Abstract
Background: Asthma is the most common chronic inflammatory disease of the airways. Patients with asthma show interferon-deficient responses to rhinovirus (RV), the most frequent trigger of asthma exacerbations. The mechanisms underlying impaired antiviral immunity are inadequately understood.
Aim: To determine the role of mRNA decay factors in RV pathophysiology and antiviral immunity in asthma.
Methods: We applied Frac-seq (subcellular fractionation and RNA-seq) in primary bronchial epithelial cells (BECs) from asthmatics and healthy controls. Frac-seq determines which cytoplasmic mRNAs bind to polyribosomes, the cellular translational machinery. We employed RNA immunoprecipitation and siRNA knock-down experiments in BECs infected with RV as well as mouse models of asthma, immunohistochemistry and confocal imaging.
Results: Frac-seq data showed decreased translation of UPF1 (upstream frameshift 1) in asthma BECs. UPF1 translational levels negatively correlated with reversibility (r=-0.7235 P=0.0067) and is also down-regulated in the lungs of house-dust mite exposed mice. UPF1 modulates RNA decay of ~10-30% of all mRNAs while STAU1 (Staufen 1) modulates translation/decay of double-stranded RNAs. We demonstrate that UPF1 and STAU1 directly bind to the RV genome, and that RV infection modulates their subcellular localization and phosphorylation. Depletion of UPF1 and STAU1 in BECs impairs interferon production and genome-wide antiviral immunity.
Conclusions: Decreased UPF1 levels in asthma BECs underlie their impaired antiviral immunity. We demonstrate for the first time the interplay between two novel factors, UPF1 and STAU1, in RV pathophysiology and induced exacerbations.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA2324.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021