Spatial transcriptomics unveils the in situ cellular and molecular hallmarks of the lung in fatal COVID-19

Severe Coronavirus disease 2019 (COVID-19) can induce progressive diffuse alveolar damage (DAD) leading to fatal outcomes. Here, we leveraged data from Visium spatial transcriptomics for COVID-19 and control lung samples to unravel insights into cellular and molecular events driving lethal COVID-19. We report a progressive loss of endothelial cell types, pneumocytes type I and natural killer cells coupled with a continuous increase of myeloid and stromal cells, mostly peribronchial fibroblasts, across acute and proliferative DAD. Spatial organization analysis also identified specific compartmentalization including immune-specific clusters across DAD patterns. Importantly, spatially informed ligand-receptor interaction analysis revealed intercellular communication signatures defining COVID-19 induced DAD. Transcription factor activity enrichment analysis identified the TGF-β pathway as DAD driver, highlighting the antagonizing roles of SMAD3 and SMAD7 activity during fibrosis. Integration of these data yielded a signaling kinase pathway in peribronchial fibroblasts with amenable novel targets. Finally, spatio-temporal trajectory analysis characterized an alveolar epithelium regeneration program. Here, Garcia-Prieto et al use spatial transcriptomics to reveal progressive endothelial, pneumocyte type I and natural killer cell loss, expansion of myeloid and stromal cells, TGF-β-driven fibrosis signaling and alveolar regeneration programs in fatal COVID-19 lung injury.