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

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

doi:10.1038/s41467-021-27318-0

Abstract

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 apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply 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.

Highlights

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
We report the most comprehensive characterisation of the human nasal epithelial response to experimental SARS-CoV-2 infection to date, observing a response dominated at later stages by IFN-I/ IIIs and their downstream interferon-stimulated genes (ISGs) products
This response partially contained SARS-CoV-2 at later times post-infection, while recombinant IFN-I/III treatment potently blocked SARS-CoV-2 replication, suggesting that mucosal delivery of IFNs could be a promising strategy for post-exposure prophylaxis

Summary

Introduction

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. As an early viral target cell, nasal epithelial cells may set the tone for the systemic immune response, potentially influencing disease outcome[9] These factors emphasise the need to study host-virus interaction in human nasal cells. SARS-CoV-2 appears sensitive to the antiviral properties of IFNI, at least in cell lines[21,22], and this activity extends to in vivo model systems[9] These findings motivate studies to improve understanding of the interaction between SARS-CoV-2 and the IFN-I system in primary human target cells, providing impetus to clinical trials of recombinant IFNs in treatment or prophylaxis of COVID-1923

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Results

Conclusion