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

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.