Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

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 IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) 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.

Automated summary

This study used spatial transcriptomics to explore the interactions between different immune and stromal cell populations in COVID-19-affected lung tissue. Through gene expression analysis of well-preserved lung samples from 3 patients, a common immune-cell signaling circuit involving cytotoxic lymphocytes and pro-inflammatory macrophages was identified in areas of severe lung damage. The expression of IFNG by cytotoxic lymphocytes was associated with the induction of chemokines, while TNF superfamily members (BAFF and TRAIL) were consistently upregulated in severely damaged areas. Validation of these findings in additional COVID-19 patient cohorts supports the potential use of this immune-mediated tissue pathology model for future therapeutic strategies.