Abstract
Background: Common cold (rhinovirus, RV) remain as the major cause of asthma exacerbations. Patients with severe asthma (SA) have interferon impaired responses, but the underlying mechanisms remain unknown. Antiviral responses have been mostly investigated transcriptionally, with post-transcriptional regulation poorly understood. Nonsense mediated decay (NMD) is an RNA decay pathway that modulates ~10% of the transcriptome and other positive strand RNA viruses.
Aim: To determine the role of NMD in RV pathophysiology and its possible role in RV-driven asthma exacerbations.
Results: Employing Frac-seq (subcellular fractionation and RNA-seq) in primary bronchial epithelial cells (BECs) from healthy controls (HC) and SA demonstrated that the core NMD helicase UPF1 is down-regulated in SA. These results were confirmed in a mouse asthma model as well as publicly available datasets. We demonstrate that UPF1 is a novel helicase that degrades RV RNA, and that RV can in turn accelerate the activity of NMD in bronchial epithelium. Frac-seq on bronchial epithelial cells depleted of UPF1 and infected with RV revealed that i) the antiviral response differs between transcriptional and translational mRNA levels ii) UPF1 depletion inhibits the production of an adequate interferon and antiviral response. Experiments in CRISPR-depleted cell lines demonstrated that UPF1 can act as a helicase to degrade RV RNA particularly when archetypical helicases RIG-I and MDA5 are absent.
Conclusions: UPF1 is a core component in the antiviral response to RV. We propose that deficient levels of UPF1 in asthma may underlie the impaired interferon responses seen in SA patients.
Footnotes
Cite this article as ERJ Open Research 2022; 8: Suppl. 8, 232.
This article was presented at the 2022 ERS Lung Science Conference, in session “Poster Session 2”.
This is an ERS Lung Science Conference 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 2022