Multi-omic immune signatures of early life cystic fibrosis lung disease and their modification by CFTR modulators

Early life inflammation is a key pathophysiological process in the evolution of cystic fibrosis (CF) lung disease. Despite this, no anti-inflammatory treatments have been developed. This is crucial even in the era of CFTR modulator therapy as evidence suggests that modulators alter but may not fully resolve pulmonary inflammation. In this study, we used clinical microbiology data, multiplex flow cytometry, scRNAseq, and immunoassays to compare pulmonary (bronchoalveolar lavage (BAL)) and systemic immunity in preschool children with CF and age-matched healthy controls. We show that inflammation in the early life CF lung is characterised by myeloid cell infiltration and upregulation of traditional and type 2 inflammatory signatures that progressively increase over the first six years of life, including IL-8, IL-13 and Pentraxin-3. Single-cell RNA sequencing showed upregulation of genes associated with fibrosis within the tissue resident macrophage pool. We further showed that inflammation in preschool CF is not due to current respiratory infection, highlighting a role for intrinsic dysregulation of inflammation that begins in early life. Systemic signatures of inflammation in preschool CF mirrored those of the lung, including type-2 responses. Finally, when exploring the efficacy of CFTR modulators to resolve inflammation, we showed that different classes of modulators have varying effects on pulmonary inflammation, with ivacaftor showing a more significant effect than lumacaftor/ivacaftor. We provide evidence for targeted anti-inflammatory intervention in early life CF to improve preschool lung health, particularly in children ineligible for CFTR modulator therapy.