Spike Protein Reservoirs Activate Mast Cells and Microglia to Drive Neuroinflammation and Long COVID
Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 17, 2026 1 hour, 13 minutes ago
Medical News: Scientists are shedding new light on why millions of people continue to suffer from Long COVID months or even years after recovering from a SARS-CoV-2 infection. A new scientific review suggests that lingering spike protein trapped in reservoirs within the body may continuously activate the brain's immune system, triggering chronic inflammation that could explain persistent brain fog, fatigue, memory loss, anxiety and other neurological complications.
Persistent spike protein reservoirs may trigger mast cells and microglia, creating chronic brain inflammation
that could drive many neurological symptoms of Long COVID.
The review was conducted by researchers from the Institute for Neuro-Immune Medicine at Nova Southeastern University in Florida, the Department of Immunology at Tufts University School of Medicine in Boston, and the Department of Natural Sciences, School of Science and Technology at Deree–The American College of Greece in Athens.
Persistent Spike Protein May Continue Damaging the Brain
Although COVID-19 is often viewed as an acute viral illness, growing evidence suggests that pieces of the virus—particularly the spike protein—can remain in the body long after the infection has resolved. According to the review, these persistent spike proteins may accumulate in tissue "reservoirs," especially in the meninges, the protective membranes surrounding the brain, as well as in other tissues such as the gut.
The researchers propose that these spike protein reservoirs continually stimulate mast cells, specialized immune cells found in large numbers around brain blood vessels and within the meninges. Once activated, mast cells release a wide range of inflammatory, neurotoxic and vasoactive substances that, in turn, activate microglia—the brain's resident immune cells.
This creates a vicious cycle of chronic neuroinflammation that may continue even without an active viral infection.
Mast Cells and Microglia Create a Self-Sustaining Inflammatory Loop
One of the review's most important findings is the growing evidence that mast cells and microglia communicate with each other, amplifying inflammation inside the brain.
Activated mast cells release inflammatory molecules including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, tryptase and histamine. These substances activate nearby microglia, which then produce additional inflammatory chemicals that further stimulate mast cells.
The researchers describe this mast cell-microglia interaction as a feed-forward inflammatory loop capable of maintaining long-lasting brain inflammation.
At the same time, inflammatory mediators released by these cells can weaken the blood-brain barrier, allowing even more inflammatory molecules—and potentially additional spike protein—to enter the brain, worsening neurological injury.
Brain Fog and Other Neurological Problems May Have a Common Cause
This
s://www.thailandmedical.news/">Medical News report highlights that this inflammatory cycle could explain why so many Long COVID patients develop persistent neurological symptoms.
According to the review, prolonged neuroinflammation may disrupt communication between brain cells, reduce blood flow to important brain regions and increase oxidative stress, ultimately impairing memory, attention, concentration and decision-making.
Beyond brain fog, the researchers link these processes to headaches, chronic fatigue, sleep disturbances, anxiety, depression, loss of smell, peripheral nerve damage and cognitive decline. Emerging evidence also suggests that persistent activation of mast cells and microglia may contribute to changes resembling those seen in early Alzheimer's disease and Parkinson's disease, although more research is needed before confirming any direct connection.
Treatment Options Remain Limited
Despite increasing understanding of Long COVID biology, there are currently no approved therapies capable of eliminating persistent spike protein reservoirs or interrupting the chronic neuroinflammatory process.
The review discusses naturally occurring flavonoids such as luteolin and eriodictyol, which have shown promising laboratory evidence of suppressing mast cell activation, calming microglia and reducing inflammatory signaling pathways activated by the spike protein. These compounds also demonstrated antioxidant and neuroprotective properties in experimental studies. However, the authors caution that robust human clinical trials are still lacking, meaning these compounds cannot yet be considered proven treatments.
Conclusion
This review presents one of the most comprehensive explanations yet for the neurological complications of Long COVID. Rather than viewing persistent symptoms as isolated problems, the researchers propose that spike protein reservoirs continuously activate mast cells and microglia, creating a self-perpetuating cycle of neuroinflammation that damages the brain and sustains illness. While additional clinical studies are essential to validate this model and identify effective therapies, the findings offer an important framework that could reshape future Long COVID research and lead to treatments targeting the underlying disease process instead of simply relieving symptoms.
The study findings were published in the peer reviewed journal: Frontiers in Neurology.
https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2026.1853951/full
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Read Also:
https://www.thailandmedical.news/articles/long-covid
https://www.thailandmedical.news/articles/coronavirus
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