A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID.
Abstract
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 TGFbeta and WNT-beta-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-kappaB1-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.
| Authors: | Kumar S, Li C, Zhou L, Zhan Q, Alaswad A, Volland S, Costa B, Krooss SA, Klefenz I, Schmaus H, Zeuzem A, von Witzendorff D, Lickei H, Pueschel L, Kraft ARM, Cornberg M, Koczulla AR, Pink I, Hoeper MM, Xu CJ, Häussler S, Wiestler M, Netea MG, Illig T, Sun |
|---|---|
| Journal: | Nat Immunol . 2026 Feb;27(2):200-212. doi: 10.1038/s41590-025-02387-1. |
| Year: | 2026 |
| PubMed: | PMID: 41535626 (Go to PubMed) |