A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID, 2026, Kumar et al

[Chandelier]

Immunologically distinct long COVID after mild acute disease - Nature Immunology

Distinct monocyte gene expression programs were identified in people with long COVID after mild-to-moderate COVID-19 versus severe acute COVID-19, providing evidence that immunological dysregulation after mild acute COVID-19 may be the result of distinct pathobiological pathways.

www.nature.com

Authors: Annukka A. R. Antar, Elizabeth C. Pasetes, Kay’La M. Z. Brennon & Andrea L. Cox

Distinct monocyte gene expression programs were identified in people with long COVID after mild-to-moderate COVID-19 versus severe acute COVID-19, providing evidence that immunological dysregulation after mild acute COVID-19 may be the result of distinct pathobiological pathways.

I‘ll update this post once more information about the study is available.

 

[V.R.T.]

This looks potentially really interesting, will be interested to see full study.

 

[Chandelier]

Merged thread
------------------

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

Li and colleagues describe a monocyte-specific transcriptional state along with a persistent elevation of inflammatory markers specifically found in individuals with long COVID who had mild-to-moderate disease during acute SARS-CoV-2 infection.

www.nature.com

Spoiler: Authors

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

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.

DOI: 10.1038/s41590-025-02387-1

 

[V.R.T.]

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.

Does this sound plausible? @jnmaciuch @Jonathan Edwards

 

[Jonathan Edwards]

I am tired of seeing abstracts full of interpretations but no data. I don't have time to plough through the papers these days.

 

[V.R.T.]

I am tired of seeing abstracts full of interpretations but no data. I don't have time to plough through the papers these days.

Thats fair. It took me a good while of scanning just to find participant numbers because its in the results! Surely that should be front and centre?

 

[jnmaciuch]

Does this sound plausible? @jnmaciuch @Jonathan Edwards

I'm sure a lot of work went into this paper. I also could not remotely follow what was being talked about between one figure at the next (and I'm pretty used to lengthy -omics analyses).

 

[Nightsong]

Haven't yet looked at the paper itself but noticed there was a useful (and perhaps more accessible) article in Nature Immunology's news section summarising it:

Immunologically distinct long COVID after mild acute disease

 

[V.R.T.]

Does anyone have any more information about this study?

It looks like the summary article is paywalled.

 

[Nightsong]

Focusing on CD14+ monocytes, the authors identified 1,737 genes that were upregulated in long COVID monocytes versus monocytes from healthy controls and recovered individuals, with these genes upregulated significantly more in LC AM individuals than in LC AS individuals[1]

The TGFβ and WNT–β-catenin signaling pathways were consistently upregulated in LC AM participants throughout the first year after infection, whereas TNF signaling was upregulated mid-year and downregulated by the year’s end. Concordantly, cytokine profiling of plasma from cohort 2 showed consistently higher levels of the chemokine CCL2 through months 9–12, and TNF levels were higher in plasma from individuals with long COVID through months 6–8, but these were not significantly different from the plasma levels of healthy control individuals by months 9–12 post-COVID

(LC_AM is the LC after mild-moderate COVID group; LC_AS is the LC after severe acute COVID group.)

Next, Kumar et al. 1 clustered monocytes from individuals with long COVID in cohort 1 into four main clusters referred to as monocyte clusters MC1–MC4, one of which was modestly associated with fatigue score (positive correlation) and measures of blood oxygenation (negative correlation).

The transcriptional signature specific for this monocyte cluster (MC4) showed upregulation of the TGFβ and WNT–β-catenin signaling pathways. snATAC-seq analysis identified the most significant transcription factors within the cluster, including SPI1, which is implicated in the differentiation of monocytes to macrophages. Specifically, in monocytes from LCAM individuals, transient accessibility for the transcription factor AP-1 at month 6 was followed by accessibility for transcription factors involved downstream of TGFβ signaling, including SPI1.

Flow cytometry was next performed on CD14+ monocytes from cohort 4 to better characterize proteins whose genes were upregulated in the MC4 monocyte profile. Some proteins were more highly expressed in long COVID than in healthy controls (such as HLA-DQ and TGFβ), whereas others showed no significant difference in expression (such as HLA-DR, IFNGR1 and CD16

Although natural killer (NK) cells and T cells were less of a focus of this work, a subcluster of GZMK+ GZMBlo CD8+ T cells were identified by gene expression in long COVID donors. In these cells, the TNF and Toll-like receptor signaling pathways were upregulated, suggesting that TNF signaling could be driven by the increased levels of TNF observed in long COVID donors at month 6 and might stimulate the proliferation of GZMK+ CD8+ T cells and NK cells. Given that GZMK+ cells can activate complement[5], this offers a potential mechanism for the dysregulated activation of complement observed in long COVID donors

 

[V.R.T.]

(LC_AM is the LC after mild-moderate COVID group; LC_AS is the LC after severe acute COVID group.)

TGF-B has been found to be higher in ME/CFS right?

Also it says they found HLA DQ was highly expressed in pwLC in the flow cytometry test