Background: Rhinovirus (RV) is the main cause of upper respiratory infections and asthma exacerbations. Patients with severe asthma (SA) have deficient antiviral immunity but the underlying mechanisms remain poorly understood. Viral RNA sensing is undertaken by helicases such as MDA5 and RIG-I, but the role of host factors such as UPF1, central in host RNA decay, is poorly understood.

Methods: We undertook Frac-seq (subcellular fractionation and RNA-sequencing) to compare transcriptional and post-transcriptional mRNA expression, qPCR, siRNA, ELISA, confocal microscopy, CRISRP/Cas9, viral titrations and RNA immunoprecipitation.

Results: We found UPF1 downregulated in human SA and in the lungs of mice chronically exposed to house dust mite. While we detected UPF1 binding RV RNA and mediating its degradation, RV infection triggered UPF1 phosphorylation and activity, as well as nucleocytoplasmic shuttling, in a time-dependent manner. UPF1 downregulation led to deficient interferon production. Frac-seq allowed us to compare the effects of RV infection on gene expression in total (transcribed) and polyribosome-bound (translated) mRNAs. RV modulated not only the transcription, but also the translation, of specific mRNA isoforms. Our data suggest that the antiviral response is not only transcriptionally but also post-transcriptionally coordinated. Overexpressing UPF1 in RIG-I- and MDA5-CRISPR/Cas9 depleted cells revealed that it is a new helicase in the pathway modulating RV replication/sensing.

Conclusions: UPF1 is a novel helicase that modulates RV pathophysiology and antiviral response in epithelium. Decreased UPF1 levels in SA patients may contribute to their deficient antiviral immunity.