Immune response triggered by COVID-19 may damage the brain

A National Institutes of Health research explains the immunological response induced by COVID-19 infection, which destroys blood vessels in the brain and may result in short- and long-term neurological problems. Researchers from the National Institute of Neurological Disorders and Stroke (NINDS) analysed brain abnormalities in nine persons who died abruptly after getting the virus in a study published in Brain.

The researchers discovered evidence that antibodies, which are proteins produced by the immune system in reaction to viruses and other intruders, are engaged in an attack on the cells lining the blood arteries in the brain, causing inflammation and damage. SARS-CoV-2 was not discovered in the patients’ brains, which is consistent with a previous research by the group, indicating that the virus was not directly invading the brain.

Understanding how SARS-CoV-2 causes brain damage might aid in the development of medicines for COVID-19 individuals with persistent neurological symptoms.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, M.D., clinical director at NINDS and the senior author of the study. “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.”

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Dr. Nath and his colleagues discovered that antibodies created in response to COVID-19 may inappropriately attack blood-brain barrier cells. Tightly packed endothelial cells contribute to the formation of the blood-brain barrier, which prevents dangerous compounds from entering the brain while enabling essential molecules to flow through. Damage to endothelial cells in blood arteries in the brain might result in protein leakage. Some COVID-19 patients get bleeding and clots, increasing their risk of stroke.

Researchers discovered immunological complexes – chemicals created when antibodies bind antigens (foreign substances) – on the surface of endothelial cells in the brains of COVID-19 patients for the first time. These immune complexes can cause tissue harm by causing inflammation.

The discovery expands on their prior findings of brain injury caused by weakening and leaky blood vessels. The researchers thought that the harm was caused by the body’s normal inflammatory reaction to the infection.

Dr. Nath and his colleagues analysed brain tissue from a subgroup of patients in the prior study to further investigate this immune response. The nine people, ranging in age from 24 to 73, were chosen because structural brain scans revealed symptoms of blood vessel damage in the brain. The samples were compared to ten controls. The researchers used immunohistochemistry, a method that employs antibodies to detect particular marker proteins in tissues, to investigate neuroinflammation and immune responses.

Researchers discovered indicators of leaky blood vessels in their previous work, based on the presence of blood proteins that ordinarily do not pass the blood brain barrier. This shows that the blood-brain barrier’s tight connections between endothelial cells are disrupted.

Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of endothelial cells, indicating that the damage was most likely caused by an immunological response.

These findings point to an antibody-mediated assault on endothelial cells. When endothelial cells are active, they produce proteins known as adhesion molecules, which induce platelets to adhere to one another. Endothelial cells in brain tissue samples were discovered to have high amounts of adhesion molecules.

“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,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Researchers discovered that in locations with endothelial cell injury, more than 300 genes exhibited decreased expression, whereas six genes showed elevated expression. These genes have been linked to oxidative stress, DNA damage, and metabolic dysfunction. This might lead to a better understanding of the molecular basis of COVID-19-related neurological symptoms, as well as novel treatment targets.

These findings provide insight into the immune response that damages the brain following COVID-19 infection. However, because the virus was not found in the brain, it is unclear which antigen the immune response is targeting. Antibodies against the SARS-CoV-2 spike protein may attach to the ACE2 receptor, which the virus uses to enter cells. More study is required to investigate this theory.

Findings might help in brain treatment

The findings might help researchers better understand and treat long-term neurological symptoms caused by COVID-19, such as headaches, exhaustion, loss of taste and smell, sleep issues, and “brain fog.” The researchers believe that if the individuals in the trial had lived, they would have acquired Long COVID.

“It is quite possible that this same immune response persists in Long COVID patients resulting in neuronal injury,” said Dr. Nath. “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.”