Findings may provide insight into long-term neurological symptoms of COVID-19-ScienceDaily

Scientists find evidence that antibodies, proteins produced by the immune system in response to viruses and other invaders, are involved in attacking cells that line blood vessels in the brain, causing inflammation and damage. Did. Consistent with previous studies by the group, SARS-CoV-2 was not detected in the patient’s brain. This suggests that the virus does not directly infect the brain.

Understanding how SARS-CoV-2 can cause brain injury may help develop treatments for patients with COVID-19 who have prolonged neurological symptoms.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological processes are not well understood,” said Dr. Avindra Nath, MD, clinical director and lead author of the study at NINDS. I am. “Previously, at autopsy, the patient’s brain had vascular damage and inflammation, but the cause of the damage was unknown. I think this treatise provided important insights into the sequence of events.”

Dr. Nath and his team discovered that antibodies produced in response to COVID-19 could mistakenly target cells important to the blood-brain barrier. The tightly packed endothelial cells help form the blood-brain barrier, prevent harmful substances from reaching the brain, and allow necessary substances to pass through. Damage to the endothelial cells of blood vessels in the brain can lead to protein leakage from the blood. This can cause bleeding and blood clots in some COVID-19 patients and increase the risk of stroke.

For the first time, researchers have observed that immune complexes, the molecules formed when antibodies bind to antigens (foreign substances), deposit on the surface of endothelial cells in the brains of COVID-19 patients. Such immune complexes can damage tissues by causing inflammation.

This study is based on their previous study, which found evidence of brain damage caused by thinning and leakage of blood vessels. They suspected that the damage could be due to the body’s natural inflammatory response to the virus.

To further investigate this immune response, Dr. Nath and his team examined brain tissue from a subset of patients in a previous study. Nine people aged 24-73 years were selected because of signs of vascular damage in the brain based on structural brain scans. The sample was compared to a sample of 10 controls. The team used immunohistochemistry to examine neuroinflammation and immune response. Immunohistochemistry is a technique that uses antibodies to identify specific marker proteins in a tissue.

As in previous studies, researchers have found signs of vascular leakage based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells of 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-a deposit of immune complexes on the surface of the cells.

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

“Activation of endothelial cells results in platelets attached to the walls of blood vessels, forming blood clots and causing leakage. At the same time, tight junctions between endothelial cells are broken and leakage occurs,” Dr. Nath said. explained. “When a leak occurs, immune cells such as macrophages can repair the damage and cause inflammation, which causes damage to neurons.”

Researchers have found that in areas where endothelial cells are damaged, more than 300 genes show reduced expression and 6 genes are increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. It provides clues to the molecular basis of the neurological symptoms associated with COVID-19 and may provide potential therapeutic targets.

Together, these findings provide insights into the immune response that damages the brain after COVID-19 infection. However, because the virus itself was not detected in the brain, it remains unclear which antigen the immune response is targeting. Antibodies to the SARS-CoV-2 spike protein may bind to the ACE2 receptor that the virus uses to invade cells. Further research is needed to explore this hypothesis.

This study may also affect the understanding and treatment of long-term neurological symptoms after COVID-19, such as headache, malaise, loss of taste and smell, sleep problems, and “brain fog”. If the patients in the study survived, the researchers believe they are likely to have developed Long COVID.

“It is quite possible that this same immune response will persist in patients with Long COVID and cause nerve damage,” said Dr. Nath. “There may be a small, lazy immune response that continues, which means that immunomodulatory therapy may help these patients. Therefore, these findings are of great therapeutic implications. I have.”

The results suggest that treatments designed to prevent the development of immune complexes observed in the study may be potential treatments for post-COVID neurological symptoms.

This study was supported by the NINDS In-Wall Research Division (NS003130) and K23NS109284, the Roy J. Curver Foundation, and the Iowa Neuroscience Institute.