Publication date: Jan 14, 2026
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-_705B1-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.
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| Concepts | Keywords |
|---|---|
| Cxcl11 | Covid |
| Driving | Dysregulation |
| Immunological | Fatigue |
| Monocytes | Immune |
| Pulmonary | Individuals |
| Lc | |
| Long | |
| Mo | |
| Monocyte | |
| Persistent | |
| Respiratory | |
| Severe | |
| Showed | |
| Systemic | |
| Transcriptional |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | long COVID |
| disease | MESH | infection |
| disease | MESH | fatigue |
| disease | MESH | dyspnea |
| disease | MESH | severe acute respiratory syndrome |
| disease | MESH | SARS CoV 2 infection |
| drug | DRUGBANK | Tretamine |
| disease | MESH | included |
| drug | DRUGBANK | Ademetionine |
| disease | MESH | AIS |
| drug | DRUGBANK | Dimercaprol |
| disease | MESH | headache |
| disease | MESH | syndrome |
| drug | DRUGBANK | Bentiromide |
| disease | MESH | IRAK4 deficiency |
| pathway | REACTOME | NOTCH1 Intracellular Domain Regulates Transcription |
| disease | MESH | Oas |
| pathway | KEGG | Platelet activation |
| drug | DRUGBANK | Oxygen |
| pathway | REACTOME | TNF signaling |
| pathway | KEGG | TNF signaling pathway |
| disease | MESH | inflammation |