CF

Question 1

Define Chronic Disease.

Answer 1

Conditions that last 1 yr or more & require ongoing medical attention or limit activties of daily living or both

Question 2

Define Chronic infection.

Answer 2

Presence of bacteria for at least 6 mths based on at least 3 positive cultures with at least 1 month intervals between them with direct or indirect signs of infection & tissue damage

Question 3

What is an example of a bacterial chronic infection?

Answer 3

CF

Question 4

Define CF.

Answer 4

Progressive, recessive, genetic disease that affects the lungs, pancreas & other organs

Question 5

What is the genetic mutation that leads to CF?

Answer 5

Having 2 mutated CFTR genes

Question 6

What does faulty CFTR do to ion transport?

Answer 6

Deficient secretion of Cl-, HCO3- & fluid
Hyper concentrated mucus
Reduced mucociliary clearance

Question 7

What causes the more severe phenotype of CF?

Answer 7

Defect types in protein synthesis & traffic

Question 8

What are 5 symptoms of CF?

Answer 8

Recurrent bacterial & fungal infection
Pneumothorax
Respiratory failure
Recurrent pancreatitis
Infection with multidrug resistant organisms

Question 9

What happens in chronic airway inflammation in CF?

Answer 9

Macrophage activation
Recruitment of neutrophils
Release of proinflammatory cytokine & ROS

Question 10

What does deficient CFTR lead to?

Answer 10

Bacterial infections which leads to chronic airway inflammation

Question 11

What 5 knock on effects does chronic airway inflammation cause?

Answer 11

Disulfide mucin cross-linking
Increase of mucus viscosity
Release of proteases
Structural lung damage
Lung function decline

Question 12

How many people have CF worldwide & how many are diagnosed?

Answer 12

162,428 pts
only 65% diagnosed

Question 13

What is the primary cause of death in CF?

Answer 13

Respiratory/cardiorespiratory

Question 14

What 5 things happen in the lung in CF?

Answer 14

Low oxygen
Low nutrient availability
Co-colonizing microbial species
Host inflammatory responses
Ab treatments decrease community diversity

Question 15

What 5 bacterial adaptations happen in CF?

Answer 15

AA metabolism
Iron acquistion mechanisms
Ab resistance
QS mutations
VF production

Question 16

What are 2 bacterial strains in CF?

Answer 16

P. aeruginosa
non tb mycobacteria

Question 17

What 4 things happen in CF lung disease progression?

Answer 17

Thickened mucus
Anaerobic pockets
Anaerobic bacteria
Mucin breakdown -> pathogen colonisation

Question 18

How do bacterial populations become different in CF?

Answer 18

1. P. aeruginosa infects lung
2. P. aeruginosa populations become isolated
3. Isolated populations evolve independently & differ functionally (different phenotypes & proteomes)

Question 19

What do stresses in CF drive?

Answer 19

Patho-adaptive changes enabling long term colonisation

Question 20

What are 4 lung stressors?

Answer 20

Hyperinflammation
Drug therapy
Mucus viscosity
No cilliary beating

Question 21

What are 5 adaptations of P. aeruginosa to the CF lung?

Answer 21

Reduced QS communication
Hb use
Auxotrophy
LPS modification
Non-flagellated

Question 22

What are regular reviews critical for?

Answer 22

to Prevent or limit symptoms & complications

Question 23

What are 4 basic assessments?

Answer 23

Clinical
Lung function testing
Respiratory secretion samples
O2 saturation

Question 24

What are 7 additional assessments?

Answer 24

Physiotherapy
Blood tests
Liver function blood tests
Chest x rays
Nutritional assessment
Psychological review
CF related diabetes

Question 25

What are 3 examples of time burdens for adults with CF?

Answer 25

Daily CF related regimen Quarterly visits to CF care centre Occasional hospital stays

Question 26

What are CFTR modulator drugs?

Answer 26

Drugs that enhance or restore the expression, function, & stability of CFTR protein

Question 27

What are 5 CFTR modulator drugs?

Answer 27

Potentiators Correctors Stabilizers Read-through agents Amplifiers

Question 28

What do potentiators do?

Answer 28

target effects of gating & conduction mutations affects the mutations that cause decrease of CFTR abundance eg. Ivafactor

Question 29

What do correctors do?

Answer 29

Target protein folding, processing & trafficking Affect protein conformational stability during ER folding process Proteostasis regulators eg. Lumacaftor

Question 30

What are stabilizers?

Answer 30

Prolong CFTR protein half-life eg. Lumacaftor

Question 31

What do read-through agents do?

Answer 31

Rescue protein synthesis Induce a ribosomal 'over-reading' of a premature termination codon eg. aminoglycoside Abs

Question 32

What do amplifiers do?

Answer 32

Increase expression of CFTR mRNA eg. Nesolicaftor

Question 33

What are 3 limitations of modulator therapy?

Answer 33

10% of people with CF are not genetically eligible for treatment Severe side effects eg. liver failure Therapy rarely restores CFTR levels to 100%

Question 34

What did Nichols et al 2023 find with ETI treatment?

Answer 34

Participants still had detectable pathogen burden Newly culture +ve for traditional CF pathogens

Question 35

What are 2 factors of prenatal modulator therapy/

Answer 35

1. no clinical trails - data from mothers treated with CFTR modulators 2. Proof of transfer through placenta to fetus

Question 36

What 3 things did a case study using Kaftiro or ETI during pregnancy show?

Answer 36

Produce false negative CF newborn screen sweat test Full pancreatic function Reduced future infertility risk

Question 37

What were 2 side effects of prenatal modulator therapy?

Answer 37

One case of mild hyperbilirubinemia Potential risk of neonatal cataracts

Question 38

What are 2 alternative ion channel targets?

Answer 38

ENaC TMEM16A

Question 39

What is the goal of targeting ENaC?

Answer 39

Enhances depletion of surface liquid & mucus hyper concentration in CF Improves mucus hydration & clearance by ENaC inhibition failed

Question 40

What is the goal of targeting TMEM16A?

Answer 40

Alternative for CFTR Stimulate to restore some ion transport Promising results in sheep model

Question 41

What are 6 challenges with gene therapy for CFTR?

Answer 41

Immune responses Gene delivery & activation Introducing additional unwanted mutations Commercial viability Heterogeneity in CFTR0expressing cell types CF = multi organ disease

Question 42

What are 5 current approaches for CF lung infections?

Answer 42

Physical methods Abs eg. Tobramycin Hypertonic saline Enzymatic treatments eg. DNAse I Vaccines

Question 43

What are 7 emerging treatments for CF lung infections?

Answer 43

Non-steroidal anti-inflammatory compounds QS inhibitors Antioxidants & Biofilm disruptors Silver NPs Bacteriophage Therapy New Vaccines Gene therapy

Question 44

What is a bacteriophage?

Answer 44

Virus that infects bacteria

Question 45

What is the lytic cycle?

Answer 45

Synthesis of new viral genomes & proteins New phages assemble Cell wall lyses New bacteriophages released

Question 46

What is the lysogenic cycle?

Answer 46

Phage DNA integrates within bacterial genome Becomes prophage Prophage replicated along with bacterial chromosome

Question 47

What 4 bacterial strains are bacteriophage treatment targeting?

Answer 47

P. aeruginosa S. aureus B. dolosa M. abscessus

Question 48

How was phage treatment used for mycobacterium infections?

Answer 48

IV or aerosol -> 55% favorable or partial

Question 49

What are 4 limitations to developing a vaccine for P.aeruginosa?

Answer 49

Correct selection of antigen & adjuvant Multiple antigenic components Adaptability of P. aeruginosa Large arsenal of VFs Opportunistic pathogens

Question 50

What are 2 aims of vaccines?

Answer 50

Prevention of colonization vs. prevention of infection Boosting of preexistent immune response

Question 51

What are examples of anti-infectives?

Answer 51

Gallium bacteriophage NO anti-biofilm anti-VF

Question 52

What is an effective way to minimise environmental impact of healthcare?

Answer 52

Provide universal high-quality care, keep individuals well & reduce need for hospital admission