Elexacaftor-Tezacaftor-Ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis

Question. Cystic Fibrosis (CF), which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), is characterized by chronic bacterial lung infection and inflammation. In CF, monocytes and monocyte-derived macrophages have been shown to display defective phagocytosis and antimicrobial activity against relevant lung pathogens, including Pseudomonas aeruginosa. Thus, we addressed the effect of the CFTR triple modulator therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI), on the activity of CF monocytes against P. aeruginosa. Materials/patients and Methods Monocytes from people with CF (PWCF) before and after 1 and 6 months of ETI therapy were isolated from blood and infected with P. aeruginosa to assess phagocytic activity and intracellular bacterial killing. The oxidative burst and IL-6 secretion were also determined. Monocytes from healthy controls were also included. Results and answer to the question Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and lung microbiology by ETI. Both the phagocytic and microbicidal deficiencies of the CF monocytes also improved significantly, although not completely. Furthermore, we measured an exuberant oxidative burst in CF monocytes before therapy, which was reduced considerably by ETI. This led to an improvement of the ROS-dependent bactericidal activity. Inflammatory response to bacterial stimuli was also lowered compared to pre-therapy. PWCF on ETI therapy, in a real-life setting, in addition to clinical recovery, showed significant improvement in monocyte activity against P. aeruginosa, which may have contributed to the overall effect of ETI on pulmonary disease. This also suggests that CF monocyte dysfunctions may be specifically targeted to ameliorate lung function in CF.