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 and Andreas Diefenbach ()
Additional contact information
Mario Witkowski: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
Caroline Tizian: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
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
Terry C. Jones: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
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
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
Irene Mattiola: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
Philipp Nawrath: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
Sophie McEwen: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin
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
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
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
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
Victor M. Corman: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Charité Mitte
Florian Kurth: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
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
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
Andreas Radbruch: an Institute of the Leibniz Association
Mir-Farzin Mashreghi: Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association
Andreas Diefenbach: Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin

Nature, 2021, vol. 600, issue 7888, 295-301

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-04142-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:600:y:2021:i:7888:d:10.1038_s41586-021-04142-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-04142-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().