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

Author

Listed:
  • Mario Witkowski

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
    Labor Berlin, Charité–Vivantes)

  • Caroline Tizian

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Marta Ferreira-Gomes

    (Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Daniela Niemeyer

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
    German Center for Infection Research (DZIF), Partner Site Berlin)

  • Terry C. Jones

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
    German Center for Infection Research (DZIF), Partner Site Berlin
    University of Cambridge)

  • Frederik Heinrich

    (Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Stefan Frischbutter

    (Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Campus Charité Mitte
    Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) Allergology and Immunology)

  • Stefan Angermair

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin)

  • Thordis Hohnstein

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Irene Mattiola

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Philipp Nawrath

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Sophie McEwen

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Silvia Zocche

    (Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum)

  • Edoardo Viviano

    (Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Gitta Anne Heinz

    (Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Marcus Maurer

    (Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt–Universität zu Berlin, Campus Charité Mitte
    Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) Allergology and Immunology)

  • Uwe Kölsch

    (Labor Berlin, Charité-Vivantes)

  • Robert Lorenz Chua

    (Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Tom Aschman

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Christian Meisel

    (Labor Berlin, Charité-Vivantes
    Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum)

  • Josefine Radke

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Birgit Sawitzki

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum)

  • Jobst Roehmel

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Kristina Allers

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin)

  • Verena Moos

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin)

  • Thomas Schneider

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin)

  • Leif Hanitsch

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum)

  • Marcus A. Mall

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Center for Lung Research (DZL), Associated Partner Berlin)

  • Christian Conrad

    (Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Helena Radbruch

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Claudia U. Duerr

    (Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin)

  • Joseph A. Trapani

    (Peter MacCallum Cancer Centre)

  • Emanuela Marcenaro

    (University of Genoa)

  • Tilmann Kallinich

    (Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Victor M. Corman

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
    German Center for Infection Research (DZIF), Partner Site Berlin)

  • Florian Kurth

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    University Medical Centre Hamburg-Eppendorf)

  • Leif Erik Sander

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Christian Drosten

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
    German Center for Infection Research (DZIF), Partner Site Berlin)

  • Sascha Treskatsch

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin)

  • Pawel Durek

    (Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association)

  • Andrey Kruglov

    (an Institute of the Leibniz Association
    M.V. Lomonosov Moscow State University
    Russian Academy of Sciences)

  • Andreas Radbruch

    (an Institute of the Leibniz Association)

  • Mir-Farzin Mashreghi

    (Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
    Charité Universitätsmedizin Berlin)

  • Andreas Diefenbach

    (Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
    Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
    Labor Berlin, Charité–Vivantes)

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-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.

Suggested Citation

  • Mario Witkowski & Caroline Tizian & Marta Ferreira-Gomes & Daniela Niemeyer & Terry C. Jones & Frederik Heinrich & Stefan Frischbutter & Stefan Angermair & Thordis Hohnstein & Irene Mattiola & Philipp, 2021. "Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells," Nature, Nature, vol. 600(7888), pages 295-301, December.
    • Handle: RePEc:nat:nature:v:600:y:2021:i:7888:d:10.1038_s41586-021-04142-6
    DOI: 10.1038/s41586-021-04142-6
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    Cited by:

    1. Ronja Mothes & Anna Pascual-Reguant & Ralf Koehler & Juliane Liebeskind & Alina Liebheit & Sandy Bauherr & Lars Philipsen & Carsten Dittmayer & Michael Laue & Regina Manitius & Sefer Elezkurtaj & Pawe, 2023. "Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Scott B. Biering & Francielle Tramontini Gomes de Sousa & Laurentia V. Tjang & Felix Pahmeier & Chi Zhu & Richard Ruan & Sophie F. Blanc & Trishna S. Patel & Caroline M. Worthington & Dustin R. Glasne, 2022. "SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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