Uncovering Cystic Fibrosis Carrier: Insights From a Heterozygous CFTR-F508del Rabbit Model

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder frequently associated with impaired mucociliary clearance and bacterial infection. Individuals carrying a single cystic fibrosis transmembrane conductance regulator (CFTR) mutation exhibit partial CFTR dysfunction and are increasingly recognized as being at risk for CRS; however, the sinonasal phenotype and host-pathogen interactions in CF carriers remain poorly defined.

We characterized heterozygous ΔF508 CF rabbits (heterozygous, n = 6) compared with wild-type (WT) (n = 5). Baseline sinonasal structure was assessed by computed tomography and histology. CFTR function was measured by nasal potential difference (NPD) and Ussing chamber analysis of primary epithelial cultures, with or without CFTR modulators. Bacterial sinusitis was induced using Pseudomonas aeruginosa (PA14), followed by longitudinal imaging, bacterial quantification, histology, and PA14 RNA sequencing.

Heterozygous rabbits demonstrated significant sinus hypoplasia compared with WT (mm³: heterozygous 77.9 vs. WT 108.1 mm³, p < 0.01) without spontaneous sinusitis. NPD revealed ∼50% reduction in chloride transport relative to WT (∆mV: heterozygous -15.5 vs. WT -35.8, p < 0.01). CFTR modulation partially restored chloride secretion in epithelial cells from heterozygous to ∼80% of WT (p < 0.0001). Following P. aeruginosa inoculation, heterozygous rabbits exhibited higher bacterial burden (p < 0.05), persistent radiographic opacification (week 4, p < 0.01), and delayed histologic recovery. PA14 RNAseq revealed a distinct transcriptional profile in the heterozygous sinonasal environment.

Heterozygous ΔF508 CF rabbits recapitulate key sinonasal features relevant to CF carriers, including reduced CFTR function, altered host defense, and impaired infection clearance. This model provides a translational platform for investigating CRS pathogenesis and evaluating CFTR-targeted therapies in CF carriers.