The pathophysiology of inflammatory airway diseases and their exacerbations is determined by a continuous interplay of local and systemic immunity, and micro-organisms residing in the airways. The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes for an ion channel involved in the pathogenesis of many chronic airway diseases. In cystic fibrosis (CF), an autosomal recessive trait in CFTR leads to thick and sticky mucus, a defect that can now be (partially) restored by CFTR modulators in patients with CF (pwCF). We hypothesize that CFTR modulation substantially changes the airway and systemic host response, leading to an improved mucociliary clearance and attenuated airway inflammation, and more balanced systemic immune responses. Blood and sputum samples from pwCF are collected before and after introduction of CFTR modulation into our existing prospective biobank. We will assess the role of CFTR in the airway microenvironment (sputum rheology, inflammatory markers, synthetic sputum model), and the host immune response (single cell analysis and flow cytometry on peripheral blood leukocytes). Through this integrated approach, pwCF in whom CFTR modulator therapy is being stepwise introduced, will serve as the basis to study mechanisms of airway inflammation and host – micro-organism interactions in the context of chronic microbial exposure, relevant to other airway diseases such as asthma, chronic obstructive pulmonary disease, and bronchiectasis.