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

Lookup NU author(s): Catherine Hatton, Dr Rachel Botting, Dr Maria Duenas FadicORCiD, Dr Iram Haq, Dr Bernard Verdon, Dr Benjamin Thompson, Dr Jarmila SpegarovaORCiD, Dr Florian Gothe, Emily Stephenson, Aaron Gardner, Dr Sandra Murphy, Jonathan Scott, Dr James Garnett, Sean Carrie, Jason PowellORCiD, Dr Anjam Khan, Dr Lei HuangORCiD, Raf Hussain, Dr Jonathan Coxhead, Tracey DaveyORCiD, Professor John SimpsonORCiD, Professor Muzlifah Haniffa, Professor Sophie Hambleton, Dr Malcolm Brodlie, Professor Christopher WardORCiD, Professor Matthias TrostORCiD, Dr Gary ReynoldsORCiD, Dr Christopher DuncanORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2021, The Author(s).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.

Publication metadata

Author(s): Hatton CF, Botting RA, Duenas ME, Haq IJ, Verdon B, Thompson BJ, Spegarova JS, Gothe F, Stephenson E, Gardner AI, Murphy S, Scott J, Garnett JP, Carrie S, Powell J, Khan CMA, Huang L, Hussain R, Coxhead J, Davey T, Simpson AJ, Haniffa M, Hambleton S, Brodlie M, Ward C, Trost M, Reynolds G, Duncan CJA

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2021

Volume: 12

Issue: 1

Print publication date: 01/12/2021

Online publication date: 07/12/2021

Acceptance date: 12/11/2021

Date deposited: 13/01/2022

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-021-27318-0

DOI: 10.1038/s41467-021-27318-0

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Funding

Funder referenceFunder name
...Sklodowska-Curie grant agreement No. 890296.
A.J.S. is a National Institute for Health Research (NIHR) Senior Investigator
C.F.H. is supported by a Medical Research Council studentship (MR/NO13840/1)
C.J.A.D. and G.R. are Wellcome Clinical Research Career Development Fellows (211153/Z/18/Z and 214539/Z/18/Z).
F.G. was supported by the Bubble Foundation.
J.P.G., C.W. and B.V. ... Grant MRF-091-0001-RGGARNE) and Boehringer Ingelheim.
J.P.G., C.W. and B.V. were supported by the Medical Research Foundation (MRF Respiratory Diseases Research Award to J.P.G.;
M.E.D. is a Marie Sklodowska Curie Fellow within the European Union’s Horizon 2020 research and innovation programme under the Marie ...
M.H. is funded by Wellcome (WT107931/Z/15/Z), The Lister Institute for Preventive Medicine and Newcastle NIHR Biomedical Research Centre (BRC).
M.T. and S.H. are funded by Wellcome Investigator Awards (215542/Z/19/Z and 207556/Z/17/Z)
M.B. by an MRC Clinician Scientist Fellowship (MR/M008797/1).
Medical Research Council SHIELD antimicrobial resistance consortium (J.S., A.J.S.).
part-funded by the Barbour Foundation (C.J.A.D., S.H., M.B., M.T., M.H., C.W.)
TEM work was supported by a BBSRC Alert17 grant (BB/R013942/1).
the UK-Coronavirus Immunology Consortium (C.J.A.D., S.H., M.H.)

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