Fronticelli Baldelli & Buonsenso (2025)
- Authors: Giovanni Fronticelli Baldelli, Danilo Buonsenso
- Institutes: Medicine and Surgery, Catholic University of Rome, Rome, Italy, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Publisher: MDPI
- Link: DOI
Summary
This review offers a unifying biological framework that explains how infections can trigger chronic neuroinflammatory conditions like ME/CFS and Long COVID. By identifying mTOR as a central metabolic switch, the researchers provide a clear target for future treatments aimed at repairing the blood-brain barrier and restoring neurological function in affected patients.
What was researched?
This review explores the role of the mechanistic target of rapamycin 💊 (mTOR) as a primary metabolic link between initial infections and subsequent neurological and immune dysfunction. It specifically examines its involvement in pediatric post-infectious syndromes, including ME/CFS, Long COVID, and PANS/PANDAS.
Why was it researched?
While early-life infections are known to cause lasting behavioral and immune changes, the specific molecular mechanism connecting peripheral inflammation to the central nervous system has remained unclear. This research aims to fill that gap by proposing a multidisciplinary model of mTOR hyperactivation.
How was it researched?
The authors conducted a multidisciplinary narrative review, synthesizing findings from clinical, translational, and experimental literature. They analyzed data across immunology, rheumatology, and psychiatry to outline a stepwise mechanistic pathway of disease development.
What has been found?
The study identifies a three-step pathway where sustained mTOR activation first drives T-cell and macrophage autoimmunity. Secondly, endothelial mTOR signaling weakens the blood-brain barrier, allowing cytokines to infiltrate the brain. Finally, these factors activate mTOR in microglia and neurons, causing neuroinflammation and disrupted synaptic maintenance.
Discussion
The proposed framework effectively accounts for shared symptoms across multiple post-infectious conditions. It highlights that modulating mTOR activity could potentially address both the immune and neurological components of these complex diseases simultaneously.
Conclusion & Future Work
The researchers conclude that mTOR hyperactivation is a testable and treatable driver of post-infectious syndromes. Future research should focus on clinical trials for mTOR-targeted interventions to validate these predictions in pediatric and adult populations.