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

Saumya Kumar; Chaofan Li; Liang Zhou; Qiuyao Zhan; Ahmed Alaswad; Sonja Volland; Bibiana Costa; Simon Alexander Krooss; Isabel Klefenz; Hagen Schmaus; Antonia Zeuzem; Dorothee von Witzendorff; Helena Lickei; Lea Pueschel; Anke R M Kraft; Markus Cornberg; Andreas Rembert Koczulla; Isabell Pink; Marius M Hoeper; Cheng-Jian Xu; Susanne Häussler; Miriam Wiestler; Mihai G Netea; Thomas Illig; Jie Sun; Yang Li

doi:10.1038/s41590-025-02387-1

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

Saumya Kumar, Chaofan Li, Liang Zhou, Qiuyao Zhan, Ahmed Alaswad, Sonja Volland, Bibiana Costa, Simon Alexander Krooss, Isabel Klefenz, Hagen Schmaus, Antonia Zeuzem, Dorothee von Witzendorff, Helena Lickei, Lea Pueschel, Anke R M Kraft, Markus Cornberg, Andreas Rembert Koczulla, Isabell Pink, Marius M Hoeper, Cheng-Jian XuSusanne Häussler, Miriam Wiestler, Mihai G Netea, Thomas Illig, Jie Sun, Yang Li

Afdeling for Klinisk Mikrobiologi DIA

1 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Immunology
Vol/bind	27
Udgave nummer	2
Sider (fra-til)	200-212
Antal sider	13
ISSN	1529-2908
DOI	https://doi.org/10.1038/s41590-025-02387-1
Status	Udgivet - feb. 2026

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10.1038/s41590-025-02387-1Licens: CC BY

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Kumar, S., Li, C., Zhou, L., Zhan, Q., Alaswad, A., Volland, S., Costa, B., Krooss, S. A., Klefenz, I., Schmaus, H., Zeuzem, A., von Witzendorff, D., Lickei, H., Pueschel, L., Kraft, A. R. M., Cornberg, M., Koczulla, A. R., Pink, I., Hoeper, M. M., ... Li, Y. (2026). A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID. Nature Immunology, 27(2), 200-212. https://doi.org/10.1038/s41590-025-02387-1

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, C-J, Häussler, S, Wiestler, M, Netea, MG, Illig, T, Sun, J & Li, Y 2026, 'A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID', Nature Immunology, bind 27, nr. 2, s. 200-212. https://doi.org/10.1038/s41590-025-02387-1

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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.",

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AU - Kumar, Saumya

AU - Li, Chaofan

AU - Zhou, Liang

AU - Zhan, Qiuyao

AU - Alaswad, Ahmed

AU - Volland, Sonja

AU - Costa, Bibiana

AU - Krooss, Simon Alexander

AU - Klefenz, Isabel

AU - Schmaus, Hagen

AU - Zeuzem, Antonia

AU - von Witzendorff, Dorothee

AU - Lickei, Helena

AU - Pueschel, Lea

AU - Kraft, Anke R M

AU - Cornberg, Markus

AU - Koczulla, Andreas Rembert

AU - Pink, Isabell

AU - Hoeper, Marius M

AU - Xu, Cheng-Jian

AU - Häussler, Susanne

AU - Wiestler, Miriam

AU - Netea, Mihai G

AU - Illig, Thomas

AU - Sun, Jie

AU - Li, Yang

PY - 2026/2

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N2 - 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.

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

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