A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID.

The mechanisms driving immune dysregulation in long COVID disease remain elusive. Here we integrated single-cell multiome data, immunological profiling and functional assays to investigate immune alterations across multiple cohorts. A transcriptional state in circulating monocytes (LC-Mo) was enriched in individuals with mild-moderate acute infection and accompanied by persistent elevations of plasma CCL2, CXCL11 and TNF. LC-Mo showed TGFβ and WNT-β-catenin signaling and correlated with fatigue severity. Protein markers of LC-Mo were increased in individuals with pronounced fatigue or dyspnea, and those with severe respiratory symptoms showed higher LC-Mo expression. Epigenetically, LC-Mo exhibited AP-1- and NF-κB1-driven profibrotic programs. LC-Mo-like macrophages in bronchoalveolar lavage samples from individuals with severe respiratory symptoms displayed a profibrotic profile, and individuals with a high LC-Mo transcriptional state showed impaired interferon responses after stimulation. Collectively, our findings define a pathogenic monocyte transcriptional state linking systemic immune dysfunction to persistent long COVID disease, providing mechanistic insights and potential therapeutic targets.