Interferon signaling in the nasal epithelium distinguishes among lethal and common cold coronaviruses and mediates 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 an 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 (33 °C) 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.
Competing Interests: Competing interests statement:S.R.W. consults for Powell Gilbert LLP. N.A.C. consults for GSK, AstraZeneca, Novartis, and Sanofi/Regeneron; and has a licensing agreement with GeneOne Life Sciences. N.A.C. has US Patent “Therapy and Diagnostics for Respiratory Infection” (10,881,698 B2, WO20913112865). S.R.W. has had an editorial/comment co-publication with the reviewers A.P. and J.U.J., within the last 4 y.