RESUMO
Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we developed a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method revealed a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and cytotoxic CD8 T cells, was found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings provide new insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
Assuntos
COVID-19 , Teratoma , Adenocarcinoma BronquioloalveolarRESUMO
Severe lung damage in COVID-19 is known to involve complex interactions between diverse populations of immune and stromal cells. In this study, we applied a spatial transcriptomics approach to better delineate the cells, pathways and genes responsible for promoting and perpetuating severe tissue pathology in COVID-19 pneumonitis. Guided by tissue histology and immunohistochemistry we performed a targeted sampling of dozens of regions representing a spectrum of diffuse alveolar damage from the post-mortem lung of three COVID-19 patients. Application of a combination of differential gene expression, weighted gene correlation network, pathway and spatial deconvolution analysis stratified the sampled regions into five distinct groups according to degree of alveolar damage, levels of cytotoxic inflammation and innate activation, epithelial reorganization, and fibrosis. Integrative network analysis of the identified groups revealed the presence of proliferating CD8 T and NK cells in severely damaged areas along with signatures of cytotoxicity, interferon signalling and high expression of immune cell chemoattractants (including CXCL9/10/11 and CCL2). Areas of milder damage were marked by innate immune signalling (including TLR response, IL-1, IL-6) together with signatures of antigen presentation, and fibrosis. Based on these data we present a cellular model of tissue damage in terminal COVID-19 that confirms previous observations and highlights novel opportunities for therapeutic intervention.
Assuntos
Fibrose , Pneumopatias , Adenocarcinoma Bronquioloalveolar , Pneumonia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , COVID-19 , InflamaçãoRESUMO
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.