CF Flashcards
Define Chronic Disease.
Conditions that last 1 yr or more & require ongoing medical attention or limit activties of daily living or both
Define Chronic infection.
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
What is an example of a bacterial chronic infection?
CF
Define CF.
Progressive, recessive, genetic disease that affects the lungs, pancreas & other organs
What is the genetic mutation that leads to CF?
Having 2 mutated CFTR genes
What does faulty CFTR do to ion transport?
Deficient secretion of Cl-, HCO3- & fluid
Hyper concentrated mucus
Reduced mucociliary clearance
What causes the more severe phenotype of CF?
Defect types in protein synthesis & traffic
What are 5 symptoms of CF?
Recurrent bacterial & fungal infection
Pneumothorax
Respiratory failure
Recurrent pancreatitis
Infection with multidrug resistant organisms
What happens in chronic airway inflammation in CF?
Macrophage activation
Recruitment of neutrophils
Release of proinflammatory cytokine & ROS
What does deficient CFTR lead to?
Bacterial infections which leads to chronic airway inflammation
What 5 knock on effects does chronic airway inflammation cause?
Disulfide mucin cross-linking
Increase of mucus viscosity
Release of proteases
Structural lung damage
Lung function decline
How many people have CF worldwide & how many are diagnosed?
162,428 pts
only 65% diagnosed
What is the primary cause of death in CF?
Respiratory/cardiorespiratory
What 5 things happen in the lung in CF?
Low oxygen
Low nutrient availability
Co-colonizing microbial species
Host inflammatory responses
Ab treatments decrease community diversity
What 5 bacterial adaptations happen in CF?
AA metabolism
Iron acquistion mechanisms
Ab resistance
QS mutations
VF production
What are 2 bacterial strains in CF?
P. aeruginosa
non tb mycobacteria
What 4 things happen in CF lung disease progression?
Thickened mucus
Anaerobic pockets
Anaerobic bacteria
Mucin breakdown -> pathogen colonisation
How do bacterial populations become different in CF?
- P. aeruginosa infects lung
- P. aeruginosa populations become isolated
- Isolated populations evolve independently & differ functionally (different phenotypes & proteomes)
What do stresses in CF drive?
Patho-adaptive changes enabling long term colonisation
What are 4 lung stressors?
Hyperinflammation
Drug therapy
Mucus viscosity
No cilliary beating
What are 5 adaptations of P. aeruginosa to the CF lung?
Reduced QS communication
Hb use
Auxotrophy
LPS modification
Non-flagellated
What are regular reviews critical for?
to Prevent or limit symptoms & complications
What are 4 basic assessments?
Clinical
Lung function testing
Respiratory secretion samples
O2 saturation
What are 7 additional assessments?
Physiotherapy
Blood tests
Liver function blood tests
Chest x rays
Nutritional assessment
Psychological review
CF related diabetes
What are 3 examples of time burdens for adults with CF?
Daily CF related regimen
Quarterly visits to CF care centre
Occasional hospital stays
What are CFTR modulator drugs?
Drugs that enhance or restore the expression, function, & stability of CFTR protein
What are 5 CFTR modulator drugs?
Potentiators
Correctors
Stabilizers
Read-through agents
Amplifiers
What do potentiators do?
target effects of gating & conduction mutations
affects the mutations that cause decrease of CFTR abundance
eg. Ivafactor
What do correctors do?
Target protein folding, processing & trafficking
Affect protein conformational stability during ER folding process
Proteostasis regulators
eg. Lumacaftor
What are stabilizers?
Prolong CFTR protein half-life
eg. Lumacaftor
What do read-through agents do?
Rescue protein synthesis
Induce a ribosomal ‘over-reading’ of a premature termination codon
eg. aminoglycoside Abs
What do amplifiers do?
Increase expression of CFTR mRNA
eg. Nesolicaftor
What are 3 limitations of modulator therapy?
10% of people with CF are not genetically eligible for treatment
Severe side effects eg. liver failure
Therapy rarely restores CFTR levels to 100%
What did Nichols et al 2023 find with ETI treatment?
Participants still had detectable pathogen burden
Newly culture +ve for traditional CF pathogens
What are 2 factors of prenatal modulator therapy/
- no clinical trails - data from mothers treated with CFTR modulators
- Proof of transfer through placenta to fetus
What 3 things did a case study using Kaftiro or ETI during pregnancy show?
Produce false negative CF newborn screen sweat test
Full pancreatic function
Reduced future infertility risk
What were 2 side effects of prenatal modulator therapy?
One case of mild hyperbilirubinemia
Potential risk of neonatal cataracts
What are 2 alternative ion channel targets?
ENaC
TMEM16A
What is the goal of targeting ENaC?
Enhances depletion of surface liquid & mucus hyper concentration in CF
Improves mucus hydration & clearance by ENaC inhibition
failed
What is the goal of targeting TMEM16A?
Alternative for CFTR
Stimulate to restore some ion transport
Promising results in sheep model
What are 6 challenges with gene therapy for CFTR?
Immune responses
Gene delivery & activation
Introducing additional unwanted mutations
Commercial viability
Heterogeneity in CFTR0expressing cell types
CF = multi organ disease
What are 5 current approaches for CF lung infections?
Physical methods
Abs eg. Tobramycin
Hypertonic saline
Enzymatic treatments eg. DNAse I
Vaccines
What are 7 emerging treatments for CF lung infections?
Non-steroidal anti-inflammatory compounds
QS inhibitors
Antioxidants & Biofilm disruptors
Silver NPs
Bacteriophage Therapy
New Vaccines
Gene therapy
What is a bacteriophage?
Virus that infects bacteria
What is the lytic cycle?
Synthesis of new viral genomes & proteins
New phages assemble
Cell wall lyses
New bacteriophages released
What is the lysogenic cycle?
Phage DNA integrates within bacterial genome
Becomes prophage
Prophage replicated along with bacterial chromosome
What 4 bacterial strains are bacteriophage treatment targeting?
P. aeruginosa
S. aureus
B. dolosa
M. abscessus
How was phage treatment used for mycobacterium infections?
IV or aerosol -> 55% favorable or partial
What are 4 limitations to developing a vaccine for P.aeruginosa?
Correct selection of antigen & adjuvant
Multiple antigenic components
Adaptability of P. aeruginosa
Large arsenal of VFs
Opportunistic pathogens
What are 2 aims of vaccines?
Prevention of colonization vs. prevention of infection
Boosting of preexistent immune response
What are examples of anti-infectives?
Gallium
bacteriophage
NO
anti-biofilm
anti-VF
What is an effective way to minimise environmental impact of healthcare?
Provide universal high-quality care, keep individuals well & reduce need for hospital admission
