Many people continue to experience breathing difficulties, fatigue, or coughing months after a SARS-CoV-2 infection—a condition known as Long COVID. But what changes in the immune system lead to lasting lung impairment?
In the current issue of Nature Immunology, an international team of researchers provides new mechanistic insights. The publication “A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID” demonstrates how a specific monocyte cell state is associated with lung function and may hold the key to new diagnostic and therapeutic approaches. The study was conducted in close collaboration between partners of the German Center for Lung Research (DZL), the German Center for Infection Research (DZIF), and other national and international institutions. The scientific leadership was provided by Prof. Dr. Thomas Illig and Prof. Dr. Yang Li, both researchers at the DZL site BREATH.
To understand the immune changes in Long COVID at the cellular and molecular level, the team employed an integrative multi-omics approach. This combined single-cell RNA sequencing of peripheral immune cells, comprehensive immune phenotyping, analysis of molecular inflammation markers, and clinical lung function data.
This approach allowed the researchers to directly link systemic immune processes to functional lung impairments and to identify disease-associated cell states with unprecedented resolution. “A central focus of our work is to analyze complex immunological processes across multiple molecular layers,” explains Prof. Dr. Yang Li, Director of the Centre for Individualised Infection Medicine (CiiM) at the DZL site BREATH. “By integrating single-cell data, additional omics layers, and clinical parameters such as lung function, we can systematically capture genetic and immunological factors and better describe their contribution to Long COVID.”
A key finding of the study is the discovery of a specific transcriptional state in circulating monocytes, which is particularly pronounced in Long COVID patients. This cell state activates several signaling pathways, including TGF-β and WNT-β-Catenin-dependent programs, which are associated with chronic inflammation, immune regulation, and tissue remodeling. The presence of this monocyte profile was closely correlated with reduced lung function and persistent respiratory symptoms, highlighting a direct link between systemic immune dysregulation and pulmonary function.
These results provide a biological basis for better understanding the clinical heterogeneity of Long COVID and for developing more targeted diagnostic and therapeutic strategies in the future. “In clinical care, we see very different courses and symptom patterns in Long COVID patients,” says Dr. Isabell Pink, head of the Post-COVID Clinic at the DZL site BREATH. “Identifying a clearly defined immunological cell state provides an important entry point for explaining these differences and for developing more precise treatment strategies.”
Original Publication: Kumar, S., Li, C., Zhou, L. et al. A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID. Nat Immunol (2026).
Source: BREATH
