TY - JOUR
T1 - Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19
AU - Lee, Jimmy Tsz Hang
AU - Barnett, Sam N.
AU - Roberts, Kenny
AU - Ashwin, Helen
AU - Milross, Luke
AU - Cho, Jae-Won
AU - Huseynov, Alik
AU - Woodhams, Benjamin
AU - Aivazidis, Alexander
AU - Li, Tong
AU - Majo, Joaquim
AU - Chaves, Patricia
AU - Lee, Michael
AU - Miranda, Antonio M. A.
AU - Jablonska, Zuzanna
AU - Arena, Vincenzo
AU - Hanley, Brian
AU - Osborn, Michael
AU - Uhlmann, Virginie
AU - Xu, Xiao-Ning
AU - McLean, Gary R.
AU - Teichmann, Sarah A.
AU - Randi, Anna M.
AU - Filby, Andrew
AU - Kaye, Paul M.
AU - Fisher, Andrew J.
AU - Hemberg, Martin
AU - Noseda, Michela
AU - Bayraktar, Omer Ali
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - COVID 19
KW - COVID 19
UR - https://publicatt.unicatt.it/handle/10807/315837
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=86000716302&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=86000716302&origin=inward
U2 - 10.1038/s41467-025-56473-x
DO - 10.1038/s41467-025-56473-x
M3 - Article
SN - 2041-1723
VL - 16
SP - 1
EP - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -
