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

Author

Listed:
  • Jimmy Tsz Hang Lee

    (Wellcome Sanger Institute)

  • Sam N. Barnett

    (Imperial College London
    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
    European Molecular Biology Laboratory (EMBL))

  • 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
    London Metropolitan University)

  • Sarah A. Teichmann

    (Wellcome Sanger Institute
    University of Cambridge)

  • Anna M. Randi

    (Imperial College London
    Imperial College London)

  • Andrew Filby

    (Newcastle University)

  • Paul M. Kaye

    (University of York)

  • Andrew J. Fisher

    (Newcastle University Translational and Clinical Research Institute
    Newcastle upon Tyne Hospitals NHS Foundation Trust)

  • Martin Hemberg

    (Massachusetts General Hospital and Harvard Medical School)

  • Michela Noseda

    (Imperial College London
    Imperial College London)

  • Omer Ali Bayraktar

    (Wellcome Sanger Institute)

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.

Suggested Citation

  • 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 & M, 2025. "Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56473-x
    DOI: 10.1038/s41467-025-56473-x
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