Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19

Jimmy Tsz Hang Lee, Sam N. Barnett, Kenny Roberts, Helen Ashwin, Luke Milross, Jae-Won Cho, Alik Huseynov, Benjamin Woodhams, Alexander Aivazidis, Tong Li, Joaquim Majo, Patricia Chaves, Michael Lee, Antonio M. A. Miranda, Zuzanna Jablonska, Vincenzo Arena, Brian Hanley, Michael Osborn, Virginie Uhlmann, Xiao-Ning Xu, Gary R. McLean, Sarah A. Teichmann, Anna M. Randi, Andrew Filby, Paul M. Kaye, Andrew J. Fisher (), Martin Hemberg (), Michela Noseda () and Omer Ali Bayraktar ()
Additional contact information
Jimmy Tsz Hang Lee: Wellcome Sanger Institute
Sam N. Barnett: Imperial College London
Kenny Roberts: Wellcome Sanger Institute
Helen Ashwin: University of York
Luke Milross: Newcastle University Translational and Clinical Research Institute
Jae-Won Cho: Massachusetts General Hospital and Harvard Medical School
Alik Huseynov: Imperial College London
Benjamin Woodhams: Wellcome Sanger Institute
Alexander Aivazidis: Wellcome Sanger Institute
Tong Li: Wellcome Sanger Institute
Joaquim Majo: Newcastle upon Tyne Hospitals NHS Foundation Trust
Patricia Chaves: Imperial College London
Michael Lee: Imperial College London
Antonio M. A. Miranda: Imperial College London
Zuzanna Jablonska: Imperial College London
Vincenzo Arena: Università Cattolica Del Sacro Cuore
Brian Hanley: Imperial College London NHS Trust
Michael Osborn: Imperial College London NHS Trust
Virginie Uhlmann: European Molecular Biology Laboratory (EMBL)
Xiao-Ning Xu: Imperial College London
Gary R. McLean: Imperial College London
Sarah A. Teichmann: Wellcome Sanger Institute
Anna M. Randi: Imperial College London
Andrew Filby: Newcastle University
Paul M. Kaye: University of York
Andrew J. Fisher: Newcastle University Translational and Clinical Research Institute
Martin Hemberg: Massachusetts General Hospital and Harvard Medical School
Michela Noseda: Imperial College London
Omer Ali Bayraktar: Wellcome Sanger Institute

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.

Date: 2025
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DOI: 10.1038/s41467-025-56473-x

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