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

Clark Donald Russell; Asta Valanciute; Naomi N. Gachanja; Jillian Stephen; Rebekah Penrice-Randal; Stuart D. Armstrong; Sara Clohisey; Bo Wang; Wael Al Qsous; William A. Wallace; Gabriel C. Oniscu; Jo Stevens; David J. Harrison; Kevin Dhaliwal; Julian A. Hiscox; J. Kenneth Baillie; Ahsan R. Akram; David A. Dorward; Christopher D Lucas

doi:10.2139/ssrn.3854606

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

Clark Donald Russell, Asta Valanciute, Naomi N. Gachanja, Jillian Stephen, Rebekah Penrice-Randal, Stuart D. Armstrong, Sara Clohisey, Bo Wang, Wael Al Qsous, William A. Wallace, Gabriel C. Oniscu, Jo Stevens, David J. Harrison, Kevin Dhaliwal, Julian A. Hiscox, J. Kenneth Baillie, Ahsan R. Akram, David A. Dorward, Christopher D Lucas

Research output: Working paper › Preprint

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.

Original language	English
Publisher	Social Science Research Network (SSRN)
DOIs	https://doi.org/10.2139/ssrn.3854606
Publication status	Published - 27 May 2021

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10.2139/ssrn.3854606

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Russell, C. D., Valanciute, A., Gachanja, N. N., Stephen, J., Penrice-Randal, R., Armstrong, S. D., Clohisey, S., Wang, B., Al Qsous, W., Wallace, W. A., Oniscu, G. C., Stevens, J., Harrison, D. J., Dhaliwal, K., Hiscox, J. A., Baillie, J. K., Akram, A. R., Dorward, D. A., & Lucas, C. D. (2021). Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes. Social Science Research Network (SSRN). https://doi.org/10.2139/ssrn.3854606

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title = "Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes",

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 {\textquoteleft}early viral{\textquoteright} and {\textquoteleft}late inflammatory{\textquoteright} 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.",

author = "Russell, {Clark Donald} and Asta Valanciute and Gachanja, {Naomi N.} and Jillian Stephen and Rebekah Penrice-Randal and Armstrong, {Stuart D.} and Sara Clohisey and Bo Wang and {Al Qsous}, Wael and Wallace, {William A.} and Oniscu, {Gabriel C.} and Jo Stevens and Harrison, {David J.} and Kevin Dhaliwal and Hiscox, {Julian A.} and Baillie, {J. Kenneth} and Akram, {Ahsan R.} and Dorward, {David A.} and Lucas, {Christopher D}",

year = "2021",

month = may,

day = "27",

doi = "10.2139/ssrn.3854606",

language = "English",

publisher = "Social Science Research Network (SSRN)",

type = "WorkingPaper",

institution = "Social Science Research Network (SSRN)",

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Russell, CD , Valanciute, A, Gachanja, NN, Stephen, J, Penrice-Randal, R, Armstrong, SD, Clohisey, S, Wang, B, Al Qsous, W, Wallace, WA, Oniscu, GC , Stevens, J, Harrison, DJ, Dhaliwal, K, Hiscox, JA, Baillie, JK , Akram, AR, Dorward, DA & Lucas, CD 2021 'Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes' Social Science Research Network (SSRN). https://doi.org/10.2139/ssrn.3854606

TY - UNPB

T1 - Mechanisms and Stages of Covid-19 Immunopathology Revealed by Tissue-Specific Proteomes

AU - Russell, Clark Donald

AU - Valanciute, Asta

AU - Gachanja, Naomi N.

AU - Stephen, Jillian

AU - Penrice-Randal, Rebekah

AU - Armstrong, Stuart D.

AU - Clohisey, Sara

AU - Wang, Bo

AU - Al Qsous, Wael

AU - Wallace, William A.

AU - Oniscu, Gabriel C.

AU - Stevens, Jo

AU - Harrison, David J.

AU - Dhaliwal, Kevin

AU - Hiscox, Julian A.

AU - Baillie, J. Kenneth

AU - Akram, Ahsan R.

AU - Dorward, David A.

AU - Lucas, Christopher D

PY - 2021/5/27

Y1 - 2021/5/27

N2 - 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.

AB - 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.

UR - http://europepmc.org/abstract/PPR/PPR360913

U2 - 10.2139/ssrn.3854606

DO - 10.2139/ssrn.3854606

M3 - Preprint

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

PB - Social Science Research Network (SSRN)

ER -

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

Abstract

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Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis -ICECAP extension

Inflammation in COVID-19 ¿ Exploration of Critical Aspects of Pathogenesis - The ICECAP COVID-19 post-mortem study

Fibroblast activation protein expressing cancer associated fibroblasts from lung cancer as imaging biomarkers for immunotherapy stratification

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

Abstract

Access to Document

Other files and links

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Projects

Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis -ICECAP extension

Inflammation in COVID-19 ¿ Exploration of Critical Aspects of Pathogenesis - The ICECAP COVID-19 post-mortem study

Fibroblast activation protein expressing cancer associated fibroblasts from lung cancer as imaging biomarkers for immunotherapy stratification

Cite this