How long COVID develops is still largely unknown. New molecular connections are revealed in a recent study led by the Center for Individualized Infection Medicine (CiiM), which is a joint institution of the Helmholtz Center for Infection Research (HZI) and Hannover Medical School (MHH). Using their approach of examining different molecular levels within individual cells, the researchers identified a specific condition in immune cells that was directly associated with elevated inflammation markers, fatigue, and respiratory problems in patients with long COVID. The study is published in the journal Nature Immunology.
After infection with the SARS-CoV-2 virus, up to 10% of those affected in Germany develop long COVID. The symptoms associated with it, such as fatigue, concentration problems, respiratory issues, or neurological problems, can last for months or years. Furthermore, the clinical picture can differ from person to person. “Long COVID is an extremely complex disease with various manifestations,” says Prof. Yang Li, head of the “Computational Biology for Individualized Medicine” department and director of CiiM. “How and to what extent COVID develops is still largely unknown. Figuratively speaking, we are unfortunately only looking at an extremely incomplete puzzle.”
Researchers dig into immune cell clues
The research team led by study director Li, together with the teams of Prof. Thomas Illig (MHH) and Prof. Jie Sun (University of Virginia, U.S.), as well as other cooperation partners, set out to find further pieces of the puzzle that could help uncover the disease-causing mechanisms behind COVID. To this end, the researchers took a closer look at immune cells from patients with COVID in their study. The samples came from MHH’s central biobank.
“We examined the cells using a so-called single-cell multiomics approach. This allowed us to record the molecules’ status within a cell and gain insights into its cellular relationships,” explains Dr. Saumya Kumar, CiiM scientist and first author of the study. The researchers also determined the content of pro-inflammatory messenger substances, known as cytokines, in blood plasma.
Linking disease severity to cell changes
“The central and innovative approach of our study is to classify patient data according to the severity of the original COVID-19 disease,” says Li. “This approach allowed us to capture the associated molecular differences in immune response across patients. Only in this way, clear molecular characteristics underlying the chronic symptoms of COVID could be identified.”
How does the molecular setting in immune cells change over the course of COVID? Are there clear molecular markers associated with the severity of fatigue or respiratory symptoms? Researchers investigated these and other questions in their big data study. And what then came into focus for the researchers from this extensive treasure trove of data was a specific molecular state of so-called CD14+ monocytes. These immune cells belong to the white blood cells and are an important part of the immune defense.
A new monocyte state emerges
“With the help of single-cell analysis, we were able to zoom in on these cells. This revealed that monocytes with a specific molecular state (i.e. molecular profile), which we called “LC-Mo,” were particularly prevalent in COVID patients who had previously experienced mild to moderate COVID-19 disease,” says Kumar. “In addition, LC-Mo correlated with the severity of fatigue and respiratory symptoms and was associated with elevated cytokine levels in blood plasma, which are an indicator of inflammatory processes in the body.”
With LC-Mo, the researchers have thus found an important new piece of the puzzle. “Its exact place in the pathogenesis of COVID has yet to be determined, but it offers exciting starting points for further studies, for example, with regard to genetic risk factors or individualized medicine,” says Li. “If we can gain a better understanding of the background to the development of COVID, it will also help us to better understand the development of possible late or long-term consequences of other infectious diseases.”
Publication details
Saumya Kumar et al, A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID, Nature Immunology (2026). DOI: 10.1038/s41590-025-02387-1
Annukka A. R. Antar et al, Immunologically distinct long COVID after mild acute disease, Nature Immunology (2026). DOI: 10.1038/s41590-025-02399-x , doi.org/10.1038/s41590-025-02399-x
Journal information:
Nature Immunology
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