Apparently, neurological symptoms are not a result of brain infection with the SARS-CoV-2 coronavirus, which causes COVID-19
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 provided evidence for this latter theory. It was published today in the journal Nature Neuroscience*.
Headaches, memory problems and fatigue are just some of the neurological effects that occur during a coronavirus infection and can last long beyond the acute phase. Even at the beginning of the pandemic, researchers speculated that a direct infection of the brain could be the cause. “We also looked at it as a hypothesis at the beginning. However, so far there has been no clear evidence that the coronavirus can remain in the brain and not multiply at all,” 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. “The evidence that the coronavirus could infect the brain, however, comes from indirect test methods and is therefore not entirely conclusive.”
Cross section through the brainstem: neurons (blue-gray) are in close contact with immune cells (purple). The blue thread-like structures are extensions of neurons that can reach distant organs in the form of nerve fibers. According to the study, immune cells and neurons in the brainstem can be activated directly via nerve fibers as a result of pneumonia. © Charité | Jenny Meinhardt
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 shown signs 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 brain infection
For the study, the research team analyzed different areas of the brain of 21 people who died in hospital, mostly in the intensive care unit, as a result of 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 visible changes and whether there were signs of the coronavirus. They then performed detailed gene and protein analysis to identify the specific processes that had occurred in individual cells.
Like previous research teams, Charité scientists found genetic material from the coronavirus in the brain in some cases. “But we didn’t find any neurons infected with SARS-CoV-2,” says Radbruch. “We assume that immune cells absorbed the virus in the body and then reached the brain. They still carry the virus, but it does not infect the brain cells. “So the coronavirus has penetrated other cells in the body, but not the brain itself.”
The brain responds to inflammation in the body
Nevertheless, the researchers observed surprising changes in the molecular processes of some brain cells of those infected with COVID-19: For example, the cells activated the interferon signaling pathway, which is normally activated during the course of a viral infection. “It is clear that some neurons respond to inflammation in the rest of the body,” says Professor 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 Radbruch. “This molecular reaction could be a good explanation for the neurological symptoms we are seeing in patients with COVID-19.” For example, the neurotransmitters released by these cells in the brainstem could lead to fatigue. “This is because the brainstem houses collections 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. Put simply, the interpretation of our data is that the vagus nerve “recognizes” the inflammatory reaction in various organs of the body and reacts to it in the brainstem without there being an actual infection of the brain tissue,” explains Radbruch. “Through this mechanism, inflammation somehow spreads from the body to the brain, which can alter brain function.”
Time-limited response
The response of neurons to inflammation is transient, as shown by a comparison of people who died during an acute coronavirus infection with those who died at least two weeks later. 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’s possible that if the inflammation becomes chronic, it causes the neurological symptoms that often occur with long COVID in some people,” says Conrad. To confirm this suspicion, the research team plans to examine the molecular signatures in the cerebrospinal fluid of long-COVID patients in more detail.
REFERENCE
Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissue in the early and late phase of COVID-19