GSE139078
RNA-sequencing of airway epithelial cells from individuals with cystic fibrosis; with and without infection with human rhinovirus and treatment with CFTR corrective therapy
Background: Respiratory viruses including rhinovirus can cause pulmonary exacerbations in cystic fibrosis (CF). Aberrant responses by the CF airway epithelium during rhinovirus infection, particularly interferon production, may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with Ivacaftor or ivacaftor/lumacaftor (Orkambi) would improve control of rhinovirus infection. Methods: Nineteen CF epithelial cultures (CFTR Class 2: 10 homozygous for p.Phe508del, CFTR Class 3: 9 p.Phe508del/p.Gly551Asp) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 hours. Culture RNA and supernatants were harvested to assess gene and protein expression respectively. Results: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated; all infected cultures (+/- treatment) were associated with the same top three over-represented biological pathways associated with interferon signalling, and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3, and only 68 genes for Class 2, related to cell metabolic pathways. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection. Conclusions: Though long term clinical data is not yet available, results presented here suggest CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Overall design: Airway epithelial cells (nasal and tracheal) were obtained from eleven individuals with cystic fibrosis; five with a class 2 mutation, six with a class 3 mutation. Cells were cultured for 24 hours alone, or with HRV +/- CFTR corrective therapy (orkambi or ivacaftor).