Big data study reveals an association with a molecular state of immune cells

How Long COVID develops is still poorly understood. A recent study led by Prof. Yang Li at the Centre for Individualised Infection Medicine (CiiM) now provides new insights into potential molecular mechanisms underlying the condition. Yang Li is also a member of the RESIST Cluster of Excellence, as are other researchers who played a key role in the publication. Using modern single-cell analyses, the researchers identified a specific molecular state in immune cells that is associated with inflammatory processes as well as typical Long COVID symptoms such as fatigue and respiratory complaints. The results have been published in the journal Nature Immunology. CiiM is a joint institution of the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH).

In Germany, up to ten percent of individuals infected with SARS-CoV-2 go on to develop Long COVID. Symptoms can vary widely and may persist for months or even years. “Long COVID is a highly complex disease with diverse manifestations, and its causes are still only fragmentarily understood,” says Prof. Yang Li, Director of CiiM.

To identify further “pieces of the puzzle” contributing to disease development, the research team led by study head Yang Li, together with teams headed by Prof. Thomas Illig (MHH) and Prof. Jie Sun (University of Virginia, USA) and additional collaborators, investigated immune cells from individuals with Long COVID obtained from MHH’s central biobank. The researchers employed a so-called single-cell multi-omics approach, enabling the simultaneous analysis of multiple molecular layers within individual cells. In addition, they measured levels of pro-inflammatory messenger molecules, known as cytokines, in blood plasma. A key element of the study design was the stratification of patients according to the severity of their initial COVID-19 illness, allowing differences in immune responses to be assessed in a targeted manner.

The analyses ultimately focused on a specific molecular state in CD14⁺ monocytes, an important subset of white blood cells. This state, termed “LC-Mo” by the researchers, was particularly prevalent in Long COVID patients who had previously experienced a mild to moderate course of COVID-19. LC-Mo also correlated with the severity of fatigue and respiratory symptoms, as well as with elevated cytokine levels, indicating ongoing inflammatory processes.

“LC-Mo represents a new and important building block in our understanding of Long COVID,” says Yang Li. Although its precise role in disease development remains to be fully elucidated, the discovery opens up promising avenues for further research, for example with regard to genetic risk factors or personalised therapeutic approaches.

The study thus aligns with the research focus of the Cluster of Excellence RESIST, which is dedicated to understanding immune deficiencies in the context of infections and their long-term consequences, including diseases such as COVID-19.

Original publication:
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: A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID. Nature Immunology (2026); https://doi.org/10.1038/s41590-025-02387-1

Further article on Long COVID and this publication:
Antar, A.A.R., Pasetes, E.C., Brennon, K.M.Z. et al.: Immunologically distinct long COVID after mild acute disease. Nature Immunology (2026); https://doi.org/10.1038/s41590-025-02399-x

Foto: Adobe Stock / stockdevil; Symbolic image of white blood cells with cell nucleus and granules