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Untimely TGFß responses in COVID-19 limit antiviral functions of NK cells.
Witkowski, Mario; Tizian, Caroline; Ferreira-Gomes, Marta; Niemeyer, Daniela; Jones, Terry C; Heinrich, Frederik; Frischbutter, Stefan; Angermair, Stefan; Hohnstein, Thordis; Mattiola, Irene; Nawrath, Philipp; McEwen, Sophie; Zocche, Silvia; Viviano, Edoardo; Heinz, Gitta Anne; Maurer, Marcus; Kölsch, Uwe; Chua, Robert Lorenz; Aschman, Tom; Meisel, Christian; Radke, Josefine; Sawitzki, Birgit; Roehmel, Jobst; Allers, Kristina; Moos, Verena; Schneider, Thomas; Hanitsch, Leif; Mall, Marcus A; Conrad, Christian; Radbruch, Helena; Duerr, Claudia U; Trapani, Joseph A; Marcenaro, Emanuela; Kallinich, Tilmann; Corman, Victor M; Kurth, Florian; Sander, Leif Erik; Drosten, Christian; Treskatsch, Sascha; Durek, Pawel; Kruglov, Andrey; Radbruch, Andreas; Mashreghi, Mir-Farzin; Diefenbach, Andreas.
  • Witkowski M; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany. mario.witkowski@charite.de.
  • Tizian C; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. mario.witkowski@charite.de.
  • Ferreira-Gomes M; Department of Microbiology and Hygiene, Labor Berlin, Charité-Vivantes, Berlin, Germany. mario.witkowski@charite.de.
  • Niemeyer D; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Jones TC; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Heinrich F; Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Frischbutter S; Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany.
  • Angermair S; German Center for Infection Research (DZIF), Partner Site Berlin, Berlin, Germany.
  • Hohnstein T; Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany.
  • Mattiola I; German Center for Infection Research (DZIF), Partner Site Berlin, Berlin, Germany.
  • Nawrath P; Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
  • McEwen S; Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Zocche S; Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany.
  • Viviano E; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) Allergology and Immunology, Berlin, Germany.
  • Heinz GA; Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Maurer M; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Kölsch U; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Chua RL; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Aschman T; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Meisel C; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Radke J; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Sawitzki B; Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • Roehmel J; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Allers K; Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • Moos V; Institute of Physiology, Center for Space Medicine and Extreme Environments Berlin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Schneider T; Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  • Hanitsch L; Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany.
  • Mall MA; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) Allergology and Immunology, Berlin, Germany.
  • Conrad C; Department of Immunology, Labor Berlin, Charité-Vivantes, Berlin, Germany.
  • Radbruch H; Center for Digital Health, Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Duerr CU; Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Trapani JA; Department of Immunology, Labor Berlin, Charité-Vivantes, Berlin, Germany.
  • Marcenaro E; Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • Kallinich T; Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Corman VM; Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • Kurth F; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Sander LE; Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.
  • Drosten C; Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.
  • Treskatsch S; Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.
  • Durek P; Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • Kruglov A; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Radbruch A; German Center for Lung Research (DZL), Associated Partner Berlin, Berlin, Germany.
  • Mashreghi MF; Center for Digital Health, Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Diefenbach A; Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1626235
ABSTRACT
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-ß (TGFß) 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 TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Killer Cells, Natural / Transforming Growth Factor beta / SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-04142-6

Full text: Available Collection: International databases Database: MEDLINE Main subject: Killer Cells, Natural / Transforming Growth Factor beta / SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-04142-6