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SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D

View ORCID ProfileMadeline J. Lee, View ORCID ProfileMichelle W. Leong, View ORCID ProfileArjun Rustagi, View ORCID ProfileAimee Beck, Leiping Zeng, View ORCID ProfileSusan Holmes, View ORCID ProfileLei S. Qi, View ORCID ProfileCatherine A. Blish
doi: https://doi.org/10.1101/2022.06.20.496341
Madeline J. Lee
1Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
2Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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  • ORCID record for Madeline J. Lee
Michelle W. Leong
2Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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Arjun Rustagi
2Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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Aimee Beck
2Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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Leiping Zeng
3Department of Bioengineering, Stanford University, Stanford, CA, 94305, United States of America
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Susan Holmes
4Department of Statistics, Stanford University, Stanford, CA, 94305, United States of America
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Lei S. Qi
3Department of Bioengineering, Stanford University, Stanford, CA, 94305, United States of America
5Sarafan Chem-H, Stanford University, Stanford, CA, 94305, United States of America
6Chan Zuckerberg Biohub, San Francisco, CA, 94157, United States of America
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Catherine A. Blish
2Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
6Chan Zuckerberg Biohub, San Francisco, CA, 94157, United States of America
7Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, 94305, United States of America
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  • For correspondence: cblish@stanford.edu
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Abstract

Natural killer (NK) cells are cytotoxic effector cells that respond rapidly to viral infection by targeting and lysing infected cells, and many viruses encode mechanisms to escape such NK cell killing. Here, we sought to investigate the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. We found that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells. We demonstrate that this escape is driven by strong downregulation of ligands for the activating receptor NKG2D on SARS-CoV-2-infected cells. Indeed, in the initial stages of viral infection, prior to NKG2D-ligand downregulation, NK cells are able to successfully target and kill infected cells; however, this ability is lost as viral proteins are expressed within infected cells. Finally, we found that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates the downregulation of NKG2D ligands and that transfection with Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work reveals that SARS-CoV-2 evades NK cell cytotoxic responses and describes a mechanism by which this occurs.

Competing Interest Statement

C.A.B. reports compensation for consulting and/or SAB membership from Catamaran Bio, DeepCell Inc., Immunebridge, Sangamo Therapeutics, Bicycle Tx, and Revelation Biosciences on topics unrelated to this study.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 21, 2022.
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SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D
Madeline J. Lee, Michelle W. Leong, Arjun Rustagi, Aimee Beck, Leiping Zeng, Susan Holmes, Lei S. Qi, Catherine A. Blish
bioRxiv 2022.06.20.496341; doi: https://doi.org/10.1101/2022.06.20.496341
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SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D
Madeline J. Lee, Michelle W. Leong, Arjun Rustagi, Aimee Beck, Leiping Zeng, Susan Holmes, Lei S. Qi, Catherine A. Blish
bioRxiv 2022.06.20.496341; doi: https://doi.org/10.1101/2022.06.20.496341

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