SARS-CoV-2 May Alter Blood-Brain Barrier Function

Servio H. Ramirez, PhD

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A new study in Neurobiology of Disease shows that spike proteins from SARS-CoV-2, the disease that causes coronavirus disease 2019 (COVID-19), trigger an inflammatory response on primary human brain microvascular endothelial cells (hBMVECs) that may reduce integrity of the blood-brain barrier (BBB).¹

Researchers from the Lewis Katz School of Medicine at Temple University cultured hBMVECs and constructed 2D and 3D BBB models to test the effects of the spike protein subunits on the BBB. With treatment of SARS-CoV-2 subunit S1 on the model, electrical resistance reached the lowest point and plateaued at 8–12 h after the initial exposure : (10 nM concentration: mean, −7.18% [standard error (SE), ±2.64]; P <.001; for 1 nM: mean, −3.79% [SE, ±1.27]; P <.001) followed by complete recovery in the case of 1 nM and 10 nM concentrations and continued decrease in the case of 0.1 nM concentration (down to −10.78% [SE, ±3.52]; P <.001).

Treatment of SARS-CoV-2 subunit S2 at 10 nM caused resistance to drop and plateau earlier (from 6 hours to 14 hours) with an average decrease of −7.56% (SE, ±2.43; P <.001) followed by recovery by 24 hours. Concentrations of 1 nM and 0.1 nM of SARS-CoV-2 subunit S2 showed a steady gradual decrease throughout the whole experiment and reached maximum at 24 hours (−6.29% [SE, ±1.62]; P <.001; and −6.54% [SE, ±1.75]; P <.001). When treated with the SARS-CoV-2 binding domain, a dose-dependent drop of barrier occurred that reached maximum at 14 hours post-exposure (10 nM: −12.19% [SE, ±2.74; P <.001; 1 nM: −8.42% [SE, ±2.53]; P <.001); 0.1 nM: − 5.4% [SE, ±2.84]; P <.001).

Anywhere from 30% to 80% of patients experience neurological symptoms of COVID-19, including dizziness, headache, nausea, and loss of concentration. Researchers from Lewis Katz School of Medicine at Temple University provide a possible explanation for these neurological effects by showing that the spike proteins that extrude from SARS-CoV-2 increase the permeability of the BBB, potentially disrupting the delicate neural networks within the brain.

“Previous studies have shown that SARS-CoV-2 infects host cells by using its spike proteins to bind to the angiotensin-converting enzyme 2 (ACE2) on the host cell surface,” explained Servio H. Ramirez, PhD, Professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine at Temple University and principal investigator on the new study.

Ramirez and colleagues examined postmortem human brain tissue for vascular ACE2 expression, using tissues from individuals without underlying health conditions and from individuals in whom hypertension and dementia had been established. Analyses showed that ACE2 is in fact expressed throughout blood vessels in the frontal cortex of the brain and is significantly increased in the brain vasculature of persons with a history of hypertension or dementia.

According to Ramirez, “since ACE2 is a major binding target for SARS-CoV-2 in the lungs and vasculature of other organs in the body, tissues that are behind the vasculature, that receive blood from affected vessels, are at risk of damage from the virus.”

Both subunits of the SARS virus were found to affect the BBB. “This is of importance because unlike subunit 1, subunit 2 of the spike protein doesn’t bind to ACE2, meaning that a breach to the blood-brain barrier could occur in a manner that is independent of ACE2,” explained postdoctoral fellow and first author on the new report, Tetyana P. Buzhdygan, PhD.

WATCH NOW: Jennifer Frontera, MD: Comparing COVID-19 Neurologic Data​

“Our findings support the implication that SARS-CoV-2, or its shed spike proteins circulating in the bloodstream, could cause destabilization of the blood-brain barrier in key brain regions,” Ramirez said. “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.”

The long-lasting effects of altered blood-brain barrier function in the presence of SARS-CoV-2 are unknown. Moreover, as Buzhdygan explained, “the brain vasculature is extremely branched, so even a small amount of neuroinflammation can be very damaging.” Due to increased ACE2 expression, neurological damage could be extensive in COVID-19 patients with hypertension and dementia, and possibly other underlying conditions.

It also remains unknown whether the virus can invade the BBB “The viral genome has not been found yet in the specific cell types of the brain,” Ramirez noted. “The next steps in our work are to look for genomic viral copies in different parts of the brain using autopsy material from COVID-19 cases and to investigate the pathogen’s ability to neuroinvade using different cell culture and tissue-engineered constructs.”

These data are not the first to suggest a neurologic complication of the disease, and recently, NeurologyLive spoke to Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine, about her research into the virus’s effects on neurologic pathology. Frontera and colleagues found a startling association with COVID-19 and neurologic disorders—namely, that 13.5% of patients with COVID-19 hospitalized during the study developed a new neurologic disorder shortly after the onset of COVID symptoms. Among these disorders were encephalopathy, seizure, and stroke. Patients that developed neurologic disorders were more likely to be older, and these data may correlate to the associations with ACE2, hypertension, and dementia.²

Watch her discuss her data below.

REFERENCE
1. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, et. al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobio Dis. Published online Oct 11, 2020. DOI: 10.1016/j.nbd.2020.105131
2. Frontera J, Sabadia S, Lalchan R, et al. A prospective study of neurologic disorders in hospitalized COVID-19 patients in New York City. Neurology. Published online October 5, 2020. doi: 10.1212/WNL.0000000000010979