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

共 104 条

[1] Early Changes in Natural Killer Cell Function Indicate Virologic Response to Interferon Therapy for Hepatitis C
Ahlenstiel, Golo
Edlich, Birgit
Hogdal, Leah J.
Rotman, Yaron
Noureddin, Mazen
Feld, Jordan J.
Holz, Lauren E.
Titerence, Rachel H.
Liang, T. Jake
Rehermann, Barbara
[J]. GASTROENTEROLOGY, 2011, 141 (04) : 1231 - U651
[2] Aibar S, 2017, NAT METHODS, V14, P1083, DOI [10.1038/NMETH.4463, 10.1038/nmeth.4463]
[3] Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway
Alvarez, Maite
Simonetta, Federico
Baker, Jeanette
Pierini, Antonio
Wenokur, Arielle S.
Morrison, Alyssa R.
Murphy, William J.
Negrin, Robert S.
[J]. JCI INSIGHT, 2019, 4 (14)
[4] destiny: diffusion maps for large-scale single cell data in R
Angerer, Philipp
Haghverdi, Laleh
Buettner, Maren
Theis, Fabian J.
Marr, Carsten
Buettner, Florian
[J]. BIOINFORMATICS, 2016, 32 (08) : 1241 - 1243
[5] [Anonymous], 2021, medRxiv
[6] Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage
Aran, Dvir
Looney, Agnieszka P.
Liu, Leqian
Wu, Esther
Fong, Valerie
Hsu, Austin
Chak, Suzanna
Naikawadi, Ram P.
Wolters, Paul J.
Abate, Adam R.
Butte, Atul J.
Bhattacharya, Mallar
[J]. NATURE IMMUNOLOGY, 2019, 20 (02) : 163 - +
[7] Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans
Arunachalam, Prabhu S.
Wimmers, Florian
Mok, Chris Ka Pun
Perera, Ranawaka A. P. M.
Scott, Madeleine
Hagan, Thomas
Sigal, Natalia
Feng, Yupeng
Bristow, Laurel
Tsang, Owen Tak-Yin
Wagh, Dhananjay
Coller, John
Pellegrini, Kathryn L.
Kazmin, Dmitri
Alaaeddine, Ghina
Leung, Wai Shing
Chan, Jacky Man Chun
Chik, Thomas Shiu Hong
Choi, Chris Yau Chung
Huerta, Christopher
McCullough, Michele Paine
Lv, Huibin
Anderson, Evan
Edupuganti, Srilatha
Upadhyay, Amit A.
Bosinger, Steve E.
Maecker, Holden Terry
Khatri, Purvesh
Rouphael, Nadine
Peiris, Malik
Pulendran, Bali
[J]. SCIENCE, 2020, 369 (6508) : 1210 - +
[8] Gene Ontology: tool for the unification of biology
Ashburner, M
Ball, CA
Blake, JA
Botstein, D
Butler, H
Cherry, JM
Davis, AP
Dolinski, K
Dwight, SS
Eppig, JT
Harris, MA
Hill, DP
Issel-Tarver, L
Kasarskis, A
Lewis, S
Matese, JC
Richardson, JE
Ringwald, M
Rubin, GM
Sherlock, G
[J]. NATURE GENETICS, 2000, 25 (01) : 25 - 29
[9] Differential Responses of Immune Cells to Type I Interferon Contribute to Host Resistance to Viral Infection
Baranek, Thomas
Manh, Thien-Phong Vu
Alexandre, Yannick
Maqbool, Muhammad Ahmad
Cabeza, Joaquin Zacarias
Tomasello, Elena
Crozat, Karine
Bessou, Gilles
Zucchini, Nicolas
Robbins, Scott H.
Vivier, Eric
Kalinke, Ulrich
Ferrier, Pierre
Dalod, Marc
[J]. CELL HOST & MICROBE, 2012, 12 (04) : 571 - 584
[10] Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Bastard, Paul
Rosen, Lindsey B.
Zhang, Qian
Michailidis, Eleftherios
Hoffmann, Hans-Heinrich
Zhang, Yu
Dorgham, Karim
Philippot, Quentin
Rosain, Jeremie
Beziat, Vivien
Manry, Jeremy
Shaw, Elana
Haljasmagi, Liis
Peterson, Part
Lorenzo, Lazaro
Bizien, Lucy
Trouillet-Assant, Sophie
Dobbs, Kerry
de Jesus, Adriana Almeida
Belot, Alexandre
Kallaste, Anne
Catherinot, Emilie
Tandjaoui-Lambiotte, Yacine
Le Pen, Jeremie
Kerner, Gaspard
Bigio, Benedetta
Seeleuthner, Yoann
Yang, Rui
Bolze, Alexandre
Spaan, Andras N.
Delmonte, Ottavia M.
Abers, Michael S.
Aiuti, Alessandro
Casari, Giorgio
Lampasona, Vito
Piemonti, Lorenzo
Ciceri, Fabio
Bilguvar, Kaya
Lifton, Richard P.
Vasse, Marc
Smadja, David M.
Migaud, Melanie
Hadjadj, Jerome
Terrier, Benjamin
Duffy, Darragh
Quintana-Murci, Lluis
van de Beek, Diederik
Roussel, Lucie
Vinh, Donald C.
Tangye, Stuart G.
[J]. SCIENCE, 2020, 370 (6515) : 423 - +

← 1 2 3 4 5 6 7 8 9 10 →