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Lookup NU author(s): Dr Luke Milross, Dr Joaquim Majo Masferrer, Professor Andrew FisherORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© The Author(s) 2025. 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.
Author(s): Lee JTH, Barnett SN, Roberts K, Ashwin H, Milross L, Cho J-W, Huseynov A, Woodhams B, Aivazidis A, Li T, Majo J, Chaves P, Lee M, Miranda AMA, Jablonska Z, Arena V, Hanley B, Osborn M, Uhlmann V, Xu X-N, McLean GR, Teichmann SA, Randi AM, Filby A, Kaye PM, Fisher AJ, Hemberg M, Noseda M, Bayraktar OA
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Online publication date: 10/03/2025
Acceptance date: 21/01/2025
Date deposited: 31/03/2025
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-025-56473-x
DOI: 10.1038/s41467-025-56473-x
Data Access Statement: The data generated for this manuscript were submitted to the European Genome-phenome Archive under accession numbers EGAS00001004442 for the snRNA-seq, EGAS00001004441 for the Control WTA data, and EGAS00001005817 for the COVID-19 WTA data. Requests for data access will be referred directly to the Data Access Committee Portal at https://ega-archive.org/dacs/EGAC00001000205 and the documentation can be found at https://ega-archive.org/access/data-access-committee/dac-portal/. The integrated sc/snRNA-seq atlas can be accessed on our webportal at https://covid19-multiomicatlas.cellgeni.sanger.ac.uk/. The spatial WTA data will be made available under the same portal. The publicly available sc/snRNA-seq datasets used in this study are documented in Supplementary Table 2.
PubMed id: 40064844
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