Small NIH study reveals how immune response triggered by COVID-19 can damage the brain

Press release

Tuesday, July 5, 2022

The results could provide insight into the long-term neurological symptoms of COVID-19.

A National Institutes of Health study describes the immune response triggered by COVID-19 infection that damages blood vessels in the brain and can lead to short- and long-term neurological symptoms. In a study published in Brainresearchers from the National Institute of Neurological Disorders and Stroke (NINDS) examined brain changes in nine people who died suddenly after contracting the virus.

Scientists have found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in attacking cells lining blood vessels in the brain, leading to inflammation and damage. Consistent with an earlier study by the group, SARS-CoV-2 was not detected in the brains of patients, suggesting that the virus was not directly infecting the brain.

Understanding how SARS-CoV-2 can trigger brain damage can help inform the development of therapies for COVID-19 patients 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 study author. “We had already shown damage to blood vessels and inflammation in the patients’ brains during autopsy, but we did not understand the cause of the damage. I think in this article we have gained important insight into the cascade of events.

Dr. Nath and his team discovered that antibodies produced in response to COVID-19 can mistakenly target cells essential to the blood-brain barrier. Tight endothelial cells help form the blood-brain barrier, which prevents harmful substances from reaching the brain while allowing necessary substances to pass through. Damage to endothelial cells in the blood vessels of the brain can cause proteins to leak from the blood. This causes bleeding and clots in some COVID-19 patients and may increase the risk of stroke.

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

The study builds on their previous research, which found evidence of brain damage caused by thinning and leaking blood vessels. They suspected the damage could be due to the body’s natural inflammatory response to the virus.

To further explore this immune response, Dr. Nath and his team examined brain tissue from a subset of patients in the previous study. The nine people, aged 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 examined neuroinflammation and immune responses using immunohistochemistry, a technique that uses antibodies to identify specific marker proteins in tissues.

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

Dr. Nath and his colleagues found evidence that endothelial cell damage was likely due to an immune response, finding deposits of immune complexes on the cell surface.

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 adhere. High levels of adhesion molecules were found in endothelial cells of brain tissue samples.

“The activation of endothelial cells causes platelets to stick to the walls of blood vessels, causing clots to form and leaks. At the same time, the tight junctions between endothelial cells are disrupted, causing them to leak,” explained Dr. Nath. “Once the leak occurs, immune cells such as macrophages can come in to repair the damage, causing inflammation. This, in turn, damages neurons.

The researchers found that in areas where endothelial cells were damaged, more than 300 genes showed reduced 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 related to COVID-19 and offer potential therapeutic targets.

Together, these findings provide insight into the brain-damaging immune response following COVID-19 infection. But it is still unclear which antigen the immune response targets, as the virus itself has not been detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein bind to the ACE2 receptor used by the virus to enter cells. Further 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 headaches, fatigue, loss of taste and smell, sleep problems and “fog cerebral”. If the patients in the study had survived, the researchers think they likely would have developed Long COVID.

“It’s entirely possible that this same immune response persists in patients with Long COVID, resulting in neuronal injury,” Dr. Nath said. “There could be a small, sluggish immune response that continues, which means that immunomodulatory therapies could help these patients. These findings therefore have very important therapeutic implications.

The results suggest that treatments designed to prevent the development of the immune complexes seen 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 nation’s leading funder of brain and nervous system research. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use this knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):
The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

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