| Summary: | <p>Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19–affected lung tissue. We applied correlation network–based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of <em>IFNG</em> by cytotoxic lymphocytes was associated with induction of chemokines, including <em>CXCL9</em>, <em>CXCL10</em>, and <em>CXCL11</em>, which are known to promote the recruitment of CXCR3<sup>+</sup> immune cells. The TNF superfamily members <em>BAFF</em> (<em>TNFSF13B</em>) and <em>TRAIL</em> (<em>TNFSF10</em>) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.</p>
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