Long COVID: accumulation of spike protein associated with lasting effects on the brain

Researchers from Helmholtz Munich and LMU have identified a mechanism that may explain the neurological symptoms of Long COVID. The study shows that the SARS-CoV-2 spike protein remains in the protective layers of the brain, the meninges, and in the bone marrow of the skull for up to four years after infection. This persistent presence of the spike protein could trigger chronic inflammation in those affected and increase the risk of neurodegenerative diseases. The team, led by Prof. Ali Ertürk, Director of the Institute for Intelligent Biotechnologies at Helmholtz Munich, also found that mRNA COVID-19 vaccines significantly reduce the accumulation of the spike protein in the brain. The spike protein remaining in the skull and meninges after an infection represents a new therapeutic target.

Spike protein accumulates in the brain

A novel AI-supported imaging technique developed by Prof. Ali Ertürk's team provides new insights into how the SARS-CoV-2 spike protein affects the brain. The method makes organs and tissue samples transparent, enabling the three-dimensional visualization of cell structures, metabolic products and, in this case, viral proteins. Using this technology, the researchers were able to uncover a previously undetectable deposition of the spike protein in tissue samples from humans with COVID-19 and mice.

The study, published in the journal Cell Host & Microbe, showed significantly increased concentrations of the spike protein in the bone marrow of the skull and in the meninges, even years after infection. The spike protein binds to so-called ACE2 receptors, which are particularly common in these regions. "This could make these tissues particularly susceptible to the long-term accumulation of the spike protein," explains Dr. Zhouyi Rong, first author of the publication. Ertürk adds: "Our data also suggest that the persistence of spike protein at the borders of the brain may contribute to the long-term neurological effects of COVID-19 and Long COVID. This includes accelerated brain ageing, which could mean the loss of five to ten years of healthy brain function for those affected."

Vaccinations reduce the accumulation

Ertürk's team discovered that the BioNTech/Pfizer mRNA COVID-19 vaccine significantly reduced the accumulation of the spike protein in the brain. Other mRNA vaccines or vaccine types such as vector or protein-based vaccines were not investigated. Mice vaccinated with the mRNA vaccine showed lower spike protein levels in both brain tissue and bone marrow of the skull compared to unvaccinated mice. However, the reduction was only about 50 percent, so any residual spike protein still poses a toxic risk to the brain. "This reduction is an important step," says Ali Ertürk: "Although our results are derived from mouse models and can only be transferred to humans to a limited extent, they point to the need for additional therapies and interventions to fully manage long-term exposure to SARS-CoV-2 infections." Further studies are also needed to investigate the relevance of the results for patients with long COVID.

The Long COVID challenge

Worldwide, 50 to 60 percent of the population is infected with COVID-19. Of these, five to ten percent suffer from long COVID. This corresponds to around 400 million people who may carry significant amounts of spike proteins. "This is not just an individual health problem - it is a societal challenge," says Ertürk: "Our study shows that mRNA vaccines can significantly reduce the risk of long-term neurological consequences and thus offer crucial protection. However, infections also occur after vaccinations, which can lead to persistent spike proteins in the body. This can result in chronic brain inflammation and an increased risk of stroke and other brain damage - which then has a significant impact on public health and healthcare systems worldwide."

Advances in diagnostics and therapy

"Our results open up new possibilities for diagnosing and treating the long-term neurological effects of COVID-19," says Ertürk. In contrast to brain tissue, the bone marrow of the skull and the meninges are more easily accessible for medical examinations. Combined with protein panels - tests to detect specific proteins in tissue samples - this could make it possible to identify spike proteins or inflammatory markers in the blood or cerebrospinal fluid. "Such markers are important for the early diagnosis of COVID-19-related neurological complications," says Ertürk: "In addition, the characterization of these proteins could support the development of targeted therapies and biomarkers to better treat or even prevent neurological impairments caused by COVID-19."

Prof. Ulrike Protzer, Senior Virologist at Helmholtz Munich and the Technical University of Munich, emphasizes the far-reaching significance of the study: "Given the ongoing global impact of COVID-19 and the increasing interest in long-term consequences, this study, which provides new insights into invasion pathways into the brain and unexpected long-term interactions with the host, is particularly relevant. These results are not only scientifically groundbreaking, but also of great societal importance."