SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 9; p. 1975
• Main Authors: Bortolotti, Daria, Gentili, Valentina, Rizzo, Sabrina, Rotola, Antonella, Rizzo, Roberta
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26-08-2020; MDPI
• Subjects: Antibodies; Betacoronavirus - chemistry; Blood & organ donations; Blood Donors; Bronchi - cytology; Cell activation; Cell adhesion & migration; Cell culture; Cell Degranulation - genetics; Cloning; Coculture Techniques; Coronavirus Infections - immunology; Coronavirus Infections - metabolism; Coronavirus Infections - virology; Coronaviruses; COVID-19; Cytotoxicity; Degranulation; Dehydrogenases; Epithelial cells; Epithelial Cells - metabolism; Flow cytometry; GATA-3 protein; Health aspects; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - metabolism; HLA antigens; HLA-E; HLA-E Antigens; Humans; Immunopathogenesis; Infections; Interferon-gamma - metabolism; K562 Cells; Killer cells; Killer Cells, Natural - immunology; Lungs; Lymphocyte Activation - genetics; Natural killer cells; NK cell; NK Cell Lectin-Like Receptor Subfamily C - metabolism; NKG2 antigen; NKG2A; Pandemics; Peptides; Peripheral blood; Physiological aspects; Pneumonia, Viral - immunology; Pneumonia, Viral - metabolism; Pneumonia, Viral - virology; Proteins; Respiratory diseases; RNA, Viral - genetics; SARS-CoV-2; Severe Acute Respiratory Syndrome - immunology; Severe Acute Respiratory Syndrome - metabolism; Severe Acute Respiratory Syndrome - virology; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome-related coronavirus - chemistry; Software; Sp1 protein; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Transfection; γ-Interferon; China; United States > US; Italy; Germany; SARS-CoV-2; NK cell; NKG2A; HLA-E
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9091975

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells' exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.