Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19

被引：149

作者：

Kraemer, Benjamin ^{[1
]}

Knoll, Rainer ^{[2
,3
]}

Bonaguro, Lorenzo ^{[2
,3
]}

ToVinh, Michael ^{[1
]}

Raabe, Jan ^{[1
]}

Astaburuaga-Garcia, Rosario ^{[4
,5
,6
,7
,8
]}

Schulte-Schrepping, Jonas ^{[2
,3
]}

Kaiser, Kim Melanie ^{[1
]}

Rieke, Gereon J. ^{[1
]}

Bischoff, Jenny ^{[1
]}

Monin, Malte B. ^{[1
]}

Hoffmeister, Christoph ^{[1
]}

Schlabe, Stefan ^{[1
,9
]}

De Domenico, Elena ^{[2
,10
,11
]}

Reusch, Nico ^{[2
,3
]}

Haendler, Kristian ^{[2
,10
,11
]}

Reynolds, Gary ^{[12
]}

Bluethgen, Nils ^{[4
,5
,6
,7
,8
]}

Hack, Gudrun ^{[1
]}

Finnemann, Claudia ^{[1
]}

Nischalke, Hans D. ^{[1
]}

Strassburg, Christian P. ^{[1
]}

Stephenson, Emily ^{[12
]}

Su, Yapeng ^{[13
]}

Gardner, Louis ^{[12
]}

Yuan, Dan ^{[13
]}

Chen, Daniel ^{[13
]}

Goldman, Jason ^{[13
,15
,16
,17
]}

Rosenstiel, Philipp ^{[18
,19
]}

Schmidt, Susanne, V ^{[20
]}

Latz, Eicke ^{[20
]}

Hrusovsky, Kevin ^{[21
]}

Ball, Andrew J. ^{[21
]}

Johnson, Joe M. ^{[21
]}

Koenig, Paul-Albert ^{[20
,22
]}

Schmidt, Florian, I ^{[20
,22
]}

Haniffa, Muzlifah ^{[12
,23
,24
,25
]}

Heath, James R. ^{[13
,14
,26
,27
]}

Kuemmerer, Beate M. ^{[9
,28
]}

Keitel, Verena ^{[29
]}

Jensen, Bjoern ^{[29
]}

Stubbemann, Paula ^{[30
]}

Kurth, Florian ^{[30
,31
]}

Sander, Leif E. ^{[30
,31
]}

Sawitzki, Birgit ^{[32
]}

Aschenbrenner, Anna C. ^{[2
,3
,10
,11
,33
,34
]}

Schultze, Joachim L. ^{[2
,3
,10
,11
]}

Nattermann, Jacob ^{[1
,9
]}

机构：

[1] Univ Hosp Bonn, Dept Internal Med 1, Bonn, Germany

[2] Deutsch Zentrum Neurodegenerat Erkrankungen, Syst Med, Bonn, Germany

[3] Univ Bonn, Life & Med Sci LIMES Inst, Bonn, Germany

[4] Charite Univ Med Berlin, Berlin, Germany

[5] Free Univ Berlin, Berlin, Germany

[6] Humboldt Univ, Inst Pathol, Berlin, Germany

[7] Humboldt Univ, IRI Life Sci, Berlin, Germany

[8] Humboldt Univ, Inst Theoret Biol, Berlin, Germany

[9] German Ctr Infect Res DZIF, Heidelberg, Germany

[10] Deutsch Zentrum Neurodegenerat Erkrankungen DZNE, PRECISE Platform Genom & Epigen DZNE, Bonn, Germany

[11] Univ Bonn, Bonn, Germany

[12] Newcastle Univ, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England

[13] Inst Syst Biol, Seattle, WA 98109 USA

[14] Board Directors Isoplexis, Branford, CT 06405 USA

[15] Swedish Med Ctr, Swedish Ctr Res & Innovat, Seattle, WA 98109 USA

[16] Providence St Joseph Hlth, Renton, WA 98057 USA

[17] Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98109 USA

[18] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[19] Univ Med Ctr Schleswig Holstein, Kiel, Germany

[20] Univ Bonn, Inst Innate Immun, Med Fac, Bonn, Germany

[21] Quanterix Corp, Billerica, MA USA

[22] Univ Bonn, Med Fac, Core Facil Nanobodies, Bonn, Germany

[23] Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge, England

[24] Newcastle Hosp NHS Fdn Trust, NIHR Newcastle Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[25] Newcastle Hosp NHS Fdn Trust, Dept Dermatol, Newcastle Upon Tyne, Tyne & Wear, England

[26] Univ Washington, Dept Bioengn, Seattle, WA 98105 USA

[27] Board Directors PACT Pharma, San Francisco, CA 94080 USA

[28] Univ Bonn, Inst Virol, Med Fac, Bonn, Germany

[29] Heinrich Heine Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany

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

[31] German Ctr Lung Res DZL, Marburg, Germany

[32] Charite Univ Med Berlin, Inst Med Immunol, Berlin, Germany

[33] Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Nijmegen, Netherlands

[34] Radboud Univ Nijmegen Med Ctr, Radboud Ctr Infect Dis RCI, Nijmegen, Netherlands

来源：

IMMUNITY | 2021年 / 54卷 / 11期

关键词：

NATURAL-KILLER-CELLS; INTERFERON-GAMMA; LIVER FIBROSIS; CYTOMETRY DATA; R PACKAGE; THERAPY; CONTRIBUTE; INDUCTION; INFECTION; INFERENCE;

D O I：

10.1016/j.immuni.2021.09.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-a plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-a signaling, while up regulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-a and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFNa-induced NK cell response with poorer disease outcome.

引用

页码：2650 / +

页数：35

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