New COVID-19 Research Indicates That SARS-CoV-2 Can Penetrate The Blood-Brain Barrier
: Scientists from Veterans Affairs Puget Sound Health Care System-Seattle, University of Washington School of Medicine- Seattle and Oregon Health & Science University-Portland have in a new study demonstrated that the spike or S protein of the SARS-CoV-2 coronavirus is able to penetrate and cross the blood-brain barrier in mice models indicating that it is most probably able to do so already in humans.
Prior to this study, it was still unclear whether the SARS-CoV-2 which causes the COVID-19 disease can enter the brain. The SARS-CoV-2 virus typically binds to cells via the S1 subunit of its spike protein.
The study team shows that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood–brain barrier in male mice, and was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver.
Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood–brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.
The study findings were published in the peer reviewed journal: Nature Neuroscience. https://www.nature.com/articles/s41593-020-00771-8
Increasing evidence coupled with medically documented cases are verifying that people with COVID-19 are suffering from cognitive effects, such as brain fog and fatigue.
This new study provides researchers as to why. The SARS-CoV-2 virus like many viruses before including HIV, is bad news for the brain.
The study team found that the spike protein, often depicted as the red arms of the virus, can cross the blood-brain barrier in mice.
The new study findings strongly suggest that SARS-CoV-2, the cause of COVID-19, can enter the brain.
Lead author Dr William A. Banks, a professor of medicine at the University of Washington School of Medicine and a Puget Sound Veterans Affairs Healthcare System physician cum researcher told Thailand Medical News that the spike protein, often called the S1 protein, dictates which cells the virus can enter.
Usually, the virus does the same thing as its binding protein. Professor Banks said binding proteins like S1 usually by themselves cause damage as they detach from the virus and cause inflammation.
Professor Banks added, "The S1 protein likely causes the brain to release cytokines and inflammatory products.”
In the medical and research community science, the intense inflammation caused by the COVID-19 infection is called a cytokine storm. The immune system, upon seeing the virus and its proteins, overreacts in its attempt to kill the invadin
g virus. The infected person is left with brain fog, fatigue and other cognitive issues.
Professor Banks and his team saw this reaction with the HIV virus and wanted to see if the same was happening with SARS CoV-2.
Professor Banks said the S1 protein in SARS-CoV2 and the gp 120 protein in HIV-1 function similarly. They are glycoproteins ie proteins that have a lot of sugars on them, hallmarks of proteins that bind to other receptors. Both these proteins function as the arms and hand for their viruses by grabbing onto other receptors. Both cross the blood-brain barrier and S1, like gp120, is likely toxic to brain tissues.
Professor Banks, who has done extensive work on HIV-1, gp120, and the blood-brain barrier commented, "It was like deja vu."
Professor Banks' lab studies the blood-brain barrier in Alzheimer's, obesity, diabetes, and HIV. But they put their work on hold and all 15 people in the lab started their experiments on the S1 protein in April. They enlisted long-time collaborator Dr Jacob Raber, a professor in the departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, and his teams at Oregon Health & Science University.
The research findings could explain many of the complications from COVID-19.
Professor Banks said, "We know that when you have the COVID infection you have trouble breathing and that's because there's infection in your lung, but an additional explanation is that the virus enters the respiratory centers of the brain and causes problems there as well.”
Dr Raber said in their experiments transport of S1 was faster in the olfactory bulb and kidney of males than females. This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes.
Professor Banks warns individuals taking the virus lightly, "You do not want to mess with this virus. Many of the effects that the COVID virus has could be accentuated or perpetuated or even caused by virus getting in the brain and those effects could last for a very long time."
Thailand Medical News had pointed out certain similarities between the HIV virus and SARS-CoV-2 in earlier articles.
The study team concluded, “It is important to note that although the study shows that I-S1 crosses the BBB in mice, this may not be the case in humans. For that reason, we used in vitro models of the human BBB, which can be useful in studying mechanisms of BBB permeability. The model used in this study is derived from human iPSCs and develops a brain endothelial cell-like phenotype that includes functional BBB influx and efflux transporters and strong barrier properties that permit the study of transport without confounding effects of high baseline leakage.In this model, we did not observe significant differences in permeability for I-S1 compared to T-Alb. The apparent absence of I-S1 transport across the BBB in this in vitro model could be due to technical issues, such as blockers of I-S1 binding in the buffers. It could also mean that the iBECs did not express the cell-membrane glycoproteins necessary for I-S1 transport, or that I-S1 is not able to cross the human BBB. A note of caution regarding the validity of using monomeric S1 as a model for SARS-CoV-2 is that S1 is normally attached to SARS-CoV-2 as a trimer. However, the S1 protein may be shed from the virus in vivo, and therefore studying S1 monomers may have validity by itself although there is currently no direct evidence that spike proteins are shed from SARS-CoV-2. Altogether, our results strongly suggest that the S1 protein can cross the murine BBB through a mechanism resembling adsorptive transcytosis and be taken up by peripheral tissues independently of human ACE2.”
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