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 COVID-19 progression remain unclear. Here, we applied single-cell multi-omics profiling to peripheral blood mononuclear cells across healthy and four COVID-19 severity stages. We identified two severity-associated classical monocyte subtypes-IL7R+ and CD163+, These subtypes exhibit distinct transcriptional and epigenetic landscapes. By constructing a gene regulatory network and <i>in silico</i> perturbations, we revealed that ETS1 is a key driver of IL7R + monocytes with T cell-like signaling features and that JDP2 is a repressor that maintains the profibrotic, anti-inflammatory identity of CD163+ monocytes by suppressing AP-1 activity. These subtypes were enriched in the moderate-to-critical stages and exhibited signaling pathways associated with tissue remodeling and immune suppression. Our findings define monocyte heterogeneity as linked to COVID-19 severity and identify ETS1 and JDP2 as central regulators, offering insights into immune dysregulation, potential therapeutic targets for fibrosis, and long-term sequelae.