ways Type II toxins damage host cell membranes?

A
  1. Insert channels into host cell membrane
    - β sheet toxins e.g. S.aureus α – toxin, δ toxin, PVL
    - α helix toxins – e.g. diphtheria toxin
  2. Enzymatical damage e.g. S. aureus β- haemolysin, PSM
42
Q

Describe the receptor mechanism utilised by Type II toxins?

A
  1. Receptor mediated

2. Receptor Independent

43
Q

Outline how receptor mediated membrane damage occurs by Type II toxins

A
  1. Soluble monomer
  2. Membrane associated monomer binds to specific
    receptor
    • ADAM10; sheddase, disintegrin + metalloproteinase
  3. Nascent oligomer/pre pore complex
  4. Membrane insertion
44
Q

Give examples of Type II toxins that cause receptor mediated damge

A

Alpha-toxin bi-component leukotoxins

  • PVL
  • LukAB 9LukGH
  • LukDE
  • gamma toxin
45
Q

Describe receptor independent type Ii toxin membrane damage

A
  1. Toxin attaches to membrane
  2. Causes membrane disintegration
    3 Formation of short-lived pores
46
Q

Give examples of Type II membrane damaging receptor independent toxins

A

many alpha-type phenol-soluble modulins (PSMs)

47
Q

How are Type III toxins activated?

A

Active within the cell – must gain access to the cell

48
Q

Describe the structure of type III intracellular toxins?

A

Usually 2 components; AB Toxins (activity binding)

  1. Receptor binding and translocation function – B
  2. Toxigenic (enzymatic) – A

May be single / multiple B units e.g. Cholera toxin AB5

49
Q

What are the different functions of the enzymatic component A in various Type III toxins?

A

ADP: Ribosyl transferases
- Exotoxin A of Pseudomonas aeruginosa, pertussis toxin.

Glycosyltransferases
- TcdA and TcdB of Clostridium difficile

Deamidase
- Dermonecrotic toxin of Bordetella pertussis.

Protease
- Clostridial neurotoxins: botulism & tetanus

Adenyl Cyclase
- EF toxin of Bacillus anthracis

50
Q

Give examples of other intracellular toxins

A

Type III secretion and toxin injection
E.g. YopE in Yersinia species

Type IV secretion and toxin injection
E.g. CagA in Helicobacter pylori

51
Q

What is the effect of exotoxins on the inflammatory response?

A

Exotoxins are able to induce inflammatory cytokine release

- IL1, IL1β, TNF, IL 6,δ interferon, IL18

52
Q

Describe the superantigen mechanism for exotoxin induction of inflamamtory cytokines

A

Superantigen – non specific bridging of MHC Class II and T- cell receptor leading to cytokine production

E.g. Staphylococcal Exfoliative Toxin A, Toxic Shock Syndrome Toxin 1 (TSST1)

53
Q

Outline how exotoxins cause inflammasome activation

A

Via activation of the different inflammasome leading to release IL1 β and IL18

e.g. S. aureus toxin A, PVL

54
Q

How are toxins inactivated?

A

Toxins can be inactivated using formaldehyde or glutaraldehyde → toxoids

55
Q

What are toxoids?

A

Toxoids are inactive proteins but still highly immunogenic – form the basis for vaccines

56
Q

Name common toxoid vaccines

A

Tetanus Vaccine
Diphtheria
Pertussis (acellular).*

57
Q

How is toxin mediated disease treated using toxoids?

A

Treatment of toxin mediated disease can be affected by administering preformed antibodies to the toxin

58
Q

Name antibodies administered for common toxoid vaccines?

A

Diphtheria antitoxin – horse antibodies.
Tetanus – pooled human immunoglobulin. Specific or normal.
Botulism – horse antibodies

59
Q

Which type of antibodies are used for research?

A

Experimental and research – monoclonal antibodies

60
Q

What is the microbiology of c.difficile bacteria

A
  • gram+ bacillus.
  • anaerobic.
  • spore-forming.
  • toxin-producing.
  • can be carried asymptomatically in gut
  • 3 toxins.
61
Q

Describe the epidemiology of C.difficile infections

A

Common hospital acquired infection worldwide.

Coloniser of the human gut up to 5% in adults.

62
Q

How is c.difficile infection spread?

A

Spread by ingestion of spores – remain dormant in environment.

63
Q

Outline risk factors of c.difficile infection

A
  • Antibiotic use
  • Age
  • Antacids
  • Prolonged hospital stay
64
Q

How do C.difficile antibiotics work?

A

Disrupt microbial ecosystem in gut
Provide a competitive advantage to spore forming anaerobes over non spore forming anaerobes
=> Allows C. difficile colonisation and growth

65
Q

What is a drawback of using antibiotics?

A 
All antibiotics have potential for causing disease
especially:
- 2nd + 3rd gen cephalosporins
- Quinolones
- Clindamycin?
66
Q

Name antibiotics that are less likely to, but still disease causing

A
  • Aminoglycosides
  • Trimethoprim
  • vancomycin
67
Q

What are the 3 main toxins of C.difficle?

A

Cytotoxin A
- TcdA coded by tcdA gene

Cytotoxin B
- TcdB coded by tcdB gene

Binary toxin

  • C. diff transferase (CDT)
  • minor role in disease
68
Q

Describe the structures of c.difficle toxins?

A

Tcd A and Tcd B – Type III AB toxins.

The A component of toxins are glycosylating enzymes

69
Q

Describe the structure of C.difficile

A

RBD - receptor binding domain

DD - hydrophobic delivery domain (allows toxin to move through the membrane)

GTD - Glucosyltransferase domain

PD - Protease domain

70
Q

Outline the toxin mediated pathogenesis of C.difficle

A
  1. Toxins enter cell through receptor mediated
    endocytosis and are internalised
  2. Endosome acidification causes release of active toxin
    component
  3. Active component forms a pore in endosome causing
    release of toxin GTD into cytoplasm
  4. GTD causes disruption in cAMP/cGMP and Ras / Rho
    proteins
71
Q

Describe the pathological effects of C.difficle

A

Cytopathic & Cytotoxic

  • Patchy necrosis w/ neutrophil infiltration
  • Epithelial ulcers
  • Pseudomembranes; leukocytes, fibrin, mucous, cell debris
72
Q

What are the asymptomatic effects of C.difficile?

A

Asymptomatic → Watery diarrhoea → Dysentery → Pseudomembranous Cells → Toxic Megacoin & Peritonitis

73
Q

What is VTEC and STEC?

A

Verocytotoxin Escherichia Coli (VTEC)

Shiga-toxin (Stx) producing E. coli (STEC)

74
Q

What is the effect of E.coli infections?

A

Can cause mild to life threatening disease - causes hemorrhagic acute watery diarrhoea

75
Q

Which E.coli strain carries the Stx?

A

Stx carried by some E. coli – most commonly O157:H7

76
Q

How is Stx identified?

A

Identified usually by growth on sorbitol MacConkey agar (SMac) – does not ferment sorbitol and hence is clear.

77
Q

Describe the epidemiology of STEC

A

E. coli O157:H7 naturally colonizes the gastrointestinal tracts of cattle who are generally asymptomatic

78
Q

How is STEC transmitted?

A

Contaminated food and water
Person to person; child day-care facilities
Animal to person; petting zoos, dairy farms, camp grounds
Very low infectious dose

79
Q

Describe the pathogenesis of VTEC

A

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

Stx, Stx1, Stx1a, 1c, 1d Stx2a, 2c, 2d – variations in a.a. sequence

Gene carried on lysogenic bacteria

80
Q

Describe the VTEC toxin structure

A

Type III exotoxin – AB5
Enzymatic component A = N-Glycosidase
Bound to 5 B subunits

81
Q

Outline the mechanism of action of Stx Toxin

A
  1. Binds to receptor globotriaosylceramide Gb3/Gb4 on host cell membrane
  2. Bound toxin internalised by receptor mediated endocytosis
  3. Carried by retrograde trafficking via Golgi apparatus to ER
  4. A subunit cleaved off by membrane bound proteases
  5. Once in cytoplasm A1 + A2 disassociate
  6. A1 binds to 28S RNA subunit – blocks protein synthesis
82
Q

Describe STEC Pathology

A

STEC closely adheres to epithelial cells of gut mucosa

Stx transported from intestine to kidneys possibly by polymorphonuclear neutrophils (PMNs)

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

83
Q

Why does STEC affect the kindeys most?

A

Very high levels of Gb3 in kidney so kidneys most affected.

84
Q

What effect does Stx have on inflammation?

A

Thought that Stx favours inflammation resulting in microvascular thrombosis and inhibition of fibrinolysis.

85
Q

Outline the severity of STEC disease

A

Can be severe and life threatening

Children < 5 years greatest risk

86
Q

What are the symptoms of STEC disease?

A

Abdominal cramps, watery or bloody diarrhoea – may not be present

87
Q

What are the urogenital symptoms of STEC?

A

Haemolytic uraemic syndrome

  • Anaemia
  • Renal Failure
  • Thrombocytopaenia
88
Q

What are the less common neurological symptoms of STEC disease?

A
  • lethargy
  • severe headache
  • convulsions
  • encephalopathy
89
Q

How do we diagnose STEC?

A

Clinical signs and symptoms
Haematological and biochemical evidence.
Stool culture – Growth on SMac
PCR for Stx genes

90
Q

What is the treatment for STEC?

A

Supportive including renal dialysis and blood product transfusion

Antibiotics have little to no role

Medical Microbiology (15 decks)

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