Proposed Mechanistic Axis of Infections and mTOR Hyperactivation: A Multidisciplinary Review of Immune, Rheumatologic, and Psychiatric Links. — CFSMEATLAS
Proposed Mechanistic Axis of Infections and mTOR Hyperactivation: A Multidisciplinary Review of Immune, Rheumatologic, and Psychiatric Links.
Fronticelli Baldelli, Giovanni, Buonsenso, Danilo · Children (Basel, Switzerland) · 2025 · DOI
Quick Summary
This review proposes that a protein called mTOR may be the key link between infections and the long-lasting symptoms seen in ME/CFS and similar post-infection illnesses. The authors suggest that when mTOR stays overactive after an infection, it can damage the barrier that protects the brain, allow immune cells to enter brain tissue, and cause ongoing inflammation that affects how the brain works. They outline a step-by-step pathway explaining how this might happen and suggest that targeting mTOR could be a new treatment approach.
Why It Matters
Understanding the mechanism underlying ME/CFS is critical for developing effective treatments. This framework offers a testable hypothesis that could explain why infections trigger prolonged neurological and immunological symptoms in ME/CFS patients and suggests potential therapeutic targets—such as mTOR inhibitors—that could be investigated in clinical trials.
Observed Findings
Early-life infections produce durable changes in immune function and behavior
mTOR activation skews T-cell and macrophage differentiation toward pro-inflammatory states
Endothelial mTOR signaling reduces blood-brain barrier tight junction integrity and increases vesicular transport
mTOR engagement in microglia and neurons drives neuroinflammation and disrupts synaptic plasticity
This framework accounts for overlapping features in Long COVID, ME/CFS, and PANS/PANDAS
Inferred Conclusions
mTOR hyperactivation serves as a mechanistic link between post-infectious peripheral inflammation and central nervous system dysfunction
Blood-brain barrier compromise is a key step allowing immune activation and cytokines to reach the brain and perpetuate neuroinflammation
Modulating mTOR-related processes in immune, endothelial, and neural compartments may offer therapeutic opportunities for post-infectious syndromes
The convergence of Long COVID, ME/CFS, and PANS/PANDAS features supports a common mTOR-driven mechanistic pathway
Remaining Questions
Is mTOR hyperactivation demonstrable in the blood and cerebrospinal fluid of ME/CFS patients, and does its level correlate with symptom severity?
What This Study Does Not Prove
This is a hypothesis-generating review based on existing literature, not original experimental data. It does not prove that mTOR hyperactivation causes ME/CFS or that mTOR inhibitors will be effective treatments. The proposed pathway requires empirical validation through direct measurement of mTOR activity, barrier permeability, and immune markers in ME/CFS patients.