TY - JOUR
T1 - Multi-omic spatial profiling reveals the unique SARS-CoV-2 lung microenvironment and collagen VI as a predictive biomarker in severe COVID-19
AU - Fennell, Éanna
AU - Taylor, Graham S.
AU - Leahy, Ciara I.
AU - Ross, Aisling M.
AU - Reynolds, Gary
AU - Perry, Tracey
AU - Youd, Esther
AU - Skidmore, Jacob
AU - Ramzi, Radwan
AU - Darwish, Radwan
AU - Hunter, Kelly J.
AU - Willcox, Benjamin E.
AU - Jermann, Philip
AU - Arif Jahangir, Chowdhury
AU - Rahman, Arman
AU - Gallagher, William M.
AU - Nikulina, Nadezhda
AU - Ben Cheikh, Bassem
AU - Braubach, Oliver
AU - Mayer, Aaron T.
AU - Young, Lawrence S.
AU - Grammatopoulos, Dimitris
AU - Faustini, Sian
AU - Richter, Alex
AU - Dowell, Alexander C.
AU - Venith, Tonny
AU - Thein, Onn S.
AU - Parekh, Dhruv
AU - Belchamber, Kylie B. R.
AU - Thickett, David R.
AU - Scott, Aaron
AU - Attanoos, Richard
AU - Mundo, Lucia
AU - Lazzi, Stefano
AU - Leoncini, Lorenzo
AU - Leopold, Gareth
AU - Steven, Neil
AU - Marie, Janine
AU - Sand, Bülow
AU - Karsdal, Morten A
AU - Julie Leeming, Diana
AU - Dojcinov, Stefan
AU - Culhane, Aedin
AU - Murray, Paul G.
AU - Pugh, Matthew R
N1 - Copyright © The authors 2025. For reproduction rights and permissions contact [email protected].
PY - 2025/9/17
Y1 - 2025/9/17
N2 - BackgroundWhile coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, few studies have characterised 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.
MethodsPost-mortem formalin-fixed paraffin-embedded lung tissue from fatal COVID-19 and nonrespiratory 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 using ELISA.
ResultsWe found that severe acute respiratory syndrome coronavirus 2 (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 hospitalised patients.
ConclusionsOur data refine the current model of respiratory COVID-19 with regard to virus distribution, immune niches and the role of the noncellular microenvironment in pathogenesis and risk stratification in COVID-19. We show that collagen deposition is an early event in the course of the disease.
AB - BackgroundWhile coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, few studies have characterised 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.
MethodsPost-mortem formalin-fixed paraffin-embedded lung tissue from fatal COVID-19 and nonrespiratory 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 using ELISA.
ResultsWe found that severe acute respiratory syndrome coronavirus 2 (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 hospitalised patients.
ConclusionsOur data refine the current model of respiratory COVID-19 with regard to virus distribution, immune niches and the role of the noncellular microenvironment in pathogenesis and risk stratification in COVID-19. We show that collagen deposition is an early event in the course of the disease.
U2 - 10.1183/13993003.01699-2023
DO - 10.1183/13993003.01699-2023
M3 - Article
C2 - 40473310
SN - 0903-1936
VL - 66
JO - The European respiratory journal
JF - The European respiratory journal
IS - 3
M1 - 2301699
ER -