Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Abstract

ABSTRACTAs the global COVID-19 pandemic continues to escalate, no effective treatment has yet been developed for the severe respiratory complications of this disease. This may be due in large part to the unclear immunopathological basis for the development of immune dysregulation and acute respiratory distress syndrome (ARDS) in severe and critical patients. Specifically, it remains unknown whether the immunological features of the disease that have been identified so far are compartment-specific responses or general features of COVID-19. Additionally, readily detectable biological markers correlated with strata of disease severity that could be used to triage patients and inform treatment options have not yet been identified. Here, we leveraged publicly available single-cell RNA sequencing data to elucidate the common and compartment-specific immunological features of clinically severe COVID-19. We identified a number of transcriptional programs that are altered across the spectrum of disease severity, few of which are common between the lung and peripheral immune environments. In the lung, comparing severe and moderate patients revealed severity-specific responses of enhanced interferon, A20/IκB, IL-2, and IL-6 pathway signatures along with broad signaling activity ofIFNG, SPP1, CCL3, CCL8, andIL18across cell types. These signatures contrasted with features unique to ARDS observed in the blood compartment, which included depletion of interferon and A20/IκB signatures and a lack of IL-6 response. The cell surface markerS1PR1was strongly upregulated in patients diagnosed with ARDS compared to non-ARDS patients in γδ T cells of the blood compartment, and we nominate S1PR1 as a potential marker for immunophenotyping ARDS in COVID-19 patients using flow cytometry.HIGHLIGHTSCOVID-19 disease severity is associated with a number of compositional shifts in the cellular makeup of the blood and lung environments.Transcriptional data suggest differentially expressed cell surface proteins as markers for COVID-19 immunophenotyping from BALF and PBMC samples.Severity-specific features COVID-19 manifest at the pathway level, suggesting distinct changes to epithelia and differences between local and systemic immune dynamics.Immune-epithelial cellular communication analysis identifies ligands implicated in transcriptional regulation of proto-oncogenes in the lung epithelia of severe COVID-19 patients.Network analysis suggests broadly-acting dysregulatory ligands in the pulmonary microenvironment as candidate therapeutic targets for the treatment of severe COVID-19.