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Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes

30 Pages Posted: 27 May 2021

See all articles by Clark Donald Russell

Clark Donald Russell

University of Edinburgh - Centre for Inflammation Research

Asta Valanciute

University of Edinburgh

Naomi N. Gachanja

University of Edinburgh

Jillian Stephen

University of Edinburgh

Rebekah Penrice-Randal

University of Liverpool

Stuart D. Armstrong

University of Liverpool

Sara Clohisey

University of Edinburgh

Bo Wang

University of Edinburgh

Wael Al Qsous

University of Edinburgh - Western General Hospital

William A. Wallace

Royal Infirmary of Edinburgh

Gabriel C. Oniscu

Royal Infirmary of Edinburgh

Jo Stevens

University of Edinburgh

David J. Harrison

University of St. Andrews - School of Medicine

Kevin Dhaliwal

University of Edinburgh - Queen’s Medical Research Institute - Centre for Inflammation Research

Julian A. Hiscox

University of Liverpool

J. Kenneth Baillie

University of Edinburgh - Roslin Institute

Ahsan R. Akram

University of Edinburgh - Centre for Inflammation Research

David A. Dorward

University of Edinburgh

Christopher D. Lucas

University of Edinburgh - Centre for Inflammation Research; University of Edinburgh - Department of Respiratory Medicine; University of Edinburgh - Institute for Regeneration and Repair

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Abstract

Background: Tissue inflammation in fatal COVID-19 is concentrated in the lung and spleen. Anti-inflammatory therapy reduces mortality but knowledge on the host response at the level of inflamed tissues is incomplete.  

Methods: We performed targeted proteomic analysis of pulmonary and splenic tissues from 13 fatal cases of COVID-19 that underwent rapid autopsy, and compared to control tissues from cancer resection (lung) and deceased organ donors (spleen). Viral RNA presence was determined by multiplex PCR, and protein was isolated from tissue by phenol extraction. Targeted multiplex immunoassay panels were used for protein detection and quantification.  

Findings: Pulmonary proteins with increased abundance in COVID-19 included the monocyte/macrophage chemoattractant MCP-3, antiviral TRIM21 and pro-thrombotic TYMP. The lung injury markers OSM and EN-RAGE/S100A12 were highly correlated and associated with tissue inflammation severity. Unsupervised clustering of lung proteomes clearly defined two COVID-19 clusters; these differed by viral presence, tissue inflammation severity and illness duration and were annotated ‘early viral’ and ‘late inflammatory’ groups. In the spleen, lymphocyte chemotactic factors and CD8A were decreased in COVID-19, with pro-apoptotic factors, B-cell signalling components and macrophage colony stimulating factor (CSF-1) all increased. To contextualise our findings, we cross-referenced an existing meta-analysis of host factors in COVID-19 (MAIC). Overlap with a substantial sub-set of factors (including DDX58, OSM, TYMP, IL-18, MCP-3 and CSF-1) was found, with numerous additional proteins also identified by our study.  
Interpretation: Tissue proteomes from fatal COVID-19 identify disease subsets and dissect host immunopathologic signatures. In doing so, this may afford unique opportunities for therapeutic intervention.

Funding Information: This work was funded by UK Research and Innovation (UKRI) (Coronavirus Disease [COVID-19] Rapid Response Initiative; MR/V028790/1 to C.D.L., D.A.D., and J.A.H.), LifeArc (through the University of Edinburgh STOPCOVID funding award, to K.D, D.A.D, C.D.L), The Chief Scientist Office (RARC-19 Funding Call, ‘Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis; COV/EDI/20/10’ to D.A.D, C.D.L, C.D.R, J.K.B and D.J.H), and Medical Research Scotland (CVG-1722-2020 to DAD, CDL, CDR, JKB, and DJH). C.D.L is funded by a Wellcome Trust Clinical Career Development Fellowship (206566/Z/17/Z). J.K.B. and C.D.R. are supported by the Medical Research Council (grant MC_PC_19059) as part of the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC-4C). C.D.R. is supported by an Edinburgh Clinical Academic Track (ECAT)/Wellcome Trust PhD Training Fellowship for Clinicians award (214178/Z/18/Z). J.A.H. is supported by the U.S. Food and Drug Administration (contract 75F40120C00085, Characterization of severe coronavirus infection in humans and model systems for medical countermeasure development and evaluation’). G.C.O is funded by an NRS Clinician award. N.N.G. is funded by a Pathological Society Award. A.R.A. is supported by a Cancer Research UK Clinician Scientist Fellowship award (A24867).

Declaration of Interests: All authors have declared that no competing interests exist.

Ethics Approval Statement: Written informed consent to undertake postmortem examinations was obtained from next-of-kin. Ethical approval was granted by the East of Scotland Research Ethics Service (16/ES/0084).

Keywords: COVID-19; lung; proteomics; inflammation; macrophages

Suggested Citation

Russell, Clark Donald and Valanciute, Asta and Gachanja, Naomi N. and Stephen, Jillian and Penrice-Randal, Rebekah and Armstrong, Stuart D. and Clohisey, Sara and Wang, Bo and Al Qsous, Wael and Wallace, William A. and Oniscu, Gabriel C. and Stevens, Jo and Harrison, David J. and Dhaliwal, Kevin and Hiscox, Julian A. and Baillie, J. Kenneth and Akram, Ahsan R. and Dorward, David A. and Lucas, Christopher D., Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes. Available at SSRN: https://ssrn.com/abstract=3854606 or http://dx.doi.org/10.2139/ssrn.3854606

Clark Donald Russell (Contact Author)

University of Edinburgh - Centre for Inflammation Research ( email )

Edinburgh BioQuarter
47 Little France Crescent
Edinburgh, EH16 4TJ
United Kingdom
0131 242 9100 (Phone)

Asta Valanciute

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

Naomi N. Gachanja

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

Jillian Stephen

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

Rebekah Penrice-Randal

University of Liverpool ( email )

Chatham Street
Brownlow Hill
Liverpool, L69 7ZA
United Kingdom

Stuart D. Armstrong

University of Liverpool ( email )

Chatham Street
Brownlow Hill
Liverpool, L69 7ZA
United Kingdom

Sara Clohisey

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

Bo Wang

University of Edinburgh

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Wael Al Qsous

University of Edinburgh - Western General Hospital ( email )

Edinburgh
United Kingdom

William A. Wallace

Royal Infirmary of Edinburgh ( email )

51 Little France Cres
Edinburgh, EH16 4SA
United Kingdom

Gabriel C. Oniscu

Royal Infirmary of Edinburgh ( email )

51 Little France Cres
Edinburgh, EH16 4SA
United Kingdom

Jo Stevens

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

David J. Harrison

University of St. Andrews - School of Medicine ( email )

St Andrews
United Kingdom

Kevin Dhaliwal

University of Edinburgh - Queen’s Medical Research Institute - Centre for Inflammation Research

Edinburgh
United Kingdom

Julian A. Hiscox

University of Liverpool ( email )

Chatham Street
Brownlow Hill
Liverpool, L69 7ZA
United Kingdom

J. Kenneth Baillie

University of Edinburgh - Roslin Institute ( email )

United Kingdom

HOME PAGE: http://baillielab.net

Ahsan R. Akram

University of Edinburgh - Centre for Inflammation Research ( email )

Edinburgh BioQuarter
47 Little France Crescent
Edinburgh, EH16 4TJ
United Kingdom

David A. Dorward

University of Edinburgh ( email )

Old College
South Bridge
Edinburgh, EH8 9JY
United Kingdom

Christopher D. Lucas

University of Edinburgh - Centre for Inflammation Research ( email )

Edinburgh BioQuarter
47 Little France Crescent
Edinburgh, EH16 4TJ
United Kingdom
0131 242 9100 (Phone)

University of Edinburgh - Department of Respiratory Medicine

51 Little France Crescent
Edinburgh, EH16 4SA
United Kingdom

University of Edinburgh - Institute for Regeneration and Repair

Edinburgh BioQuarter
47 Little France Crescent
Edinburgh, EH16 4TJ
United Kingdom