Deep spatial proteomics reveals region-specific features of severe COVID-19-related pulmonary injury

As a primary target of severe acute respiratory syndrome coronavirus 2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding of coronavirus disease 2019 (COVID-19)-related pulmonary injury. Here, we generate a region-resolved proteomic atlas of hallmark pathological pulmonary structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins are quantified across 71 post-mortem specimens. We identify a spectrum of pathway dysregulations in alveolar epithelium, bronchial epithelium, and blood vessels compared with non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data reveal the region-specific enrichment of functional markers in bronchiole mucus plugs, pulmonary fibrosis, airspace inflammation, and alveolar type 2 cells, uncovering their distinctive features. Furthermore, we detect increased protein expression associated with viral entry and inflammatory response across multiple regions, suggesting potential therapeutic targets. Collectively, this study provides a distinct perspective for deciphering COVID-19-caused pulmonary dysfunction by spatial proteomics. [Display omitted] •Sensitive method quantifies over 10,000 proteins in microdissected COVID-19 lung autopsies•Region-specific proteomic dysregulations in key pulmonary structures are identified•Enrichment of cell type and functional markers in hallmark lesions is revealed Lung exhibits heterogeneous histopathological changes in COVID-19 patients. Mao et al. generate an in-depth proteomic map of pulmonary structures in COVID-19 autopsies by a sensitive pipeline. Region-specific dysregulation and enrichment of key protein markers and pathways are detected in hallmark lesions, uncovering their molecular basis.