SARS-CoV-2 host-shutoff impacts innate NK cell functions, but antibody-dependent NK activity is strongly activated through non-spike antibodies

  1. Ceri Alan Fielding
  2. Pragati Sabberwal
  3. James C Williamson
  4. Edward JD Greenwood
  5. Thomas WM Crozier
  6. Wioleta Zelek
  7. Jeffrey Seow
  8. Carl Graham
  9. Isabella Huettner
  10. Jonathan D Edgeworth
  11. David A Price
  12. B Paul Morgan
  13. Kristin Ladell
  14. Matthias Eberl
  15. Ian R Humphreys
  16. Blair Merrick
  17. Katie Doores
  18. Sam J Wilson
  19. Paul J Lehner
  20. Eddie CY Wang
  21. Richard J Stanton  Is a corresponding author
  1. Cardiff University, United Kingdom
  2. University of Cambridge, United Kingdom
  3. King's College London, United Kingdom
  4. Guy's and St Thomas' NHS Foundation Trust, United Kingdom
  5. Cardiff University School of Medicine, United Kingdom
  6. 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)

The following data sets were generated

Article and author information

Author details

  1. Ceri Alan Fielding

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5817-3153
  2. Pragati Sabberwal

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. James C Williamson

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Edward JD Greenwood

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5224-0263
  5. Thomas WM Crozier

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Wioleta Zelek

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffrey Seow

    Department of Infectious Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Carl Graham

    Department of Infectious Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Isabella Huettner

    Department of Infectious Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonathan D Edgeworth

    Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. David A Price

    Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9416-2737
  12. B Paul Morgan

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Kristin Ladell

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Matthias Eberl

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9390-5348
  15. Ian R Humphreys

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Blair Merrick

    Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Katie Doores

    Department of Infectious Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Sam J Wilson

    MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6065-0895
  19. Paul J Lehner

    Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9383-1054
  20. Eddie CY Wang

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2243-4964
  21. Richard J Stanton

    Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
    For correspondence
    stantonrj@cardiff.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6799-1182

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.

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.

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.

Metrics

  • 2,332
    views
  • 541
    downloads
  • 48
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ceri Alan Fielding
  2. Pragati Sabberwal
  3. James C Williamson
  4. Edward JD Greenwood
  5. Thomas WM Crozier
  6. Wioleta Zelek
  7. Jeffrey Seow
  8. Carl Graham
  9. Isabella Huettner
  10. Jonathan D Edgeworth
  11. David A Price
  12. B Paul Morgan
  13. Kristin Ladell
  14. Matthias Eberl
  15. Ian R Humphreys
  16. Blair Merrick
  17. Katie Doores
  18. Sam J Wilson
  19. Paul J Lehner
  20. Eddie CY Wang
  21. Richard J Stanton
(2022)
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

Share this article

https://doi.org/10.7554/eLife.74489

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    3. Microbiology and Infectious Disease
    Edited by Diane M Harper et al.
    Collection

    eLife has published the following articles on SARS-CoV-2 and COVID-19.

    1. Immunology and Inflammation
    Jian Liu, YuYing Jiang ... ZhiQiang Yin
    Research Article

    Psoriasis is a multifactorial immune-mediated inflammatory disease. Its pathogenesis involves abnormal accumulation of neutrophils and T-cell-related abnormalities. Pyroptosis is a type of regulated cell death associated with innate immunity, but its role in psoriasis is unclear. In this study, we found that gasdermin D (GSDMD) is higher in human psoriatic skin than that in normal skin, and in imiquimod-induced psoriasis-like mouse skin, the expression of Gsdmd was most significantly altered in neutrophils and Il1b was also mainly expressed in neutrophils. Immunohistochemical staining of serial sections of skin lesions from psoriasis patients and healthy control also showed that GSDMD expression is higher in psoriasis lesion, especially in neutrophils. Gsdmd deficiency mitigates psoriasis-like inflammation in mice. GSDMD in neutrophils contributes to psoriasis-like inflammation, while Gsdmd depletion in neutrophils attenuates the development of skin inflammation in psoriasis and reduces the release of the inflammatory cytokines. We found that neutrophil pyroptosis is involved in and contributes to psoriasis inflammation, which provides new insights into the treatment of psoriasis by targeting neutrophil pyroptosis.