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LF255 - Clinical Microbiology > Lecture 6/7: Microbiology of Cystic Fibrosis > Flashcards

Lecture 6/7: Microbiology of Cystic Fibrosis Flashcards

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Biology 101 flashcards
1
Q

What is cystic fibrosis?

A

A genetic disorder that leads to chronic lung infection

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2
Q

What is cystic fibrosis caused by?

A

Autosomal recessive mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Gene

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3
Q

What is the CFTR gene responsible for?

A

An ATP-dependent chloride channel

Makes exocrine secretions too thick, sticky and salty

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4
Q

What proportion of people are carriers for CF?

A

1/25 are carriers

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5
Q

What proportion of people are born with CF?

A

1/3000 born with CF

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6
Q

What is the most common CFTR mutation in Europeans?

A

Phe508

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7
Q

What does the Phe508 mutation cuase?

A

Misfolded protein tagged for protease destruction

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8
Q

Where does expression of the CFTR gene cause thickened exocrine secretions?

A

Thickened gastric mucus - meconium ileus

Thickened mucus in pancreatic ducts - totally blocked

Lack of digestive enzymes and poor nutrient absorption

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9
Q

When was the CF gene identified?

A

1989

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10
Q

When was the sweat chloride test developed?

A

1959

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11
Q

What did thick, sticky mucus in the lungs and sinuses lead to?

A

Chronic colonisation by pathogens

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12
Q

What effects do the sticky mucus in the lungs lead to?

A

Pancreatitis/ diabetes, liver damage due to bile backlog

Reduced fertility due to thick cervical mucus or blocked vas deferens

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13
Q

When did a massive breakthrough occur due to the understanding on the molecular biology of CF?

A

2010s

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14
Q

What percentage of people die from respiratory failure?

A

90%

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15
Q

What growth conditions come associated of those with CF?

A

Nutrient availability
Oxygen tension
Temperature
pH
Concentration of inflammatory cells
Activation of inflammatory cells
Local microbial competition
Host epithelial cell interactions

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16
Q

What is the effect of CF lung infection on the patient?

A

Bronchiectasis: bronchi widen and fill with mucus

Decrease in FEV - down to 20% normal function by age 20-30 not uncommon

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17
Q

What is bronchiectasis?

A

When bronchi widen and fill with mucus

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18
Q

What are the microbial niches of someone with CF lung infection?

A

Mucus gives some protection from immune cells

Decreased oxygen (get anaerobes can live in the lung)

Amino acids from damaged tissues as carbon source

Tissue damage - increased iron

Hyperinflammatory response

Biofilm

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19
Q

What makes biofilms so peristent?

A

Genetic adaptation or changes in expression

Quiescence/ persistence allow bacteria to hide from antibiotics that target

Efflux pumps

Antibiotic breakdown/ modification

Target modification/ bypass

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20
Q

What are the key pathogens surrounding CF lung infection?

A

Staphylococcus aureus

Pseudomonas aeruginosa

Burkholderia cepacia complex

Aspergillus fumigatus (fungus)

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21
Q

What is the microbiology of staphylococcus aureus?

A

Gram positive

Thick peptidoglycan layer (protects from desiccation)

Persistence on surfaces and be transmitted indirectly

Facultative anaerobe

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22
Q

What antibiotic resistance has been associated with Staphylococcus aureus?

A

Beta-lactamases, efflux pumps and mecA gene

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23
Q

What are the virulent factors associated with Staphylococcus aureus?

A

Toxins that damage cell membranes

Toxins that cause tissue damage

Invasins that promote spread in tissues

Molecules that protect bacteria from immune-produced oxygen radicals

Small colony variants - very persistent, resistant to host antimicrobial peptides

Hypermutable or mutator strains

24
Q

What is the treatment of Staphylococcus aureus?

A

Flucloxacilin, fusidic acid, vancomycin, linezolid

25
Q

What is the ultimate CF pathogen?

A

Pseudomonas aeruginosa

26
Q

What is the microbiology of pseudomonas aeruginosa?

A

Gram negative

Outer membrane gives intrinsic resistance to many antibiotics

Huge genome (large availability to modify environment)

Hypermutable clones arise

Forms biofilms using range of polymers

Biofilms aids persistence - hard to break down and clear

27
Q

What is the treatment of pseudomonas aeruginosa?

A

A range of antibiotics used

Tobramycin binds bacterial ribosomes, blocking protein synthesis

28
Q

What kind of bacterial cells won’t be affected by tobramycin?

A

Cells with no protein synthesis

Biofilm in quiescent stage

Only targets metabolically active cells - no translation happening

29
Q

What do biofilms grown on polycarbonate membranes contain?

A

Inner zones of low oxygen and metabolically inactive cells

30
Q

What is the microbiology of the burkholderia cenocepacia complex?

A

Gram negative

Intrinsic resistance to many antibiotics

Motile

Can be transmissible

31
Q

What percentage of colonisation is by the Burkholderia cepacia complex?

A

2-8%

32
Q

What is Cepacia syndrome?

A

Aggressive pneumonia

Bacteraemia

33
Q

What niche does B. cenocepacia occupy?

A

Invades phagocytes and epithelial cells

Rather than existing in extracellular biofilm

Moves into alveoli causing pneumonia

34
Q

What is the treatment of Burkholderia cenocapacia complex?

A

Range of oral/ IV antibiotics

35
Q

What is the fungus associated with cystic fibrosis infection?

A

Aspergillus fumigatus

36
Q

What are the characteristics of Aspergillus fumigatus?

A

Forms long-lived spores (inhaled and penetrate deeply into alveoli)

Hypersensitive immune response to spores dur to existing infection in CF

Proteases can damage and evade immune cells produce toxins

37
Q

What is the treatment of Aspergillus fumigatus?

A

Steroid to dampen immune response and antifungal agent

38
Q

What are potentiators?

A

Open and close mutations

39
Q

When was Ivacaftor approved and how was it discovered?

A

Available on the NHS in late 2016

High throughput screen for CFTR potentiators

40
Q

What are the 3 correctors used for misfolding in CF>?

A

Elexacaftor

Tezacftor

Lumacaftor

41
Q

What is Ivacaftor used to treat with CF mutations?

A

Potentiator for gating

42
Q

What is Orkambi?
(combination of, treatment for, year made available on NHS)

A

Lumacaftor and Ivacaftor

For people with 2 copies of F508

2019

43
Q

What is Symkevi?
(combination of, treatment for, year made available on NHS)

A

Tezacaftor and Ivacaftor

For people with 2 copies F508 or F508 + another residual function mutation

2019

44
Q

What is Trikafta/Kaftrio?
(combination of, treatment for, year made available on NHS)

A

Elexacaftor, Tezacaftor, Lumacaftor

2020

For people with 2 copies F508 or F508+ another residual function mutation

2020

45
Q

What pathogen dominates the CF infected lung over time?

A

Pseudomonas aeurginosa

46
Q

What are the 4 types of bacterial interaction?

A

Niche construction

Cross-protection

Competition

Signalling

47
Q

What is the bacterial interaction niche interaction?

A

Amino acids and short-chain fatty acids are used a primary carbon sources

Produced from mucins by anaerobic bacteria that metabolise the mucins by fermentation

48
Q

How does niche construction occur?

A

Fermentation of gram-positive anaerobes

49
Q

What is the bacterial interaction - signalling?

A

Many bacteria use diffusible small molecules to co-regulate the expression of virulence factors - quorum sensing

Increases virulence factor production

50
Q

What are some examples of cross-species quorum sensing with P. aeruginosa?

A

Signals from oropharyngeal flora have shown to upregulate P. aeruginosa virulence

P. aeruginosa signals can trigger biofilm formation by S. aureus

51
Q

What is the bacterial interaction - cross-protection?

A

Mixed-species biofilm can have higher antibiotic tolerance than single -species biofilm

Similar effect of within-species diversity

Diversification of a founding clone - lots of micro-niches in the lung

52
Q

What factors affect whether cystic fibrosis communities are relevant?

A

How close/ far apart the species are in the lung

Environment or community in different individual patients

Genotype of infecting strains

Evolution within the lung over time

53
Q

Why do evolutionary changes occur of the community in the lung?

A

Adaptation to the host
To chronic lifestyle
Clinical intervention
Rest of the community

54
Q

Why are chronic infections complex, polymicrobial ecosystems?

A

The environment and community bacteria inhabit is crucial in determining their gene expression and physiology

Influences their virulence and susceptibility to antibiotics

Hard to predict which antibiotics will work against these infections

55
Q

How is a pig lung a good match for modelling chronic CF lung infection?

A

Good match for human lung structure and chemistry

Ethical

Realistic, cheap and high throughput

56
Q

How much of a colistin dose can enter the biofilm matrix?

A

10-20%

57
Q
A

LF255 - Clinical Microbiology (10 decks)

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