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Nature
12, 2021;600 (7888): 295-301.

Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells.

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 McEwen, 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
Author Information
  1. Mario Witkowski: 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. ORCID
  2. Caroline Tizian: 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. ORCID
  3. Marta Ferreira-Gomes: Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
  4. Daniela Niemeyer: Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany. ORCID
  5. Terry C Jones: Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany. ORCID
  6. Frederik Heinrich: Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
  7. Stefan Frischbutter: 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. ORCID
  8. Stefan Angermair: 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. ORCID
  9. Thordis Hohnstein: 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.
  10. Irene Mattiola: 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. ORCID
  11. Philipp Nawrath: 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.
  12. Sophie McEwen: 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.
  13. Silvia Zocche: 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.
  14. Edoardo Viviano: 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.
  15. Gitta Anne Heinz: Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
  16. Marcus Maurer: 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. ORCID
  17. Uwe Kölsch: Department of Immunology, Labor Berlin, Charité-Vivantes, Berlin, Germany. ORCID
  18. Robert Lorenz Chua: 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.
  19. Tom Aschman: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ORCID
  20. Christian Meisel: Department of Immunology, Labor Berlin, Charité-Vivantes, Berlin, Germany. ORCID
  21. Josefine Radke: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ORCID
  22. Birgit Sawitzki: Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany. ORCID
  23. Jobst Roehmel: 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. ORCID
  24. Kristina Allers: 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.
  25. Verena Moos: 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.
  26. Thomas Schneider: 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.
  27. Leif Hanitsch: Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  28. Marcus A Mall: 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. ORCID
  29. Christian Conrad: 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.
  30. Helena Radbruch: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ORCID
  31. Claudia U Duerr: Laboratory of Mucosal 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. ORCID
  32. Joseph A Trapani: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  33. Emanuela Marcenaro: Department of Experimental Medicine, University of Genoa, Genoa, Italy. ORCID
  34. Tilmann Kallinich: 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.
  35. Victor M Corman: Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany. ORCID
  36. Florian Kurth: Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ORCID
  37. Leif Erik Sander: Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ORCID
  38. Christian Drosten: Institute of Virology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte, Berlin, Germany. ORCID
  39. Sascha Treskatsch: 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. ORCID
  40. Pawel Durek: Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  41. Andrey Kruglov: Chronic Inflammation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  42. Andreas Radbruch: Cell Biology, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
  43. Mir-Farzin Mashreghi: Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany. ORCID
  44. Andreas Diefenbach: 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. andreas.diefenbach@charite.de. ORCID
PMID: 34695836 DOI: 10.1038/s41586-021-04142-6

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 viruses. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype. 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.

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MeSH Term

Atlases as Topic
COVID-19
Gene Expression Regulation
Humans
Immunity, Innate
Influenza, Human
Killer Cells, Natural
RNA-Seq
SARS-CoV-2
Single-Cell Analysis
Time Factors
Transforming Growth Factor beta
Viral Load
Virus Replication

Chemicals

Transforming Growth Factor beta
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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