News release
Tuesday, July 5, 2022
The findings could provide insight into the long-term neurological symptoms of COVID-19.
A study by the National Institutes of Health describes the immune response caused by COVID-19 infection that damages the blood vessels in the brain and can cause neurological symptoms in the short and long term. 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.
Scientists found evidence that antibodies (proteins produced by the immune system in response to viruses and other invaders) are involved in an attack on cells lining the blood vessels of the brain, causing inflammation and damage. According to a previous study by the group, SARS-CoV-2 was not detected in the brains of patients, suggesting that the virus was not infecting the brain directly.
Understanding how SARS-CoV-2 can cause brain damage may help inform the development of therapies for patients with COVID-19 who have persistent neurological symptoms.
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, MD, clinical director of NINDS and lead author of the study. “We had previously shown damage to blood vessels and inflammation in the brains of patients at autopsy, but we did not understand the cause of the damage. I think in this paper we have gained an important insight into the cascade of events.”
Dr. Nath and his team found that antibodies produced in response to COVID-19 can be mistakenly targeted to cells crucial to the blood-brain barrier. Well-packaged endothelial cells help form the blood-brain barrier, which prevents harmful substances from reaching the brain while allowing the passage of necessary substances. Damage to endothelial cells in the blood vessels of the brain can lead to the leakage of proteins from the blood. This causes bleeding and clots in some patients with COVID-19 and may increase the risk of stroke.
For the first time, researchers observed deposits of immune complexes (molecules formed when antibodies bind to antigens (foreign substances)) on the surface of the endothelial cells of the brains of patients with COVID-19. These immune complexes can damage the tissue causing inflammation.
The study is based on his previous research, which found evidence of brain damage caused by thinned and leaking blood vessels. They suspected the damage could have been due to the body’s natural inflammatory response to the virus.
To further explore this immune response, Dr. Nath and his team examined the brain tissue of a subset of patients in the previous study. The nine individuals, ages 24 to 73, were chosen because they showed signs of damage to blood vessels in the brain based on structural brain scans. The samples were compared with those of 10 controls. The team analyzed neuroinflammation and immune responses using immunohistochemistry, a technique that uses antibodies to identify tissue-specific marker proteins.
As in their previous study, the researchers found signs of blood vessel vessels, based on the presence of blood proteins that do not normally 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 colleagues found evidence that damage to endothelial cells was likely due to an immune response, discovering deposits 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. High levels of adhesion molecules were found in the endothelial cells of brain tissue samples.
“Activation of endothelial cells produces platelets that adhere to the walls of blood vessels, causing clots to form and leaks. At the same time, tight junctions between endothelial cells are disrupted by making that can be filtered out, ”Dr. Nath explained. “Once the leak occurs, immune cells such as macrophages can repair the damage, creating inflammation. This, in turn, causes damage to the neurons.”
The researchers found that in areas with endothelial cell damage, more than 300 genes showed decreased expression, while six genes increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. This may provide clues on the molecular basis of COVID-19-related neurological symptoms and provide potential therapeutic targets.
Taken together, these findings provide insight into the brain-damaging immune response after COVID-19 infection. But it is still unclear to which antigen the immune response is directed, as 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 explore this hypothesis.
The study may also have implications for understanding and treating long-term neurological symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” If the patients in the study had survived, the researchers believe they would probably have developed Long COVID.
“It is very possible that this same immune response persists in long-term patients with COVID-19, causing neuronal injury,” Dr. Nath said. “There could be a small indolent immune response that continues, which means that immunomodulatory therapies could help these patients. Therefore, these findings have very important therapeutic implications.”
The results suggest that treatments designed to prevent the development of immune complexes observed in the study could be potential therapies for post-COVID neurological symptoms.
This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.
NINDS is the main funder of research on the country’s brain and nervous system. The mission of NINDS is to seek basic knowledge about the brain and nervous system and use that knowledge to reduce the burden of neurological disease.
About the National Institutes of Health (NIH): NIH, the country’s medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the leading federal agency that conducts and supports basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for common and rare diseases. For more information about NIHs and their programs, visit www.nih.gov.
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