S58 UPF1 is a novel modulator of antiviral responses against rhinovirus and is deficient in patients with severe asthma. (11th November 2022)

• Record Type: Journal Article
• Authors: Richardson, A; Ponde, N; Ong, S; Khooshemehri, P; Bagley, D; Bucca, G; Hesketh, A; Smith, C; Rosenblatt, J; Martinez-Nunez, RT
• Is Part Of: Thorax. Volume 77(2022)Supplement 1
• Page Start: A37
• Page End: A38
• Publication Date: 2022-11-11
• Subjects: Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thorax-2022-BTSabstracts.64
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : Background: Asthma is the most common chronic inflammatory disease of the airways, with rhinovirus (RV) being the main cause of asthma exacerbations. Patients with severe asthma (SA) present deficient antiviral/interferon responses but the mechanisms underlying this remain poorly understood. RV is a single positive strand RNA virus recognised by RNA sensing helicases, and may also bind to host RNA binding proteins that mediate transcriptome surveillance such as UPF1 within the nonsense mediated decay pathway. Methods: Frac-seq (subcellular fractionation and RNA-sequencing) to investigate transcriptional and post-transcriptional mRNA expression, qPCR, siRNA and CRISRP/Cas9 as well as RNA immunoprecipitation (RIP). Results: UPF1 is dysregulated in SA bronchial epithelial cells. UPF1 directly binds RV RNA and mediates its degradation. On the other hand, RV infection is able to increase UPF1 phosphorylation and activity in a time-dependent manner. Frac-seq allowed us to compare the effects of RV infection on gene expression in different subcellular compartments: 'total' (current 'transcriptomics') 'and 'polyribosomes' (mRNAs heavily translated). RV modulated not only the transcription, but also the translation, of specific mRNA isoforms, pointing towards novel antiviral targets that modulate RV pathophysiology. UPF1 downregulation modulated the antiviral response against RV, at both transcriptional and post-transcriptional levels. Lastly, CRISPR/Cas9 modulation of the archetypical helicases RIG-I and MDA5 showed that UPF1 exerts its effects as a novel helicase within the pathway. Conclusions: UPF1 is a novel modulator of RV pathophysiology in epithelium and its depleted levels in SA may potentially contribute to deficient antiviral immunity in these patients.