ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

10.1101/2021.04.06.438630

bioRxiv

7th April 2021

Contributing to research themes:

This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.


SARS-CoV-2 antagonises the cellular interferon response, but whether the virus manipulates cellular immunity is unclear. An unbiased proteomic approach to determine how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells showed downregulation of activating NK cell ligands: B7-H6, MICA, ULBP2, and Nectin1, but no effect on surface MHC-I expression. NK ligand downregulation correlated with a reduction in NK cell activation by infected cells, and was overcome by antibody-dependent NK cell activation (ADNKA). Depletion of spike-specific antibodies confirmed their dominant role in virus neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other viral 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.

Author list:

Affiliations

  1. Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN
  2. Cambridge Institute for Therapeutic Immunology & Infectious Disease, Jeffrey Cheah
  3. Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge
  4. CB2 0AW, UK
  5. Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's
  6. College London, London, UK
  7. Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London
  8. MRC - University of Glasgow Centre for Virus Research, 464 Bearsden Road, Glasgow, G61
  9. 1QH

 

Authors

Fielding CA1, Sabberwal P1, Williamson JC2, Greenwood EJD2, Crozier TWM2, Zelek W1, Seow J3, Graham C3, Huettner I3, Edgeworth JD3,4, Morgan BP1, Ladell K1, Eberl M1, Humphreys IR1, Merrick B3,4, Doores K3, Wilson SJ5, Lehner PJ2, Wang ECY1, Stanton RJ1*