Many COVID-19 patients experience neurological symptoms after being infected with SARS-CoV-2, leading researchers to speculate that the virus is able to cross the blood-brain barrier (BBB) and enter the brain. New research recently published in Nature Neuroscience suggests the spike protein of the virus is able to cross the BBB in mice.
The main symptoms of infection with SARS-CoV-2 are a persistent cough, fever, and temporary loss of smell and taste, with the latter related to the central nervous system. Other neurological symptoms include headaches, seizures, twitching, nerve pain, vision impairment, vomiting, and cerebral hemorrhage, amongst others. These symptoms suggest the virus does have the ability to enter the brain. Previous studies on other coronaviruses also suggest they have the ability to cross the BBB and enter the brain, including the SARS coronavirus that caused the 2003-2004 outbreak in China.
SARS-CoV-2 gains entry into cells using the S1 subunit of its spike protein, so the researchers tested whether the S1 subunit can cross the BBB. If the S1 subunit is able to cross the BBB, there is a strong possibility that the virus can too.
The researchers injected radioiodinated S1 (I-S1) intravenously into mice and showed that i-S1 readily crossed the BBB in male mice and was also taken in by cells in other organs such as the kidney, liver, lung, and spleen. They also showed that intranasally administered I-S1 also entered the brain, although at around ten times lower levels than intravenous injection.
The researchers showed that update in the brain occurs through adsorptive transcytosis, and murine angiotensin-converting enzyme 2 is involved in update in both the brain and lung, but not in the spleen, kidney, and liver.
While the sex of the mice did not affect uptake, there was variability between males and females, with uptake faster in the olfactory bulb and kidney of males than females. This could help to explain why males tend to experience more severe symptoms than females.
The researchers suggest that the S1 protein is likely toxic to brain tissues and causes the brain to release cytokine and inflammatory products, as is the case with the gp 120 protein in HIV-1.
William A. Banks, MD, a professor of medicine at the University of Washington School of Medicine, has performed extensive work on HIV-1 and the gp120 protein and explained that both gp 120 and the S1 protein – which are both glycoproteins – function in similar ways.
Patients have difficulty breathing when they are infected with SARS-CoV-2, which can be explained by infection in the lungs, but the new research suggests that if the virus crosses the BBB, it could also cause problems in the respiratory centers in the brain. The presence of the virus in the brain could also help to explain long-COVID, where symptoms continue for many weeks or months after infection.
You can read more about the study in the paper – The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice – which was recently published in Nature Neuroscience. DOI: 10.1038/s41593-020-00771-8