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Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells
Nature  (IF49.962),  Pub Date : 2021-10-25, DOI: 10.1038/s41586-021-04142-6
Mario Witkowski, Caroline Tizian, Marta Ferreira-Gomes, Daniela Niemeyer, Terry C. Jones, Frederik Heinrich, Stefan Frischbutter, Stefan Angermair, Thordis Hohnstein, Irene Mattiola, Philipp Nawrath, Sophie Mc Ewen, Silvia Zocche, Edoardo Viviano, Gitta Anne Heinz, Marcus Maurer, Uwe Kölsch, Robert Lorenz Chua, Tom Aschman, Christian Meisel, Josefine Radke, Birgit Sawitzki, Jobst Roehmel, Kristina Allers, Verena Moos, Thomas Schneider, Leif Hanitsch, Marcus A. Mall, Christian Conrad, Helena Radbruch, Claudia U. Duerr, Joseph A. Trapani, Emanuela Marcenaro, Tilmann Kallinich, Victor M. Corman, Florian Kurth, Leif Erik Sander, Christian Drosten, Sascha Treskatsch, Pawel Durek, Andrey Kruglov, Andreas Radbruch, Mir-Farzin Mashreghi, Andreas Diefenbach

SARS-CoV-2 is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). Given its acute and often self-limiting course, components of the innate immune system are likely central in controlling virus replication thereby determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and ‘adaptive’ phenotype3,4. Here we show that viral load decline in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show remarkable defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA-sequencing (scRNA-seq) of NK cells along the time course of the entire COVID-19 disease spectrum reveals a unique gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant TGFβ response signature with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFβ peak during the first 2 weeks of infection, and serum obtained from these patients profoundly inhibits NK cell function in a TGFβ-dependent manner. Our data reveal that untimely production of TGFβ is a hallmark of severe COVID-19 and may inhibit NK cell function and early virus control.