Single-cell transcriptomics reveals a compartmentalized antiviral interferon response in the nasal epithelium of mice

Type III interferons (IFNs) primarily act on epithelial cells and protect against virus infection of the mucosa, whereas type I IFNs act more systemically. To date, it has been unknown which epithelial subtypes in the upper airways, the primary site for initial infection for most respiratory viruses, primarily rely on type III IFN or type I IFNs for antiviral protection. To address this question, we performed a single-cell transcriptomics analysis of the epithelial IFN-mediated response focusing on the upper airways of mice. This work identified nine distinct cell types derived from the olfactory epithelium and thirteen distinct cell types from the respiratory epithelium. Interestingly, type I IFNs induced a stronger antiviral transcriptional response than type III IFN in respiratory epithelial cells, whereas in olfactory epithelial cells, including sustentacular (SUS) and Bowman's gland cells (BGC), type III IFN was more dominant compared to type I IFN. SUS and BGC, which provide structural support and maintain the integrity of olfactory sensory neurons, were highly susceptible to infection with a mouse-adapted variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 MA20) but were protected against infection if the animals were prophylactically treated with type III IFN. These findings demonstrate a high degree of cell type heterogeneity in terms of interferon-mediated antiviral responses and reveal a potent role for type III IFNs in protecting the olfactory epithelium.IMPORTANCESARS-CoV-2 infects SUS and BGC in the olfactory epithelium, causing an impairment of structural support and integrity of olfactory sensory neurons that can result in severe olfactory dysfunctions. We observed an unexpected compartmentalization of the IFN-mediated transcriptional response within the airway epithelium, and we found that olfactory epithelial cells preferentially respond to type III IFN, which resulted in robust antiviral protection of SUS and BGC. Given the proximity of the olfactory epithelium to the central nervous system, we hypothesize that evolution favored a type III IFN-biased antiviral immune response in this tissue to limit inflammatory responses in the brain. Cell type-specific antiviral responses in the upper airways, triggered by the different types of IFNs, should be investigated in more detail and carefully taken into consideration during the development of IFN-based antivirals for clinical use.