NIH study shows immune response to COVID-19 may damage brain

Antibodies produced in response to COVID-19 may mistakenly target cells essential to the blood-brain barrier, which can cause bleeds and clots in patients and increase the risk for stroke, researchers reported in Brain.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke and coauthor of the study, said in an NIH press release. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

Nath and colleagues examined brain tissue from nine patients, aged 24 to 73 years, who died between March and July 2020 during the pandemic and who tested positive for SARS-CoV-2 before or after death. All patients showed signs of blood vessel damage in the brain on postmortem MRI. Researchers assessed neuroinflammation and immune responses using immunohistochemistry and compared patient samples with 10 non-COVID controls.

The study, which was funded by NIH, shows that antibodies generated in response to COVID-19 are involved in an attack on the cells that line the brain’s blood vessels, which leads to inflammation and damage. Additionally, the researchers reported that SARS-CoV-2 was not detected in the brain, which suggests the virus does not affect the brain directly.

Nath and colleagues found that the antibodies target tightly packed endothelial cells that form the blood-brain barrier, which keeps harmful cells from reaching the brain, while allowing necessary substances to pass through. Damage to the endothelial cells in blood vessels in the brain can lead to a leakage of proteins from the blood, which can cause bleeds and clots.

According to the release, this study builds on previous research, which found evidence of brain damage caused by thinning and leaking blood vessels.

The researchers reported that an antibody-mediated attack activated endothelial cells, which express proteins called adhesion molecules that cause platelets to stick together. High levels of adhesion molecules were found in endothelial cells in the tissue samples.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time the tight junctions between the endothelial cells get disrupted, causing them to leak,” Nath said in the release. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Nath and colleagues reported that in areas with endothelial cell damage, more than 300 genes showed a decrease in expression, while six genes were increased. Those genes were associated with oxidative stress, DNA damage and metabolic dysregulation.

“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” Nath said. “There could be a small indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”

Reference:

NIH. Small NIH study reveals how immune response triggered by COVID-19 may damage the brain. https://www.nih.gov/news-events/news-releases/small-nih-study-reveals-how-immune-response-triggered-covid-19-may-damage-brain. Published July 5, 2022. Accessed July 5, 2022.