Pharmacological Improvement of CFTR Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.

RATIONALE:Pharmacological improvement of CFTR function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes to patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular level in the airways of CF patients remain unknown. OBJECTIVES:To investigate effects of ETI on the transcriptiome of nasal epithelial and immune cells from children with CF at the single cell level. METHODS:Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and three months after initiation of ETI, subjected to scRNA-seq and compared to swabs from 12 age-matched healthy children. MEASUREMENTS AND MAIN RESULTS:Proportions of CFTR-positive cells were decreased in epithelial basal, club and goblet cells, but not in ionocytes from children with CF at baseline and were restored on ETI therapy to near healthy levels. Single cell transcriptomics revealed an impaired interferon signalling and reduced expression of MHC I and II encoding genes in epithelial cells of CF children at baseline, which was partially restored by ETI. Additionally, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. CONCLUSIONS:Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).