While Covid-19 is typically associated with respiratory symptoms, a significant number of patients also present with neurological complications, ranging from headaches and dizziness to fatal microclots in the brain. According to a new study in the journal Neurobiology of Disease, these effects arise due to the ability of spike proteins on the SARS-CoV-2 virus to disrupt the blood-brain barrier.
Since the early days of the pandemic, scientists have known that the virus uses spike proteins to attach to certain receptors on the surface of host cells. These proteins have a particularly strong affinity for an enzyme called ACE2, which the virus uses as a gateway into the cells it invades. The fact that ACE2 is widely expressed in the endothelial cells that line the lungs therefore makes the respiratory system highly susceptible to the virus.
However, until now it had not been established whether ACE2 is also present on the endothelial cells that form the blood-brain barrier. To investigate, the study authors examined post-mortem brain tissue and found that the enzyme is indeed expressed throughout the vasculature of the frontal cortex, indicating that the coronavirus may have a way into the central nervous system. Moreover, ACE2 was found to be upregulated in the brains of people who had suffered from dementia and hypertension, suggesting that the virus may pose an elevated risk to those with these conditions.
The researchers then introduced the spike proteins to brain endothelial cells in a petri dish and observed that this decreased the electrical resistance of the cell culture, suggesting that it had become leaky. This was then confirmed when the study authors noted that the cells had become more permeable, indicating a loss of barrier function.
Closer analysis revealed that the presence of SARS-CoV-2 spike proteins triggered an inflammatory immune response in brain tissue, much like it does in the lungs, therefore illuminating the pathway by which the virus produces neurological symptoms. Further tests using microfluidics that are designed to mimic human brain capillaries showed that these too became more permeable in the presence of SARS-CoV-2 spike proteins.
"Our findings support the implication that SARS-CoV-2, or its shed spike proteins circulating in the blood stream, could cause destabilization of the blood-brain barrier in key brain regions," explained principal investigator Servio Ramirez, a professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine at Temple University, in a statement. "Altered function of this barrier, which normally keeps harmful agents out of the brain, greatly increases the possibility of neuroinvasion by this pathogen, offering an explanation for the neurological manifestations experienced by Covid-19 patients."
