Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2

Hatton, Catherine F; Botting, Rachel A; Dueñas, Maria Emilia; Haq, Iram J; Verdon, Bernard; Thompson, Benjamin J; Spegarova, Jarmila Stremenova; Gothe, Florian; Stephenson, Emily; Gardner, Aaron I; Murphy, Sandra; Scott, Jonathan; Garnett, James P; Carrie, Sean; Powell, Jason; Khan, C M Anjam; Huang, Lei; Hussain, Rafiqul; Coxhead, Jonathan; Davey, Tracey; Simpson, A John; Haniffa, Muzlifah; Hambleton, Sophie; Brodlie, Malcolm; Ward, Chris; Trost, Matthias; Reynolds, Gary; Duncan, Christopher J A

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we applied single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrated widespread tropism for nasal epithelial cell types. The host response was dominated by type I and III IFNs and interferon-stimulated gene products. This response was notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response began to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induced an efficient antiviral state that potently restricted SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data suggest that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.