New Insights into the Molecular Causes of Long COVID

Post-COVID – also known as Long COVID – affects millions of people worldwide and causes persistent symptoms, the underlying mechanisms of which are still not fully understood. An interdisciplinary research team involving DZL scientists from the ARCN, BREATH, and CPC-M sites has now identified new molecular mechanisms contributing to the development of post-COVID syndrome (PCS). The results have been published in the journal Nature Communications.

The study was conducted by researchers from the Forschungszentrum Borstel – Leibniz Lung Center (FZB), University of Lübeck, Christian-Albrechts University of Kiel, University Medical Center Schleswig-Holstein (UKSH), and other partners. Nasal biopsies from 25 participants of the nationwide NAPKON cohort served as the basis for the analyses. Using cutting-edge single-cell transcriptomics (scRNA-seq) and human nasal tissue models, the team investigated cellular and molecular changes in the airway mucosa of PCS patients.

The researchers found that the mucosa of the upper airways remains structurally altered months after infection—even in the absence of active viral infection. Two key signaling molecules, TNFα and TGFβ, were identified as drivers of persistent misprogramming of epithelial cells. These inflammatory processes impair the regeneration of the ciliated epithelium and may explain typical PCS symptoms such as respiratory difficulties and increased susceptibility to infections. DZL scientists confirmed these mechanisms in innovative human airway models.

The identified signaling pathways could provide new targets for therapeutic interventions against PCS. Modulating these inflammatory pathways could help alleviate symptoms or prevent long-term damage to the nasal mucosa. Moreover, these findings may also be relevant to other chronic lung diseases.

The study was conducted within the framework of the Excellence Cluster “Precision Medicine in Chronic Inflammation” (PMI), funded by the German Excellence Strategy. PMI brings together around 400 researchers across eight institutions in Kiel, Lübeck, Plön, and Borstel. The cluster aims to accelerate the translation of interdisciplinary inflammation research into clinical practice—particularly in the areas of early detection, prediction of disease progression, and individualized therapies.

Source: New Study Uncovers Molecular Drivers of Long COVID

Original publication: Reddy, KD, Maluje, Y, Ott, F et al.: scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome. Nat Commun (2025). https://doi.org/10.1038/s41467-025-64778-0