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Discovery of Key Regulators in Classical Monocyte Phenotypes Linked to COVID-19 Severity using Single-cell Multi-omics Sequencing

ABSTRACT: Dysregulated immune responses often accompany severe COVID-19, but the underlying epigenetic mechanisms driving monocyte heterogeneity and disease progression remain poorly understood. Here, we applied single-cell multi-omics profiling to peripheral blood mononuclear cells from individuals across five COVID-19 severity stages. We identified two severity-associated classical monocyte subtypes-IL7R+ and CD163+-characterized by distinct transcriptional and epigenetic landscapes. Using constructing of gene regulatory network and in silico TF perturbations, we revealed ETS1 as a key driver of IL7R+ monocytes with T cell-like signaling features, and JDP2 as a repressor maintaining the pro-fibrotic, anti-inflammatory identity of CD163+ monocytes via suppression of AP-1 activity. These subtypes were enriched in moderate-to-critical stages and exhibited signaling pathways associated with tissue remodeling and immune suppression. Our findings define monocyte heterogeneity linked to COVID-19 severity and identify ETS1 and JDP2 as central regulators, offering insight into immune dysregulation and potential therapeutic targets for fibrosis and long-term sequelae.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297529 | GEO | 2026/01/22

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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Discovery of Key Regulators in Classical Monocyte Phenotypes Linked to COVID-19 Severity using Single-cell Multi-omics Sequencing

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