作者
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 G. Hanitsch,Marcus 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
摘要
SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and 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 a decline in viral load 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 defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-β (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 two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFβ-dependent manner. Our data reveal that an untimely production of TGFβ is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.