Publication
As part of the NMCB research project Immunostratify, Bart Humer, Dr. Willem Dik, and Dr. Marjan Versnel, among others, recently published a study in the Journal of Clinical Immunology on how the immune system in post-COVID patients reacts to viral stimuli. In this publication, they examine whether immune cells from people with post-COVID react more strongly to viral stimuli than those from healthy controls, and what this could mean for understanding underlying disease processes in post-COVID and other post-acute infection syndromes.
Background and Research Question
Post-COVID is associated with a wide range of often debilitating symptoms, such as severe fatigue, post-exertional malaise, and cognitive issues. The biological mechanisms behind these symptoms remain largely unknown. Therefore, the NMCB is investigating whether a dysregulated immune response plays a central role in the development and persistence of these symptoms.
Previous research has shown that acute infections can cause lasting changes in the immune system. In particular, innate immune cells can develop what is known as an epigenetic memory, causing them to react more quickly and strongly to later stimuli. This can lead to a long-term hyperactive immune profile. The researchers wanted to determine whether such a mechanism is also visible in post-COVID, specifically in the activation of the type I interferon system (IFN-I), a key component of antiviral defense.
Study design
For this study, peripheral blood mononuclear cells (PBMCs) were examined from two independent post-COVID cohorts:
- The Immunofatigue cohort, consisting of patients who had been hospitalized for COVID-19 several months earlier.
- The Microx cohort, consisting of patients with long-term post-COVID (on average, over three years of symptoms), who had experienced a relatively mild acute infection but reported persistent symptoms such as post-exertional malaise.
Both groups were compared with age- and sex-matched controls without post-COVID.
In the laboratory, the immune cells were exposed to synthetic viral stimuli that activate specific intracellular sensors: RIG-I, which detects viral RNA, and cGAS, which detects cytosolic DNA.
After this stimulation, the biological activity of type I interferons was measured using a specialized reporter assay.
Key findings
The study shows that immune cells from people with post-COVID produce significantly more type I interferons after exposure to viral stimuli than those from healthy controls. This effect was consistently found in both cohorts.
Under baseline conditions, without stimulation, there were no differences between patients and controls. The abnormal profile only emerged when the antiviral immune system was actively stimulated.
Using uncontrolled (unsupervised) hierarchical clustering, the researchers also demonstrated that participants could be divided into two distinct groups: one group with a low response to viral stimuli, primarily consisting of controls, and another group with a high response, largely made up of post-COVID patients. This indicates fundamentally different interferon response profiles between people with and without post-COVID.
In the Microx cohort, a moderate but statistically significant relationship was found between the strength of the interferon response and the severity of fatigue. This relationship was not observed in the Immunofatigue cohort. The researchers emphasize that this is an association, not a causal link
Importantly, differences in interferon response could not be explained by differences in the composition of the immune cells: the numbers of monocytes, T-cells, B-cells, and NK-cells were similar between patients and controls.
Interpretation and meaning:
The results support the idea that post-COVID involves a hyperresponsive antiviral immune system. The immune cells seem to be ‘on edge’: when they are re-exposed to viral stimuli, they produce more interferons than usual.
This fits within the hypothesis that previous infections can cause lasting epigenetic changes in immune cells and their precursor cells, leading to long-term dysregulation of the immune system. Such dysregulation may contribute to persistent symptoms like fatigue, although no direct cause-and-effect relationship can be established based on this study.
The authors point out that type I interferons, when used therapeutically, are known to cause fatigue as a side effect, which underscores the clinical relevance of these findings. At the same time, they emphasize that further studies are needed to understand
- What exactly causes this hyperresponsiveness,
- Whether this mechanism also plays a role in vivo (in the body),
- And whether the interferon system could serve as a target for future treatments.
Conclusion
This study by Humer, Dik, and Versnel, among others, shows that immune cells from people with post-COVID react excessively in vitro to viral stimuli with increased production of type I interferons. This research provides an important biological clue for understanding immune dysregulation in post-COVID and other PAIS. The findings do not offer direct treatment advice but provide a solid foundation for further research into underlying mechanisms and possible therapeutic implications.
Publication
The findings from this study have been published in the international, peer-reviewed journal Journal of Clinical Immunology. The article is available open access.
Titel
Exaggerated IFN-I Response in Long COVID PBMCs Following Exposure to Viral Mimics
Auteurs
Humer B, Berentschot JC, van Helden-Meeuwsen CG, Bek LM, de Bie M, Defesche TM, Boly CA, Drost M, Hellemons ME, Dik WA, Versnel MA
Tijdschrift
Journal of Clinical Immunology, Volume 46, Article number 5 (2026)
Gepubliceerd: 10 december 2025
Link to the publication
https://link.springer.com/article/10.1007/s10875-025-01969-w
For who wants to know more: Marjan Versnel answers questions on the project and immunesignatures in these video’s