SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells

Cell Rep. 2022 Mar 8;38(10):110503. doi: 10.1016/j.celrep.2022.110503. Epub 2022 Feb 21.


Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.

Keywords: COVID-19; HLA-E; NK cells; NKG2A; SARS-CoV-2; missing self.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / immunology
  • HLA-E Antigens
  • Histocompatibility Antigens Class I* / immunology
  • Humans
  • Killer Cells, Natural* / immunology
  • Methyltransferases* / immunology
  • NK Cell Lectin-Like Receptor Subfamily C* / immunology
  • NK Cell Lectin-Like Receptor Subfamily C* / metabolism
  • Peptides / metabolism
  • RNA Helicases* / immunology
  • SARS-CoV-2*
  • Viral Nonstructural Proteins* / immunology


  • Histocompatibility Antigens Class I
  • KLRC1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • Peptides
  • Viral Nonstructural Proteins
  • Methyltransferases
  • Nsp13 protein, SARS-CoV
  • RNA Helicases