Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI). HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33ºC) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics. Overall design: To investigate and comapre the differences in interferon signaling in nasal cell cultures infected with multiple respiratory viruses, we pooled primary nasal epithelial cells from four to six donors and grew them in air-liquid interface cultures. These cultures were then mock infected or infected with the indicated viruses at MOI = 1 for 96 hours (MERS-CoV, SARS-CoV-2, HCoV-229E, HCoV-NL63) or 48 hours (IAV and HRV-16). We examined differences in gene expression using data obtained from bulk RNA sequencing from each infection in triplicate (duplicate for IAV). Differential gene expression analysis was done by comparing gene expression levels in each infection condition compared to the respective mock infection for that experiment (Mock vs. MERS-CoV, Mock vs. IAV, etc.).