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.

Additional Metadata
Keywords Cystic fibrosis, ER stress, F508del-CFTR, Inflammation, RNA-seq, Tissue remodeling, Unfolded protein response (UPR)
Persistent URL dx.doi.org/10.1016/j.jcf.2020.04.005, hdl.handle.net/1765/127384
Journal Journal of Cystic Fibrosis
Citation
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