A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

doi:10.1016/j.cell.2022.01.012

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.

Original language	English
Pages (from-to)	916-938.e58
Number of pages	82
Journal	Cell
Volume	185
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2022.01.012
Publication status	Published - 3 Mar 2022
Externally published	Yes

Bibliographical note

Funding Information:
Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants (Data S1) including BHF RG/13/9/303269 FS/18/63/34184; CAMS IFMS 2018-I2M-2-002; CRUK C130623/A249471; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1; Emerson Collective; Gilead; Huo Family Foundation; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059; NIH U192U19AI082630 R24DK106766; NIHR; Rosetrees R35579/AA002/M85-F2; Royal Society RGF\EA\201074 UF150238; UKDHSC PITCH UK-COG; UKRI MR/S005471/1; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z. Patient recruitment and cohorts (A.J.M. M. Ainsworth, A.A. C.V.A.-C. J.K.B. B.A. A.B. S. Beer, T.B. A. Brent, A. Brown, C.P.C. N.D. J. Dequaire, S.J.D. A.E. R. Fairhead, S. Fassih, J.F. M.F.M. T.F. A. Fries, V.G.S. D.G. C. Hinds, C. Hird, P.H. K. Jeffery, D.K. P. Klenerman, J.C.K. A.K. T.L. J.M. P.C.M. S. McKechnie, D. O'Donnell, A.N. I. Pavord, E.P. T.R. M.R. M.G.S. D. Skelly, A. Sobrinodiaz, L. Stafford, A. Taylor, H.T. L.T. H.U. P.W. R.K.Y. J.Y.), sample processing and extraction (A.J.M. A.A. C.A. A. Beveridge, S. Bibi. T.B. L.B. A. Brown, D.B. S.C. E.A.C. F.C. C.D. T.D. H.D. S. Felle, L.G. A.G. J. Hill, E.J. J.C.K. A.K. A. Lee, A. Linder, L.L. M. Lopopolo. S. Marinou, A.M. Y.P. A.J.P. L.S.-R. C.S.R. C.S.K. G. Scozzafava, H.S. L. Stockdale, M. Strickland, A. Trebes, M.V. L. Witty, K.W. Z.Y. J.Y.), clinical phenotyping (A.J.M. J.K.B. E.B. T.B. C.A.D. L.G. L.-P.H. J.C.K. A.K. L.J. T.P.Q. F.R. S.N.S. M.G.S. A.S.D. L.T. J.Y.), mass and flow cytometry (G.N. M. Salio, C.M. I.U. D.J.A. Y.-X.Z. Z.A. L.D. R. Etherington, J.C.K. P. Kurupati, A.K. M.M. G.O. I. Park, M.P.P. E.R. D.T. E.v.G. L. Wang), whole blood total RNA-seq (A.J.M. M. Attar, K.L.B. E.E.D. J. Docker, C.G. C.H. J.C.K. A.K. A. Linder, D. O'Connor, S.R. J.W.), 10X CITE-seq and repertoire (S.N.S. C.A.D. L.J. J.C.K. R.B.-R. B.F. D.A. M. Attar, P.B. A.P.C. F.C. T.D. R. Ferreira, L.C.G. M.G.V. A.J.-B. A.J. K. Jansen, P. Klenerman, P.K.S. A.K. A. Linder, A.M. A.J.M. R.M. G.N. I.N. L.O. Y.P. F. Penkava, B.P. E.R. S.R. J.-B.R. C.R.-G. H.S. B.S. C.T. S. Thongjuea, O.T. F.A.T. A.V. G.W. R.W. H.Y.Y. Y.-X.Z.), ATAC-seq (T.S.-S. I.C.F. M. Lukoseviciute, M. Attar, S.R. J.C.K. A.K. A. Linder, H.S. M.W.), genetics (L.J. A.C. C.A.D. D.D. C.E. B.F. J. Hughes, J.C.K. A.J.M. Y.M. I.N. R.S. S.N.S. P.Z.), proteomics (mass spectrometry) (R. Fischer, A.S.D. G.B. P.C. S.D. R. Heilig, S.H. J.C.K. Y.M. D.P.O. I.V.) (Luminex) (L.X. W.C. Y.-L.C. D.A.D. P. Klenerman, J.L. C.M. G.O. I. Pavord, I.U.), data integration (J.C.K. M.A.A. R.B.-R. K.L.B. H.B. M.C. F.C. C.A.D. A. Forrow, R. Fischer, T.G. H.A.H. L.-P.H. R. Hoekzema, J. Hughes, M.A.J.-W. L.J. S. McGowan, A.J.M. Y.M. G.N. E.R. F.R. R.S.P. A.S.D. S.N.S. M. Sergeant, A. Seigal, D. Sims, O.S. S. Taylor, A. Tomic, J.W.), data management (B.M. J.B. A.P.C. R. Esnouf, H.F. H.H. L.J. J.C.K. G.K. P. Klenerman, V.K. A.J.M. F. Powrie, S.N.S. D. Sims, J.A.T. D.W.), report and manuscript writing (J.C.K. R.B.-R. K.L.B. F.C. C.A.D. A.S.D. B.F. H.F. R. Fischer, L.C.G. H.A.H. C. Hinds, L.J. A.K. P. Klenerman, A.J.M. B.M. Y.M. G.N. F.R. C.R.-G. A. Seigal, S.N.S. M. Sergeant, T.S-S. B.S. J.A.T. F.A.T. A. Tomic, S. Taylor, J.W. L.X.), steering committee (R.C. F. Powrie, J.C.K. P. Klenerman, A.J.M. H.McS. G.O. A.J.P. G. Screaton, J.A.T.), leadership and oversight (J.C.K. R.B.-R. C.A.D. B.F. R. Fischer, L.J. P. Klenerman, B.M. A.J.M. G.N. S.N.S. T.S.-S. J.A.T. L.X.). Further details and CRediT taxonomy in Data S1. R.B.-R. (co-founder and consultant Alchemab Therapeutics Ltd), R.C. (founder MIROBio), J. Hughes (director and shareholder Nucleome Therapeutics), G.S. (GSK Vaccines SAB), J.A.T. (GSK Human Genetics SAB). Other authors declare no competing interests.

Funding Information:
Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants ( Data S1 ) including BHF RG/13/9/303269 FS/18/63/34184 ; CAMS IFMS 2018-I2M-2-002 ; CRUK C130623/A249471 ; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1 ; Emerson Collective ; Gilead ; Huo Family Foundation ; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803 ; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059 ; NIH U192U19AI082630 R24DK106766 ; NIHR ; Rosetrees R35579/AA002/M85-F2 ; Royal Society RGF\EA\201074 UF150238 ; UKDHSC PITCH UK-COG ; UKRI MR/S005471/1 ; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z .

Publisher Copyright:
© 2022 The Author

Keywords

COVID-19
SARS-CoV-2
blood
coronavirus
epigenetics
immune
multi-omics
personalized medicine
proteomics
transcriptomics

Access to Document

10.1016/j.cell.2022.01.012

Cite this

@article{cfdd33d5deef46a4b8b0d00e173c8a16,

title = "A blood atlas of COVID-19 defines hallmarks of disease severity and specificity",

abstract = "Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.",

keywords = "COVID-19, SARS-CoV-2, blood, coronavirus, epigenetics, immune, multi-omics, personalized medicine, proteomics, transcriptomics",

author = "{COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium} and Ahern, {David J.} and Zhichao Ai and Mark Ainsworth and Chris Allan and Alice Allcock and Brian Angus and Ansari, {M. Azim} and Arancibia-C{\'a}rcamo, {Carolina V.} and Dominik Aschenbrenner and Moustafa Attar and Baillie, {J. Kenneth} and Eleanor Barnes and Rachael Bashford-Rogers and Archana Bashyal and Sally Beer and Georgina Berridge and Amy Beveridge and Sagida Bibi and Tihana Bicanic and Luke Blackwell and Paul Bowness and Andrew Brent and Andrew Brown and John Broxholme and David Buck and Burnham, {Katie L.} and Helen Byrne and Susana Camara and {Candido Ferreira}, Ivan and Philip Charles and Wentao Chen and Chen, {Yi Ling} and Amanda Chong and Clutterbuck, {Elizabeth A.} and Mark Coles and Conlon, {Christopher P.} and Richard Cornall and Cribbs, {Adam P.} and Fabiola Curion and Davenport, {Emma E.} and Neil Davidson and Simon Davis and Dendrou, {Calliope A.} and Julie Dequaire and Lea Dib and James Docker and Christina Dold and Tao Dong and Damien Downes and Hal Drakesmith",

note = "Funding Information: Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants (Data S1) including BHF RG/13/9/303269 FS/18/63/34184; CAMS IFMS 2018-I2M-2-002; CRUK C130623/A249471; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1; Emerson Collective; Gilead; Huo Family Foundation; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059; NIH U192U19AI082630 R24DK106766; NIHR; Rosetrees R35579/AA002/M85-F2; Royal Society RGF\EA\201074 UF150238; UKDHSC PITCH UK-COG; UKRI MR/S005471/1; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z. Patient recruitment and cohorts (A.J.M. M. Ainsworth, A.A. C.V.A.-C. J.K.B. B.A. A.B. S. Beer, T.B. A. Brent, A. Brown, C.P.C. N.D. J. Dequaire, S.J.D. A.E. R. Fairhead, S. Fassih, J.F. M.F.M. T.F. A. Fries, V.G.S. D.G. C. Hinds, C. Hird, P.H. K. Jeffery, D.K. P. Klenerman, J.C.K. A.K. T.L. J.M. P.C.M. S. McKechnie, D. O'Donnell, A.N. I. Pavord, E.P. T.R. M.R. M.G.S. D. Skelly, A. Sobrinodiaz, L. Stafford, A. Taylor, H.T. L.T. H.U. P.W. R.K.Y. J.Y.), sample processing and extraction (A.J.M. A.A. C.A. A. Beveridge, S. Bibi. T.B. L.B. A. Brown, D.B. S.C. E.A.C. F.C. C.D. T.D. H.D. S. Felle, L.G. A.G. J. Hill, E.J. J.C.K. A.K. A. Lee, A. Linder, L.L. M. Lopopolo. S. Marinou, A.M. Y.P. A.J.P. L.S.-R. C.S.R. C.S.K. G. Scozzafava, H.S. L. Stockdale, M. Strickland, A. Trebes, M.V. L. Witty, K.W. Z.Y. J.Y.), clinical phenotyping (A.J.M. J.K.B. E.B. T.B. C.A.D. L.G. L.-P.H. J.C.K. A.K. L.J. T.P.Q. F.R. S.N.S. M.G.S. A.S.D. L.T. J.Y.), mass and flow cytometry (G.N. M. Salio, C.M. I.U. D.J.A. Y.-X.Z. Z.A. L.D. R. Etherington, J.C.K. P. Kurupati, A.K. M.M. G.O. I. Park, M.P.P. E.R. D.T. E.v.G. L. Wang), whole blood total RNA-seq (A.J.M. M. Attar, K.L.B. E.E.D. J. Docker, C.G. C.H. J.C.K. A.K. A. Linder, D. O'Connor, S.R. J.W.), 10X CITE-seq and repertoire (S.N.S. C.A.D. L.J. J.C.K. R.B.-R. B.F. D.A. M. Attar, P.B. A.P.C. F.C. T.D. R. Ferreira, L.C.G. M.G.V. A.J.-B. A.J. K. Jansen, P. Klenerman, P.K.S. A.K. A. Linder, A.M. A.J.M. R.M. G.N. I.N. L.O. Y.P. F. Penkava, B.P. E.R. S.R. J.-B.R. C.R.-G. H.S. B.S. C.T. S. Thongjuea, O.T. F.A.T. A.V. G.W. R.W. H.Y.Y. Y.-X.Z.), ATAC-seq (T.S.-S. I.C.F. M. Lukoseviciute, M. Attar, S.R. J.C.K. A.K. A. Linder, H.S. M.W.), genetics (L.J. A.C. C.A.D. D.D. C.E. B.F. J. Hughes, J.C.K. A.J.M. Y.M. I.N. R.S. S.N.S. P.Z.), proteomics (mass spectrometry) (R. Fischer, A.S.D. G.B. P.C. S.D. R. Heilig, S.H. J.C.K. Y.M. D.P.O. I.V.) (Luminex) (L.X. W.C. Y.-L.C. D.A.D. P. Klenerman, J.L. C.M. G.O. I. Pavord, I.U.), data integration (J.C.K. M.A.A. R.B.-R. K.L.B. H.B. M.C. F.C. C.A.D. A. Forrow, R. Fischer, T.G. H.A.H. L.-P.H. R. Hoekzema, J. Hughes, M.A.J.-W. L.J. S. McGowan, A.J.M. Y.M. G.N. E.R. F.R. R.S.P. A.S.D. S.N.S. M. Sergeant, A. Seigal, D. Sims, O.S. S. Taylor, A. Tomic, J.W.), data management (B.M. J.B. A.P.C. R. Esnouf, H.F. H.H. L.J. J.C.K. G.K. P. Klenerman, V.K. A.J.M. F. Powrie, S.N.S. D. Sims, J.A.T. D.W.), report and manuscript writing (J.C.K. R.B.-R. K.L.B. F.C. C.A.D. A.S.D. B.F. H.F. R. Fischer, L.C.G. H.A.H. C. Hinds, L.J. A.K. P. Klenerman, A.J.M. B.M. Y.M. G.N. F.R. C.R.-G. A. Seigal, S.N.S. M. Sergeant, T.S-S. B.S. J.A.T. F.A.T. A. Tomic, S. Taylor, J.W. L.X.), steering committee (R.C. F. Powrie, J.C.K. P. Klenerman, A.J.M. H.McS. G.O. A.J.P. G. Screaton, J.A.T.), leadership and oversight (J.C.K. R.B.-R. C.A.D. B.F. R. Fischer, L.J. P. Klenerman, B.M. A.J.M. G.N. S.N.S. T.S.-S. J.A.T. L.X.). Further details and CRediT taxonomy in Data S1. R.B.-R. (co-founder and consultant Alchemab Therapeutics Ltd), R.C. (founder MIROBio), J. Hughes (director and shareholder Nucleome Therapeutics), G.S. (GSK Vaccines SAB), J.A.T. (GSK Human Genetics SAB). Other authors declare no competing interests. Funding Information: Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants ( Data S1 ) including BHF RG/13/9/303269 FS/18/63/34184 ; CAMS IFMS 2018-I2M-2-002 ; CRUK C130623/A249471 ; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1 ; Emerson Collective ; Gilead ; Huo Family Foundation ; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803 ; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059 ; NIH U192U19AI082630 R24DK106766 ; NIHR ; Rosetrees R35579/AA002/M85-F2 ; Royal Society RGF\EA\201074 UF150238 ; UKDHSC PITCH UK-COG ; UKRI MR/S005471/1 ; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z . Publisher Copyright: {\textcopyright} 2022 The Author",

year = "2022",

month = mar,

day = "3",

doi = "10.1016/j.cell.2022.01.012",

language = "English",

volume = "185",

pages = "916--938.e58",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

AU - COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

AU - Ahern, David J.

AU - Ai, Zhichao

AU - Ainsworth, Mark

AU - Allan, Chris

AU - Allcock, Alice

AU - Angus, Brian

AU - Ansari, M. Azim

AU - Arancibia-Cárcamo, Carolina V.

AU - Aschenbrenner, Dominik

AU - Attar, Moustafa

AU - Baillie, J. Kenneth

AU - Barnes, Eleanor

AU - Bashford-Rogers, Rachael

AU - Bashyal, Archana

AU - Beer, Sally

AU - Berridge, Georgina

AU - Beveridge, Amy

AU - Bibi, Sagida

AU - Bicanic, Tihana

AU - Blackwell, Luke

AU - Bowness, Paul

AU - Brent, Andrew

AU - Brown, Andrew

AU - Broxholme, John

AU - Buck, David

AU - Burnham, Katie L.

AU - Byrne, Helen

AU - Camara, Susana

AU - Candido Ferreira, Ivan

AU - Charles, Philip

AU - Chen, Wentao

AU - Chen, Yi Ling

AU - Chong, Amanda

AU - Clutterbuck, Elizabeth A.

AU - Coles, Mark

AU - Conlon, Christopher P.

AU - Cornall, Richard

AU - Cribbs, Adam P.

AU - Curion, Fabiola

AU - Davenport, Emma E.

AU - Davidson, Neil

AU - Davis, Simon

AU - Dendrou, Calliope A.

AU - Dequaire, Julie

AU - Dib, Lea

AU - Docker, James

AU - Dold, Christina

AU - Dong, Tao

AU - Downes, Damien

AU - Drakesmith, Hal

N1 - Funding Information: Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants (Data S1) including BHF RG/13/9/303269 FS/18/63/34184; CAMS IFMS 2018-I2M-2-002; CRUK C130623/A249471; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1; Emerson Collective; Gilead; Huo Family Foundation; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059; NIH U192U19AI082630 R24DK106766; NIHR; Rosetrees R35579/AA002/M85-F2; Royal Society RGF\EA\201074 UF150238; UKDHSC PITCH UK-COG; UKRI MR/S005471/1; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z. Patient recruitment and cohorts (A.J.M. M. Ainsworth, A.A. C.V.A.-C. J.K.B. B.A. A.B. S. Beer, T.B. A. Brent, A. Brown, C.P.C. N.D. J. Dequaire, S.J.D. A.E. R. Fairhead, S. Fassih, J.F. M.F.M. T.F. A. Fries, V.G.S. D.G. C. Hinds, C. Hird, P.H. K. Jeffery, D.K. P. Klenerman, J.C.K. A.K. T.L. J.M. P.C.M. S. McKechnie, D. O'Donnell, A.N. I. Pavord, E.P. T.R. M.R. M.G.S. D. Skelly, A. Sobrinodiaz, L. Stafford, A. Taylor, H.T. L.T. H.U. P.W. R.K.Y. J.Y.), sample processing and extraction (A.J.M. A.A. C.A. A. Beveridge, S. Bibi. T.B. L.B. A. Brown, D.B. S.C. E.A.C. F.C. C.D. T.D. H.D. S. Felle, L.G. A.G. J. Hill, E.J. J.C.K. A.K. A. Lee, A. Linder, L.L. M. Lopopolo. S. Marinou, A.M. Y.P. A.J.P. L.S.-R. C.S.R. C.S.K. G. Scozzafava, H.S. L. Stockdale, M. Strickland, A. Trebes, M.V. L. Witty, K.W. Z.Y. J.Y.), clinical phenotyping (A.J.M. J.K.B. E.B. T.B. C.A.D. L.G. L.-P.H. J.C.K. A.K. L.J. T.P.Q. F.R. S.N.S. M.G.S. A.S.D. L.T. J.Y.), mass and flow cytometry (G.N. M. Salio, C.M. I.U. D.J.A. Y.-X.Z. Z.A. L.D. R. Etherington, J.C.K. P. Kurupati, A.K. M.M. G.O. I. Park, M.P.P. E.R. D.T. E.v.G. L. Wang), whole blood total RNA-seq (A.J.M. M. Attar, K.L.B. E.E.D. J. Docker, C.G. C.H. J.C.K. A.K. A. Linder, D. O'Connor, S.R. J.W.), 10X CITE-seq and repertoire (S.N.S. C.A.D. L.J. J.C.K. R.B.-R. B.F. D.A. M. Attar, P.B. A.P.C. F.C. T.D. R. Ferreira, L.C.G. M.G.V. A.J.-B. A.J. K. Jansen, P. Klenerman, P.K.S. A.K. A. Linder, A.M. A.J.M. R.M. G.N. I.N. L.O. Y.P. F. Penkava, B.P. E.R. S.R. J.-B.R. C.R.-G. H.S. B.S. C.T. S. Thongjuea, O.T. F.A.T. A.V. G.W. R.W. H.Y.Y. Y.-X.Z.), ATAC-seq (T.S.-S. I.C.F. M. Lukoseviciute, M. Attar, S.R. J.C.K. A.K. A. Linder, H.S. M.W.), genetics (L.J. A.C. C.A.D. D.D. C.E. B.F. J. Hughes, J.C.K. A.J.M. Y.M. I.N. R.S. S.N.S. P.Z.), proteomics (mass spectrometry) (R. Fischer, A.S.D. G.B. P.C. S.D. R. Heilig, S.H. J.C.K. Y.M. D.P.O. I.V.) (Luminex) (L.X. W.C. Y.-L.C. D.A.D. P. Klenerman, J.L. C.M. G.O. I. Pavord, I.U.), data integration (J.C.K. M.A.A. R.B.-R. K.L.B. H.B. M.C. F.C. C.A.D. A. Forrow, R. Fischer, T.G. H.A.H. L.-P.H. R. Hoekzema, J. Hughes, M.A.J.-W. L.J. S. McGowan, A.J.M. Y.M. G.N. E.R. F.R. R.S.P. A.S.D. S.N.S. M. Sergeant, A. Seigal, D. Sims, O.S. S. Taylor, A. Tomic, J.W.), data management (B.M. J.B. A.P.C. R. Esnouf, H.F. H.H. L.J. J.C.K. G.K. P. Klenerman, V.K. A.J.M. F. Powrie, S.N.S. D. Sims, J.A.T. D.W.), report and manuscript writing (J.C.K. R.B.-R. K.L.B. F.C. C.A.D. A.S.D. B.F. H.F. R. Fischer, L.C.G. H.A.H. C. Hinds, L.J. A.K. P. Klenerman, A.J.M. B.M. Y.M. G.N. F.R. C.R.-G. A. Seigal, S.N.S. M. Sergeant, T.S-S. B.S. J.A.T. F.A.T. A. Tomic, S. Taylor, J.W. L.X.), steering committee (R.C. F. Powrie, J.C.K. P. Klenerman, A.J.M. H.McS. G.O. A.J.P. G. Screaton, J.A.T.), leadership and oversight (J.C.K. R.B.-R. C.A.D. B.F. R. Fischer, L.J. P. Klenerman, B.M. A.J.M. G.N. S.N.S. T.S.-S. J.A.T. L.X.). Further details and CRediT taxonomy in Data S1. R.B.-R. (co-founder and consultant Alchemab Therapeutics Ltd), R.C. (founder MIROBio), J. Hughes (director and shareholder Nucleome Therapeutics), G.S. (GSK Vaccines SAB), J.A.T. (GSK Human Genetics SAB). Other authors declare no competing interests. Funding Information: Research supported by the University of Oxford COVID-19 Research Response Fund and NIHR Oxford Biomedical Research Centre. Work of contributing authors supported by grants ( Data S1 ) including BHF RG/13/9/303269 FS/18/63/34184 ; CAMS IFMS 2018-I2M-2-002 ; CRUK C130623/A249471 ; EPSRC EP/R018472/1 EP/R005125/1 EP/T001968/1 ; Emerson Collective ; Gilead ; Huo Family Foundation ; Kennedy Trust for Rheumatology Research KENN151612 KENN192004 KENN171803 ; MRC HIU Core MCUU00016/14 12009/14 MR/S035850/1 MCPC19059 ; NIH U192U19AI082630 R24DK106766 ; NIHR ; Rosetrees R35579/AA002/M85-F2 ; Royal Society RGF\EA\201074 UF150238 ; UKDHSC PITCH UK-COG ; UKRI MR/S005471/1 ; Wellcome 106130/Z/14/Z 109965MA 107212/A/15/Z 201488/Z/16/Z 203141/Z/16/Z 204826/Z/16/Z 204290/Z/16/Z 204969/Z/16/Z 205228/Z/16/Z 206194 4-SRA-2017-473-A-A 211276/B/18/Z 215097/Z/18/Z 220171/Z/20/Z . Publisher Copyright: © 2022 The Author

PY - 2022/3/3

Y1 - 2022/3/3

N2 - Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.

AB - Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.

KW - COVID-19

KW - SARS-CoV-2

KW - blood

KW - coronavirus

KW - epigenetics

KW - immune

KW - multi-omics

KW - personalized medicine

KW - proteomics

KW - transcriptomics

UR - http://www.scopus.com/inward/record.url?scp=85125467136&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.01.012

DO - 10.1016/j.cell.2022.01.012

M3 - Article

C2 - 35216673

AN - SCOPUS:85125467136

VL - 185

SP - 916-938.e58

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

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