Interferon signaling in the nasal epithelium distinguishes among lethal and common cold coronaviruses and mediates viral clearance

Author:

Otter Clayton J.12ORCID,Renner David M.12ORCID,Fausto Alejandra12,Tan Li Hui3,Cohen Noam A.345,Weiss Susan R.12ORCID

Affiliation:

1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

2. Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

3. Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

4. Department of Surgery, Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center, Philadelphia, PA 19104

5. Monell Chemical Senses Center, Philadelphia, PA 19104

Abstract

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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

U.S. Department of Veterans Affairs

Publisher

Proceedings of the National Academy of Sciences

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