Tissue proteomic analysis identifies mechanisms and stages of immunopathology in fatal COVID-19

Clark D. 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 James Harrison, Kevin Dhaliwal, Julian A Hiscox, J Kenneth Baillie, Ashan R. Akram, David A. Dorward, Christopher D. Lucas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)
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Immunopathology occurs in the lung and spleen in fatal COVID-19, involving monocytes/macrophages and plasma cells. Anti-inflammatory therapy reduces mortality but additional therapeutic targets are required. We aimed to gain mechanistic insight into COVID-19 immunopathology by targeted proteomic analysis of pulmonary and splenic tissues. Lung parenchymal and splenic tissue was obtained from 13 post-mortem examinations of patients with fatal COVID-19. Control tissue was obtained from cancer resection samples (lung) and deceased organ donors (spleen). Protein was extracted from tissue by phenol extraction. Olink® multiplex immunoassay panels were used for protein detection and quantification. Proteins with increased abundance in the lung included MCP-3, antiviral TRIM21 and pro-thrombotic TYMP. OSM and EN-RAGE/S100A12 abundance was correlated, and associated with inflammation severity. Unsupervised clustering identified ‘early viral’ and ‘late inflammatory’ clusters with distinct protein abundance profiles, and differences in illness duration prior to death and presence of viral RNA. In the spleen, lymphocyte chemotactic factors and CD8A were decreased in abundance, and pro-apoptotic factors were increased. B-cell receptor signalling pathway components and macrophage colony stimulating factor (CSF-1) were also increased. Additional evidence for a sub-set of host factors (including DDX58, OSM, TYMP, IL-18, MCP-3 and CSF-1) was provided by overlap between (i) differential abundance in spleen and lung tissue, (ii) meta-analysis of existing datasets, and (iii) plasma proteomic data. This proteomic analysis of lung parenchymal and splenic tissue from fatal COVID-19 provides mechanistic insight into tissue anti-viral responses, inflammation and disease stages, macrophage involvement, pulmonary thrombosis, splenic B-cell activation and lymphocyte depletion.
Original languageEnglish
Pages (from-to)196-205
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number2
Early online date28 Oct 2021
Publication statusPublished - Feb 2022


  • COVID-19
  • Lung
  • Inflammation
  • Macrophages
  • Proteomics


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