Multi-omic spatial profiling reveals the unique SARS-CoV-2 lung microenvironment and collagen VI as a predictive biomarker in severe COVID-19
Fennell, Éanna Taylor, Graham S Leahy, Ciara I Ross, Aisling M Reynolds, Gary Perry, Tracey Youd, Esther Skidmore, Jacob Ramzi, Radwan Darwish, Radwan
Fennell, Éanna
Taylor, Graham S
Leahy, Ciara I
Ross, Aisling M
Reynolds, Gary
Perry, Tracey
Youd, Esther
Skidmore, Jacob
Ramzi, Radwan
Darwish, Radwan
Affiliation
University of Limerick; University of Birmingham; University of Glasgow; Royal College of Surgeons in Ireland; Medical University of Bahrain; University Hospital Basel; University College Dublin; Justus Liebig University Giessen; Akoya Biosciences; Bruker Spatial Biology; Enable Medicine; University of Warwick; University Hospitals Birmingham NHS Foundation Trust; University Hospital of Wales; University of Siena; Swansea Bay University Health Board; Nordic Bioscience; Dana-Farber Cancer Institute; Harvard TH Chan School of Public Health
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Publication date
2025-07-17
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Abstract
Background: Whilst COVID-19 is primarily a respiratory infection, few studies have characterized the immune response to COVID-19 in lung tissue. We sought to understand the pathogenic role of microenvironmental interactions and the extracellular matrix in post-mortem COVID-19 lung using an integrative multi-omic approach.
Methods: Post-mortem formalin fixed paraffin embedded lung tissue from fatal COVID-19 and non-respiratory death control lung underwent multi-omic evaluation by Quantseq Bulk RNA sequencing, Nanostring GeoMX spatial transcriptomics, RNAscope, multiplex immunofluorescence and immunohistochemistry, to evaluate virus distribution, immune composition and the extracellular matrix. Markers of extracellular synthesis and breakdown were measured in the serum of 215 patients with COVID-19 and 54 healthy volunteer controls by ELISA.
Results: We found that SARS-CoV-2 infection was restricted to the pneumocytes and macrophages of early-stage disease. Spatial analyses revealed an immunosuppressive virus microenvironment, enriched for PDL1+IDO1+ macrophages and depleted of T-cells. Oligoclonal T-cells in COVID-19 lung showed no enrichment of SARS-CoV-2 specific T-cell receptors. Collagen VI was upregulated and contributed to alveolar wall thickening and impaired gas exchange in COVID-19 lung. Serum from COVID-19 patients showed increased levels of PRO-C6, a marker of collagen VI synthesis, predicted mortality in hospitalized patients.
Conclusions: Our data refine the current model of respiratory COVID-19 with regard to virus distribution, immune niches, and the role of the non-cellular microenvironment in pathogenesis and risk stratification in COVID-19. We show that collagen deposition is an early event in the course of the disease.
Citation
Fennell É, Taylor GS, Leahy CI, Ross AM, Reynolds G, Perry T, Youd E, Skidmore J, Darwish RRR, Hunter KJ, Willcox BE, Jermann P, Arif Jahangir C, Rahman A, Gallagher WM, Nikulina N, Ben Cheikh B, Braubach O, Mayer AT, Young LS, Grammatopoulos D, Faustini S, Richter A, Dowell AC, Venith T, Thein OS, Parekh D, Belchamber KBR, Thickett DR, Scott A, Attanoos R, Mundo L, Lazzi S, Leoncini L, Leopold G, Steven N, Bülow Sand JM, Karsdal MA, Leeming DJ, Dojcinov S, Culhane A, Murray PG, Pugh MR. Multi-omic spatial profiling reveals the unique SARS-CoV-2 lung microenvironment and collagen VI as a predictive biomarker in severe COVID-19. Eur Respir J. 2025 Sep 17;66(3):2301699. doi: 10.1183/13993003.01699-2023.
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Article