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

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.