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

Abstract

SummaryNatural killer (NK) cells are cytotoxic effector cells that target and lyse virally-infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogated 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 downregulation of ligands for the activating receptor NKG2D ("NKG2D-L"). Indeed, early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed. Finally, we found that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work reveals that SARS-CoV-2 evades NK cell cytotoxicity and describes a mechanism by which this occurs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/496341v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@bcffeeorg.highwire.dtl.DTLVardef@469b0eorg.highwire.dtl.DTLVardef@16dd205org.highwire.dtl.DTLVardef@f78070_HPS_FORMAT_FIGEXP M_FIG C_FIG