Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells
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Untimely TGFβ 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.
in: NATURE, Jahrgang 600, Nr. 7888, 12.2021, S. 295-301.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells
AU - Witkowski, Mario
AU - Tizian, Caroline
AU - Ferreira-Gomes, Marta
AU - Niemeyer, Daniela
AU - Jones, Terry C
AU - Heinrich, Frederik
AU - Frischbutter, Stefan
AU - Angermair, Stefan
AU - Hohnstein, Thordis
AU - Mattiola, Irene
AU - Nawrath, Philipp
AU - McEwen, Sophie
AU - Zocche, Silvia
AU - Viviano, Edoardo
AU - Heinz, Gitta Anne
AU - Maurer, Marcus
AU - Kölsch, Uwe
AU - Chua, Robert Lorenz
AU - Aschman, Tom
AU - Meisel, Christian
AU - Radke, Josefine
AU - Sawitzki, Birgit
AU - Roehmel, Jobst
AU - Allers, Kristina
AU - Moos, Verena
AU - Schneider, Thomas
AU - Hanitsch, Leif
AU - Mall, Marcus A
AU - Conrad, Christian
AU - Radbruch, Helena
AU - Duerr, Claudia U
AU - Trapani, Joseph A
AU - Marcenaro, Emanuela
AU - Kallinich, Tilmann
AU - Corman, Victor M
AU - Kurth, Florian
AU - Sander, Leif Erik
AU - Drosten, Christian
AU - Treskatsch, Sascha
AU - Durek, Pawel
AU - Kruglov, Andrey
AU - Radbruch, Andreas
AU - Mashreghi, Mir-Farzin
AU - Diefenbach, Andreas
N1 - © 2021. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Atlases as Topic
KW - COVID-19/immunology
KW - Gene Expression Regulation/immunology
KW - Humans
KW - Immunity, Innate
KW - Influenza, Human/immunology
KW - Killer Cells, Natural/immunology
KW - RNA-Seq
KW - SARS-CoV-2/immunology
KW - Single-Cell Analysis
KW - Time Factors
KW - Transforming Growth Factor beta/blood
KW - Viral Load/immunology
KW - Virus Replication/immunology
U2 - 10.1038/s41586-021-04142-6
DO - 10.1038/s41586-021-04142-6
M3 - SCORING: Journal article
C2 - 34695836
VL - 600
SP - 295
EP - 301
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7888
ER -
