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

被引：163

作者：

Witkowski, Mario ^{[1
,2
,3
,4
,5
]}

Tizian, Caroline ^{[1
,2
,3
,4
]}

Ferreira-Gomes, Marta ^{[6
]}

Niemeyer, Daniela ^{[7
,8
,9
,10
]}

Jones, Terry C. ^{[7
,8
,9
,10
,11
]}

Heinrich, Frederik ^{[6
]}

Frischbutter, Stefan ^{[8
,9
,12
,13
]}

Angermair, Stefan ^{[2
,3
,14
]}

Hohnstein, Thordis ^{[1
,2
,3
,4
]}

Mattiola, Irene ^{[1
,2
,3
,4
]}

Nawrath, Philipp

McEwen, Sophie

Zocche, Silvia ^{[15
,16
,17
]}

Viviano, Edoardo ^{[18
,19
,20
]}

Heinz, Gitta Anne ^{[6
]}

Maurer, Marcus ^{[8
,9
,12
,13
]}

Koelsch, Uwe ^{[21
]}

Chua, Robert Lorenz ^{[19
,20
,22
,23
]}

Aschman, Tom ^{[19
,20
,24
]}

Meisel, Christian ^{[16
,17
,21
,25
]}

Radke, Josefine ^{[19
,20
,24
]}

Sawitzki, Birgit ^{[16
,17
,25
]}

Roehmel, Jobst ^{[19
,20
,26
]}

Allers, Kristina ^{[2
,3
,27
,28
]}

Moos, Verena ^{[2
,3
,27
,28
]}

Schneider, Thomas ^{[2
,3
,27
,28
]}

Hanitsch, Leif ^{[16
,17
,25
]}

Mall, Marcus A. ^{[19
,20
,26
,29
]}

Conrad, Christian ^{[19
,20
,22
,23
]}

Radbruch, Helena ^{[19
,20
,24
]}

Duerr, Claudia U. ^{[2
,3
,30
]}

Trapani, Joseph A. ^{[31
]}

Marcenaro, Emanuela ^{[32
]}

Kallinich, Tilmann ^{[19
,20
,26
,33
]}

Corman, Victor M. ^{[7
,8
,9
,10
]}

Kurth, Florian ^{[19
,20
,34
,35
,36
]}

Sander, Leif Erik ^{[19
,20
,34
]}

Drosten, Christian ^{[7
,8
,9
,10
]}

Treskatsch, Sascha ^{[2
,3
,14
]}

Durek, Pawel ^{[6
]}

Kruglov, Andrey ^{[37
,38
,39
,40
]}

Radbruch, Andreas ^{[41
]}

Mashreghi, Mir-Farzin ^{[6
,42
]}

Diefenbach, Andreas ^{[1
,2
,3
,4
,5
]}

机构：

[1] Charite Univ Med Berlin, Inst Microbiol Infect Dis & Immunol, Inst Microbiol, Campus Benjamin Franklin, Berlin, Germany

[2] Free Univ Berlin, Campus Benjamin Franklin, Berlin, Germany

[3] Humboldt Univ, Campus Benjamin Franklin, Berlin, Germany

[4] Deutsch Rheuma Forschungszentrum DRFZ, Mucosal & Dev Immunol, Berlin, Germany

[5] Charite Vivantes, Lab Berlin, Dept Microbiol & Hyg, Berlin, Germany

[6] Deutsch Rheuma Forschungszentrum DRFZ, Therapeut Gene Regulat, Berlin, Germany

[7] Charite Univ Med Berlin, Inst Virol, Campus Charite Mitte, Berlin, Germany

[8] Free Univ Berlin, Campus Charite Mitte, Berlin, Germany

[9] Humboldt Univ, Campus Charite Mitte, Berlin, Germany

[10] German Ctr Infect Res DZIF, Partner Site Berlin, Berlin, Germany

[11] Univ Cambridge, Ctr Pathogen Evolut, Dept Zool, Cambridge, England

[12] Charite Univ Med Berlin, Dermatol Allergol, Allergie Ctr Charite, Dept Dermatol & Allergy,Campus Charite Mitte, Berlin, Germany

[13] Fraunhofer Inst Translat Med & Pharmacol ITMP All, Berlin, Germany

[14] Charite Univ Med Berlin, Dept Anesthesiol & Intens Care Med, Campus Benjamin Franklin, Berlin, Germany

[15] Charite Univ Med Berlin, Dept Pediat Gastroenterol Nephrol & Metab Dis, Campus Virchow Klinikum, Berlin, Germany

[16] Free Univ Berlin, Campus Virchow Klinikum, Berlin, Germany

[17] Humboldt Univ, Campus Virchow Klinikum, Berlin, Germany

[18] Charite Univ Med Berlin, Inst Physiol, Ctr Space Med & Extreme Environm Berlin, Berlin, Germany

[19] Free Univ Berlin, Berlin, Germany

[20] Humboldt Univ, Berlin, Germany

[21] Charite Vivantes, Lab Berlin, Dept Immunol, Berlin, Germany

[22] Berlin Inst Hlth BIH, Ctr Digital Hlth, Berlin, Germany

[23] Charite Univ Med Berlin, Berlin, Germany

[24] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany

[25] Charite Univ Med Berlin, Inst Med Immunol, Campus Virchow Klinikum, Berlin, Germany

[26] Charite Univ Med Berlin, Dept Pediat Resp Med Immunol & Crit Care Med, Berlin, Germany

[27] Charite Univ Med Berlin, Dept Med Gastroenterol Infect Dis Rheumatol, Berlin, Germany

[28] Berlin Inst Hlth, Campus Benjamin Franklin, Berlin, Germany

[29] German Ctr Lung Res DZL, Associated Partner Berlin, Berlin, Germany

[30] Charite Univ Med Berlin, Lab Mucosal Immun, Inst Microbiol Infect Dis & Immunol, Campus Benjamin Franklin, Berlin, Germany

[31] Peter MacCallum Canc Ctr, Canc Immunol Program, Melbourne, Vic, Australia

[32] Univ Genoa, Dept Expt Med, Genoa, Italy

[33] Deutsch Rheuma Forschungszentrum DRFZ, Chron Inflammat Childhood, Berlin, Germany

[34] Charite Univ Med Berlin, Dept Infect Dis & Resp Med, Berlin, Germany

[35] Univ Med Ctr Hamburg Eppendorf, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany

[36] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany

[37] Deutsch Rheuma Forschungszentrum DRFZ, Chron Inflammat, Berlin, Germany

[38] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia

[39] Moscow MV Lomonosov State Univ, Biol Fac, Moscow, Russia

[40] Russian Acad Sci, Ctr Precis Genome Editing & Genet Technol Biomed, Engelhardt Inst Mol Biol, Moscow, Russia

[41] Deutsch Rheuma Forschungszentrum DRFZ, Cell Biol, Berlin, Germany

[42] Charite Univ Med Berlin, BIH Ctr Regenerat Therapies BCRT, Berlin, Germany

来源：

NATURE | 2021年 / 600卷 / 7888期

基金：

俄罗斯基础研究基金会; 欧洲研究理事会;

关键词：

NATURAL-KILLER-CELLS; GROWTH-FACTOR-BETA; IGA PRODUCTION; CYTOTOXICITY; HOMEOSTASIS; MATURATION; PERFORIN; REVEALS;

D O I：

10.1038/s41586-021-04142-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1,2). NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype(3,4). 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-beta (TGF beta) 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 TGF beta peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGF beta-dependent manner. Our data reveal that an untimely production of TGF beta is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

引用

页码：295 / +

页数：30

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