Inflammation inside and outside the brain may contribute to the development of neurological complications in COVID-19

COVID-19 affects hundreds of millions of people worldwide and is often associated with long-term neurological abnormalities. Common symptoms include the loss of taste and smell, dizziness, „brain fog”, headache, confusion, memory impairment, chronic fatigue, and autonomic nervous system dysfunction, which can have a major impact on the quality of life of patients. Clinical imaging studies have shown that focal tissue abnormalities can develop in many areas of the brain during the acute phase of the disease, while in post-COVID cases, a reduction in cortical thickness, loss of the integrity of the blood brain barrier or disturbances in cerebral circulation may persist for many months. However, the causes of neurological symptoms associated with the disease are currently unknown.

The Laboratory of Neuroimmunology, led by Dr. Adam Denes at the HUN-REN Institute of Experimental Medicine, Budapest, Hungary aimed to explore the role of the brain's primary immune cells, microglia, in the development of inflammation and neurological symptoms induced by SARS-CoV-2 infection. To this end, a new method was developed that allowed detailed histological and molecular biological studies to be performed on tissue samples of the brain and peripheral organs from patients who died as a result of COVID-19.

One of the main findings of the research programme is that focal microglial dysfunction and vascular inflammation are strongly correlated with the extent of neuronal damage in brain areas affected by COVID-19. Researchers have shown that P2Y12R receptors, which play a key role in microglial communication with neurons and blood vessels, are greatly reduced in brain areas where vascular inflammation was present alongside with the accumulation viral proteins.

It has also been shown that microglia dysfunction is associated with damage to mitochondria, which are also responsible for cellular energy production. Microglia dysfunction and cell death in the brain not only paralleled vascular inflammation, but also marked sites of damage to synapses and myelin sheaths that play a crucial role in neuronal communication. While the observed neuropathological changes were regionally heterogenous in different patients, pathologies were most severe in the dorsal medulla, where key autonomic centers controlling respiration and circulation are located. The cerebral cortex, hypothalamus and thalamus were also affected, and damage to these areas may be associated with the development of hormonal, autonomic nervous system, memory or sleep disturbances as a result of COVID-19.

Researchers at HUN-REN KOKI also observed that SARS-CoV-2 virus proteins accumulate inside and around blood as well as in circulating immune cells that are recruited to inflamed areas of the brain. In these areas, dysfunction of microglial cells was associated with blood-brain barrier injury. Surprisingly, the researchers found that the elevated levels of inflammatory proteins in the circulation and peripheral organs also showed a strong correlation with the inflammation and viral RNA levels in the brain tissue of each patient. They also showed the induction of inflammasomes, which regulate the recognition of viral proteins and RNA and control inflammation, in the brain tissue, lung, liver and spleen. However, no evidence for substantial infection of neurons by SARS-CoV-2 was found. This suggests that neurological complications of COVID-19 may not be due to a classical neurotropic virus infection in the brain, while vascular inflammation and metabolic dysfunction of glial cells could be a considerable contributor to these changes.

"The observed inflammatory processes may contribute to the development of neurological symptoms such as memory impairment, concentration difficulties, chronic fatigue or depression that affect many people, both during acute SARS-CoV-2 infection and in post-COVID syndrome," said Ádám Dénes, the lead investigator of the study. He added that further studies are needed to explore the extent to which the identified brain inflammatory changes contribute to the development of long-term cognitive disturbances and other neurological disorders, and how targeted inhibition of these changes could help the development of more effective therapies to alleviate the neurological symptoms of COVID-19.