Newswise – Scientists are still unsure how neurological symptoms arise in COVID-19. Is it because SARS-CoV-2 infects the brain? Or are these symptoms the result of inflammation in the rest of the body? A study by the Charité – Universitätsmedizin Berlin has now provided evidence for the latter theory. It was published in the magazine today Natural neuroscience.*

Headaches, memory problems and fatigue are just some of the neurological effects that occur during a coronavirus infection and can last well beyond the acute phase. Even at the beginning of the pandemic, researchers suspected that a direct infection of the brain could be the cause. “We assumed that as our hypothesis at the beginning. But so far there is no clear evidence that the coronavirus can remain in the brain or even multiply,” explains Dr. Helena Radbruch, head of the Chronic Neuroinflammation working group at the Charité Clinic for Neuropathology. “To do this, we would have had to find evidence of intact virus particles in the brain, for example. Instead, the evidence that the coronavirus could infect the brain comes from indirect testing methods and is therefore not entirely conclusive.”

According to a second hypothesis, the neurological symptoms would be a kind of side effect of the strong immune response that the body uses to fight off the virus. Previous studies had suggested that this might be the case. The current Charité study now supports this theory with detailed molecular biological and anatomical results from autopsies.

No signs of direct infection of the brain

For the study, the research team analyzed different areas of the brains of 21 people who died in hospital, typically in the intensive care unit, from a severe coronavirus infection. For comparison, the researchers examined nine patients who died of other causes after treatment in the intensive care unit. First, they examined whether the tissue showed any visible changes and looked for evidence of the coronavirus. They then conducted a detailed analysis of genes and proteins to identify the specific processes that had occurred in individual cells.

Like other research teams before them, the Charité scientists found genetic material from the coronavirus in the brain in some cases. “But we did not find any neurons infected with SARS-CoV-2,” notes Radbruch. “We assume that immune cells absorbed the virus in the body and then reached the brain. They still carry the virus, but it doesn’t infect brain cells. So the coronavirus has invaded other cells in the body, but not the brain itself.”

The brain responds to inflammation in the body

Nevertheless, the researchers found striking changes in molecular processes in some cells in the brains of those infected with COVID-19: For example, the cells increased the interferon signaling pathway, which is typically activated during the course of a viral infection. “Some neurons apparently react to the inflammation in the rest of the body,” says Prof. Christian Conrad, head of the Intelligent Imaging working group at the Berlin Institute of Health at the Charité (BIH) and one of the main researchers of the study. along with wheel breakage. “This molecular response could be a good explanation for the neurological symptoms we see in COVID-19 patients. For example, the neurotransmitters released by these cells in the brainstem could lead to fatigue. This is because the brainstem is home to groups of cells that control drive, motivation and mood.”

The reactive nerve cells were mainly located in the so-called nuclei of the vagus nerve. These are nerve cells in the brain stem that extend to organs such as the lungs, intestines and heart. “To put it simply, we interpret our data in such a way that the vagus nerve “feels” the inflammatory reaction in various organs of the body and reacts to it in the brain stem – without actually infecting brain tissue,” explains Radbruch. “Through this mechanism, inflammation spreads from the body to the brain in a way that can impair brain function.”

Time-limited response

The neurons’ response to inflammation is temporary, as shown by a comparison of people who died during an acute coronavirus infection with those who died at least two weeks afterward. The molecular changes are most noticeable during the acute phase of infection, but return to normal afterwards – at least in the vast majority of cases.

“We think it is possible that if the inflammation becomes chronic, this could be the cause of the neurological symptoms often seen in long COVID in some people,” says Conrad. To investigate this suspicion, the research team now plans to examine the molecular signatures in the brain fluid of Long COVID patients in more detail.

About the study
The study was made possible by the explicit consent of the patients and/or their family members, for which the research group is grateful. The work was carried out as part of the National Autopsy Network (NATON), a research infrastructure in the University Medicine Network (NUM), the university research network for medicine funded by the Federal Ministry of Education and Research (BMBF). . NUM was initiated and coordinated by the Charité. It combines the strengths of the 36 university hospitals in Germany.

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