Humer et al. (2025)
- Authors: Bart Humer, Julia C. Berentschot, Cornelia G. van Helden-Meeuwsen, L. Martine Bek, Maaike de Bie, Tobias M. Defesche, Chantal A. Boly, Manon Drost, Merel E. Hellemons, Willem A. Dik, Marjan A. Versnel
- Institutes: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, Department of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, Department of Intensive Care, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, Reinier Hage Medisch Diagnostisch Centrum (RHMDC), Laboratory Medical Immunology, Delft, The Netherlands
- Publisher: Journal of Clinical Immunology
- Link: DOI
Summary
This research identifies a clear biological signature of immune over-reactivity in Long COVID, demonstrating that patients’ immune cells are ‘primed’ to over-produce interferon when they encounter viral signals. By linking this exaggerated response directly to the severity of patient fatigue, the findings validate patient experiences as a measurable consequence of immune dysregulation. This work provides a strong rationale for future clinical trials testing existing interferon-blocking medications to alleviate symptoms.
What was researched?
The study investigated whether immune cells (PBMCs) from Long COVID patients exhibit a hyperresponsive type I interferon (IFN-I) response when exposed to synthetic viral mimics.
Why was it researched?
Researchers sought to test if the chronic symptoms of Long COVID are driven by a ‘trained’ or hypersensitive immune system, potentially caused by lasting epigenetic changes following the initial infection.
How was it researched?
The team collected immune cells from two distinct Long COVID cohorts and healthy controls, stimulating them with viral DNA/RNA mimics (G3-YSD and 3p-RNA) targeting the cGAS and RIG-I pathways. They then measured the resulting IFN-I bioactivity using a reporter cell line and assessed correlations with fatigue severity scores.
What has been found?
Immune cells from Long COVID patients produced significantly more IFN-I bioactivity upon stimulation than those from healthy controls. Additionally, the magnitude of the IFN-I response to RIG-I stimulation was significantly associated with the severity of fatigue reported by the patients.
Discussion
The results suggest that ‘trained immunity’—a state where cells remain in high alert—may be a key driver of Long COVID pathophysiology. While the study is limited by specific cohort sizes, the results highlight the diagnostic potential of cellular response testing and the therapeutic potential of targeting the interferon pathway.
Conclusion & Future Work
The study concludes that Long COVID involves a hyperresponsive immune phenotype, establishing a biological link between immune activation and chronic fatigue. Future research is needed to evaluate whether inhibitors of this pathway can successfully treat the condition.