SARS-CoV-2 Spike Proteins Disrupt Blood-Brain Barrier

Spike proteins on the SARS-CoV-2 virus promote inflammatory responses that disrupt the blood-brain barrier, which could explain neurological symptoms, ranging from dizziness, headache and loss of concentration to microclots and encephalitis, a new study found.

The research, published in Neurobiology of Disease, provides a possible explanation for neurological symptoms experienced by 30 to 80 percent of patients with coronavirus disease 2019 (COVID-19).

“It has become better appreciated that this deadly pathogen (SARS-CoV-2) could have negative effects on brain function,” Servio H. Ramirez, PhD, professor at the Lewis Katz School of Medicine at Temple University and principal investigator on the new study told Contagion®. “For example, some patients with COVID-19 have reported neurological symptoms such as headache, dizziness and trouble thinking or concentrating (colloquially the term ‘COVID fog’ or ‘brain fog’ has been used). One possibility is that if the virus enters the bloodstream it could find its way into the brain. The virus uses small antennae-like projections (called spike proteins) to infect cells. The results from our study suggests that these ‘antennae-like’ projections could potentially make the blood vessels of the brain ‘leaky.’ This is bad because leaky vessels in the brain disrupt the delicate neural networks responsible for proper functioning of our ‘command center.’”

The virus enters host cells by using its spike proteins to bind to the angiotensin-converting enzyme 2 (ACE2) on the surface of the host cell. Examining postmortem human brain tissue, investigators determined that ACE2 is expressed in brain vasculature in the frontal cortex and is significantly increased in patients with a history of hypertension and dementia.

“One of the surprises was related to the spike protein,” Ramirez said. “The spike protein (those antennae described above) consist of two parts/subunits. We tested each subunit for the possibility to induce a vessel leakiness and our data shows that both subunits are capable of inducing blood-brain barrier disruption (the technical term for leakiness to brain vessels).”

In cell culture models, the investigators examined how the virus’ spike protein affected endothelial cells. Disruptions to the blood-brain barrier could occur independent of ACE2, the investigators learned, because subunit 1 binds to ACE2, but subunit 2 doesn’t.

“Our data helps explain why COVID19 patients may experience neurological symptoms, thus dispelling some of the mystery associated with the pathology of COVID-19,” Ramirez said. “Perhaps health care providers could enhance their vigilance of neurological symptoms associated with COVID-19. If the virus or its shed spike proteins can induce vascular compromise in the brain then perhaps consider ways in which the vasculature can be restored in order to protect against damage to nerve cells. Lastly, if COVID-19 patients manifest with neurological symptoms, it is important to keep in mind the possibility of long-term effects.”

More research is needed to better understand the long-term effects and to determine whether the virus can invade neurons or glial cells beyond the barrier.

“Our next steps are to look for replication of the virus in different parts of the brain,” Ramirez said. “This will help us determine what areas of the brain may be more vulnerable to attack. Also, we would like to know the effect of comorbidities (hypertension, neurodegeneration, diabetes, etc.) has of the ability for this virus to make the vessels of the brain leakier.”

Respiratory symptoms have been the primary concern of COVID-19, however, neurological complications have been a topic of interest. An assessment of 509 patients in the Chicago area found that neurological symptoms may be a greater concern for many, including younger patients with the disease. That study showed that neurological symptoms—such as myalgia, headaches, encephalopathy, dizziness, dysgeusia and anosmia—were present at disease onset in 42.2%, at hospitalization in 62.7%, and at any time during the disease course in 82.3%.