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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

ABSTRACT: Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including prominent hyperactivation signatures in neutrophils and monocytes with anti-inflammatory features. We also leverage epigenomic analysis to identify loss of accessibility at NF-kB binding sites within pro-inflammatory cytokine gene loci as a potential mechanism for the striking lack of cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174072 | GEO | 2021/05/08

REPOSITORIES: GEO

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Project description:The clinical presentations and outcomes of SARS-CoV-2 infection are highly variable, ranging from asymptomatic infections to severe conditions, and the underlying mechanisms remain largely unknown. In this study, we performed the single-cell RNA sequencing to examine the profiles of the peripheral blood mononuclear cells (PBMCs) from the healthy controls (HC), asymptomatic individuals (AS) and symptomatic COVID-19 patients (SM) with various clinical features and disease severity. We first identified nine major cell types, including T cells, B cells, monocytes, natural killer (NK) cells, dendritic cells (DC), platelets, neutrophils, plasma cells and stem cells from a total of 119,799 single cells captured and filtered for the final analysis, and then divided these cell types into separate cell clusters and sub-clusters, respectively. We revealed that SARS-CoV-2 infection resulted in profound alternations in various cellular compartments and identified a number of distinct immune cell subsets that were associated with various clinical presentations, disease severity and viral persistence of COVID-19. (NCAM1+CD160+) NK cells increased significantly in AS and SM individuals compared with the HC. SM patients showed a significant increase in (LAG3+CD160+CD8+) NKT cells and a decrease in (CD4-CD8-) double negative T cells compared with the AS subjects. (CD68-CSF1R-IL1BhiCD14+) classical monocytes were significantly higher in patients with severe disease (SD) than the patients with moderate disease (MD). (CD68-CSF1R-IL1BhiCD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were positively and negatively correlated with the age-related disease severity of COVID-19 patients, respectively. Increases in (CD33-HLA-DMA-CD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were associated with long-term nucleic acid test positive (LTNP) patients compared with the short-term nucleic acid test positive (STNP) individuals. Increases in (LAG3+CD160+CD8+) NKTcells and (FOXP3+IL2RA+IL7R+CD4+) Treg cells were observed in a patient lacking B cells and plasma cells. Dramatic increases in neutrophils, (CD33-HLA-DMA-CD14+) classical monocytes, and (CD68-CSF1R-IL1BhiCD14+) classical monocytes were detected at a later stage of a fatal patient. Our findings may enhance our understanding of the immune cell alternations involved in the pathogenesis of COVID-19 and the protective immune responses against SARS-CoV-2 infection.

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

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