Global assessment of the integrated stress response in CF patient-derived airway and intestinal tissues

• Type of Material: Article
• Authors: Giovana B Bampi, University of Hamburg; Robert Rauscher, University of Hamburg; Sebastian Kirchner, University of Hamburg; Kathryn Oliver, Emory University; Marcel JC Bijvelds, Erasmus MC University Medical Center, Rotterdam; Leonardo A Santos, University of Hamburg; Johannes Wagner, University of Hamburg; Raymond A Frizzell, University of Pittsburgh; Hugo R de Jonge, Erasmus MC University Medical Center; Eric Sorscher, Emory University; Zoya Ignatova, University of Hamburg
• Language: English
• Date: 2020-11-01
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcf.2020.04.005
• Title of Journal or Parent Work: JOURNAL OF CYSTIC FIBROSIS
• Volume: 19
• Issue: 6
• Start Page: 1021
• End Page: 1026
• Grant/Funding Information: Funding for this research was provided by the Cystic Fibrosis Foundation (OLIVER17F0 to KEO; IGNATO17XXO to ZI; SORSCH13XXO and SORSCH14XXO to EJS), National Institutes of Health (R01HL136414 to EJS), Burroughs Wellcome Fund (Collaborative Research Travel Grant to KEO), German Cystic Fibrosis Foundation muko e.V. (1603 to ZI).
• Keywords: RNA-seq; ER stress; INFLAMMATION; Inflammation; Cystic fibrosis; EXPANSION; UNFOLDED PROTEIN RESPONSE; Tissue remodeling; ACTIVATION; CELLS; Science & Technology; Respiratory System; Unfolded protein response (UPR); CHILDREN; F508del-CFTR; Life Sciences & Biomedicine

Abstract

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.