The single-cell transcriptional landscape of the pediatric cystic fibrosis lung from minimally invasive respiratory specimens.

Cystic fibrosis (CF) lung disease is characterized by the presence of marked, neutrophil-dominant inflammation that contributes to tissue injury and the development of irreversible structural lung disease. Here, we describe a dysregulated, neutrophil-dominant inflammation and an accompanying pro-inflammatory airway epithelium in the pediatric CF lung through the application of single-cell RNA sequencing (scRNA-seq) to minimally invasive respiratory specimens collected during flexible bronchoscopy. These findings were present in both an infant and an adolescent with CF, the latter on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, suggesting a common pathological program that starts early in life and may be challenging to reverse once structural lung disease is established. Intercellular communication network analysis further revealed potential mechanisms whereby airway epithelial cells modulate the ongoing, destructive airway inflammation present in the CF lung. Importantly, the scRNA-seq workflow leveraged in this study provides a unique opportunity to investigate and monitor disease-related changes in the composition, function, and interaction of the immune and airway epithelial cell populations in CF and other respiratory diseases across the life course.