SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies
- Cardiff University, United Kingdom
- University of Cambridge, United Kingdom
- King's College London, United Kingdom
- Guy's and St Thomas' NHS Foundation Trust, United Kingdom
- Cardiff University School of Medicine, United Kingdom
- University of Glasgow, United Kingdom
Abstract
The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.
Data availability
All data generated are presented within the manuscript, with the exception of proteomics data. This has been uploaded to PRIDE (identifier PXD025000)
Article and author information
Author details
Ceri Alan Fielding
Edward JD Greenwood
Funding
National Institute for Health Research (MR/V028448/1)
- Ceri Alan Fielding
- Pragati Sabberwal
- Eddie CY Wang
- Richard J Stanton
Medical Research Council (MR/N013700/1)
- Carl Graham
Medical Research Council (MR/S00971X/1)
- Richard J Stanton
Wellcome Trust (204870/Z/16/Z)
- Ceri Alan Fielding
- Eddie CY Wang
- Richard J Stanton
Ser Cymru (NA)
- Ceri Alan Fielding
- Eddie CY Wang
- Richard J Stanton
Medical Research Council (MR/P001602/1)
- Eddie CY Wang
Medical Research Council (MR/V000489/1)
- Richard J Stanton
Wellcome Trust (210688/Z/18/Z)
- Paul J Lehner
Medical Research Council (MR/V011561/1)
- Paul J Lehner
Wellcome Trust (208354/Z/17/Z)
- Katie Doores
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Stipan Jonjic, University of Rijeka, Croatia
Ethics
Human subjects: PBMC were extracted from apheresis cones obtained from the Welsh Blood Service (WBS) via an ad-hoc agreement or from blood samples from healthy volunteers and stored in liquid N2 until use. Use of healthy volunteer PBMC for this project, including those from WBS, was ethically approved by the Cardiff University School of Medicine Research Ethics Committee (SMREC) nos. 20/55 and 20/101. Recruitment of healthy volunteers after vaccination was covered by the Cardiff University School of Medicine Research Ethics Committee under reference no. 18/04.
Version history
- Preprint posted: April 6, 2021 (view preprint)
- Received: October 6, 2021
- Accepted: May 17, 2022
- Accepted Manuscript published: May 19, 2022 (version 1)
- Accepted Manuscript updated: May 20, 2022 (version 2)
- Version of Record published: June 28, 2022 (version 3)
Copyright
© 2022, Fielding et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies
eLife 11:e74489.
https://doi.org/10.7554/eLife.74489
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