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 paperPreprint

Abstract / Description of output

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 languageEnglish
PublisherSocial Science Research Network (SSRN)
DOIs
Publication statusPublished - 27 May 2021

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