Immune response triggered by Covid-19 infection can damage brain, study finds

A National Institutes of Health (NIH) study said the immune response is triggered by: Covid-19 infection can damage the blood vessels of the brain and lead to short- and long-term neurological symptoms.

In a study published in Brain, researchers at the National Institute of Neurological Disorders and Stroke (NINDS) examined brain changes in nine people who died suddenly after contracting the virus.

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The scientists found evidence that antibodies — proteins produced by the immune system in response to viruses and other invaders — are involved in attacking the cells lining the brain’s blood vessels, leading to inflammation and damage. Consistent with a group’s previous study, SARS-CoV-2 was not detected in the patients’ brains, suggesting that the virus did not directly infect the brain.

Understanding how SARS-CoV-2 can cause brain damage could help develop therapies for COVID-19 patients with persistent neurological symptoms, according to the NIH.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, MD, clinical director at NINDS and the study’s senior author. “We had previously demonstrated damage to blood vessels and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we gained important insight into the cascade of events.”

dr. Nath and his team found that antibodies produced in response to COVID-19 can mistakenly target cells critical to the blood-brain barrier. Tightly packed endothelial cells help form the blood-brain barrier, which keeps harmful substances from reaching the brain, while allowing necessary substances to pass through. Damage to endothelial cells in blood vessels in the brain can lead to leakage of proteins from the blood. This causes bleeding and clots in some COVID-19 patients and can increase the risk of stroke.

For the first time, researchers observed deposits of immune complexes — molecules formed when antibodies bind antigens (foreign substances) — on the surface of endothelial cells in the brains of COVID-19 patients. Such immune complexes can damage tissue by triggering inflammation.

The study builds on their previous research, which found evidence of brain damage caused by thinning and leaky blood vessels. They suspected the damage may have been due to the body’s natural inflammatory response to the virus, the NIH said.

To further investigate this immune response, Dr. Nath and his team collected brain tissue from a subset of patients in the previous study. The nine subjects, ages 24 to 73, were chosen because they showed signs of blood vessel damage in the brain based on structural brain scans. The samples were compared with those of 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry, a technique that uses antibodies to identify specific marker proteins in the tissues.

As in their previous study, researchers found signs of leaky blood vessels, based on the presence of blood proteins that normally don’t cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier are damaged.

dr. Nath and his colleagues found evidence that damage to endothelial cells was likely due to an immune response — discovering deposits of immune complexes on the cells’ surface.

These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules, which cause platelets to stick together. High levels of adhesion molecules were found in endothelial cells in the brain tissue samples.

“Activation of the endothelial cells causes platelets to stick to the blood vessel walls, causing clots and leakage. At the same time, the tight connections between the endothelial cells are disrupted, causing them to leak,” explains Dr. Nathan out. “Once leakage occurs, immune cells such as macrophages can repair the damage and cause inflammation. This in turn causes damage to neurons.”

Researchers found that in areas of endothelial cell damage, more than 300 genes showed decreased expression, while six genes were increased. These genes were associated with oxidative stress, DNA damage and metabolic dysregulation. This may provide clues to the molecular basis of neurological symptoms associated with COVID-19 and provide potential therapeutic targets.

Together, these findings provide insight into the immune response that damages the brain after COVID-19 infection. But it remains unclear which antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies to the SARS-CoV-2 spike protein can bind to the ACE2 receptor used by the virus to enter cells. More research is needed to investigate this hypothesis.

According to the NIH, the study may also have implications for understanding and treating long-term neurological symptoms after COVID-19, including headaches, fatigue, loss of taste and smell, sleep problems and “brain fog.” If the patients in the study had survived, the researchers think they likely would have developed lung COVID.

“It is entirely possible that the same immune response persists in lung COVID patients, resulting in neuronal damage,” said Dr. nath. “There may be a small indolent immune response that persists, meaning immunomodulatory therapies could help these patients. So these findings have very important therapeutic implications.”

The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for neurological symptoms after COVID.

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