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.

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Publication Details

Journal
Nature Immunology
Published
2026-01-14
DOI
https://doi.org/10.1038/s41590-025-02387-1
Citations
1
Primary Topic
Long-Term Effects of COVID-19
Type
article
Field-Weighted Citation Impact
39.15
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article

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

Andreas Rembert Koczulla, Lea Pueschel, H Lickei, Antonia Zeuzem et al.
1 citations
Nature Immunology
Long-Term Effects of COVID-19
39.15
article

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

Andreas Rembert Koczulla, Lea Pueschel, H Lickei, Antonia Zeuzem, Saumya Kumar, Bibiana Costa, Cheng‐Jian Xu, Simon Krooss, Dorothee von Witzendorff, Qiuyao Zhan, Hagen Schmaus, Isabel Klefenz, Chaofan Li, Isabell Pink, Jie Sun, Miriam Wiestler, Ahmed Alaswad, Markus Cornberg, Susanne Häussler, Sonja Volland, Anke R. M. Kraft, Thomas Illig, Mihai G. Netea, Liang Zhou, Yang Li
article en
1 citations

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 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.

Nature ImmunologyVol. 27(2)
Carter Center (US), University of Bonn (DE), Radboud University Nijmegen (NL), Philipps University of Marburg (DE), Paracelsus Medical University (AT), Rigshospitalet (DK), Radboud University Medical Center (NL), Medizinische Hochschule Hannover (DE), Radboud Institute for Molecular Life Sciences (NL), German Center for Infection Research (DE), Helmholtz Centre for Infection Research (DE), German Center for Lung Research (DE), Universities of Giessen and Marburg Lung Center (DE), Centre for Individualised Infection Medicine (DE), Center for Experimental and Clinical Infection Research (DE), Schön Klinik Berchtesgadener Land (DE), Artificial Intelligence in Medicine (Canada) (CA), University of Virginia (US)
Good health and well-being
Openalex Percentile: Top 2%
Long-Term Effects of COVID-19
39.15
DOIOpen Access PDFOpenAlex
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