Background: Chronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers. Methods: Using RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids. Results: Primary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon. Conclusion: Despite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.

Cystic fibrosis, ER stress, F508del-CFTR, Inflammation, RNA-seq, Tissue remodeling, Unfolded protein response (UPR),
Journal of Cystic Fibrosis
Erasmus MC: University Medical Center Rotterdam

Bampi, G.B. (Giovana B.), Rauscher, R. (Robert), Kirchner, S. (Sebastian), Oliver, K.E. (Kathryn E.), Bijvelds, M.J.C, Santos, L.A. (Leonardo A.), … Ignatova, Z. (Zoya). (2020). Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues. Journal of Cystic Fibrosis. doi:10.1016/j.jcf.2020.04.005