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SARS-CoV-2 can invade the brain and directly act on brain cells, causing neuroinflammation, new animal research suggests.

Investigators injected spike 1 (S1), which is found on the tufts of the "red spikes" of the virus, into mice and found that it crossed the blood-brain barrier (BBB) and was taken up not only by brain regions and the brain space but also by other organs specifically, the lungs, spleen, liver, and kidneys.

"We found that the S1 protein, which is the protein COVID-19 uses to 'grab onto' cells, crosses the BBB and is a good model of what the virus does when it enters the brain," lead author William A. Banks, MD, professor of medicine, the University of Washington School of Medicine, Seattle, Washington, told Medscape Medical News.

"When proteins such as the S1 protein become detached from the virus, they can enter the brain and cause mayhem, causing the brain to release cytokines, which, in turn, cause inflammation and subsequent neurotoxicity," said Banks, who is also associate chief of staff and a researcher at the Puget Sound Veterans Affairs Healthcare System.

The study was published online December 16 in Nature Neuroscience.

COVID-19 is associated with a variety of central nervous system symptoms, including the loss of taste and smell, headaches, confusion, stroke, and cerebral hemorrhage, the investigators note.

Banks explained that SARS-CoV-2 may enter the brain by crossing the BBB, acting directly on the brain centers responsible for other body functions. The respiratory symptoms of COVID-19 may therefore result partly from the invasion of the areas of the brain responsible for respiratory functions, not only from the virus' action at the site of the lungs.

The researchers set out to assess whether a particular viral protein S1, which is a subunit of the viral spike protein could cross the BBB or enter other organs when injected into mice.

They found that when intravenously injected S1 (I-S1) was cleared from the blood, tissues in multiple organs, including the lung, spleen, kidney, and liver, took it up.

Notably, uptake of I-S1 was higher in the liver, "suggesting that this protein is cleared from the blood predominantly by the liver," Banks said. In addition, uptake by the lungs is "important, because that's where many of the effects of the virus are," he added.

The researchers found that I-S1 in the brains of the mice was "mostly degraded" 30 minutes following injection. "This indicates that I-S1 enters the BBB intact but is eventually degraded in the brain," they write.

Moreover, by 30 minutes, more than half of the I-S1 proteins had crossed the capillary wall and had fully entered into the brain parenchymal and interstitial fluid spaces, as well as other regions.

The researchers then induced an inflammatory state in the mice through injection of lipopolysaccharide (LPS) and found that inflammation increased I-S1 uptake in both the brain and the lung (where uptake was increased by 101%).

"These results show that inflammation could increase S1 toxicity for lung tissue by increasing its uptake," the authors suggest. Moreover, inflammation also increased the entry of I-S1 into the brain, "likely due to BBB disruption."

In human beings, male sex and APOE4 genotype are risk factors for both contracting COVID-19 and having a poor outcome, the authors note. As a result, they examined I-S1 uptake in male and female mice that expressed human APOE3 or APOE4 (induced by a mouse ApoE promoter).

Multiple-comparison tests showed that among male mice that expressed human APOE3, the "fastest I-S1 uptake" was in the olfactory bulb, liver, and kidney. Female mice displayed increased APOE3 uptake in the spleen.

"This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes," coauthor Jacob Raber, PhD, professor, Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, Oregon Health and Science University, Portland, Oregon, said in a press release.

In addition to intravenous I-S1 injection, the researchers also investigated the effects of intranasal administration. They found that although it also entered the brain, it did so at levels roughly 10 times lower than those induced by intravenous administration.

Banks said his laboratory has studied the BBB in conditions such as Alzheimer's disease, obesity, diabetes, and HIV.

"Our experience with viruses is that they do an incredible number of things and have a frightening number of tricks," he said. In this case, "the virus is probably causing inflammation by releasing cytokines elsewhere in the body that get into the brain through the BBB."

Conversely, "the virus itself may enter the brain by crossing the BBB and directly cause brain cells to release their own cytokines," he added.

An additional finding of the study is that whatever the S1 protein does in the brain is a model for what the entire virus itself does, because these proteins often bring the viruses along with them, he added.

Banks said the clinical implications of the findings are that antibodies from those who have already had COVID-19 could potentially be directed against S1. Similarly, he added, so can COVID-19 vaccines, which induce production of S1.

"When an antibody locks onto something, it prevents it from crossing the BBB," Banks noted.

Commenting on the study for Medscape Medical News, Howard E. Gendelman, MD, Margaret R. Larson Professor of Internal Medicine and Infectious Diseases and professor and chair of the Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, said the study is confirmatory.

"What this paper highlights, and we have known for a long time, is that COVID-19 is a systemic, not only a respiratory, disease involving many organs and tissues and can yield not only pulmonary problems but also a whole host of cardiac, brain, and kidney problems," he said.

"So the fact that these proteins are getting in [the brain] and are able to induce a reaction in the brain itself, and this is part of the complex progressive nature of COVID-19, is an important finding," added Gendelman, who is also the director of the Center for Neurodegenerative Disorders. He was not involved with the study.

The study was supported by the Veterans Affairs Puget Sound Healthcare System and by grants from the National Institutes of Health. The authors and Gendelman have disclosed no relevant financial relationships.

Nat Neurosci. Published online December 16, 2020. Full text

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New Evidence COVID-19 Invades the Brain - Medscape