COVID harms the brain through inflammation, not infection

The global battle against COVID-19 has unveiled many mysteries about how the virus affects the human body, including its impact on the brain. 

Early in the pandemic, the direct infection of the brain by SARS-CoV-2 was considered a potential cause for the neurological symptoms observed in patients.

But now, research conducted by Charité-Universitätsmedizin Berlin  has provided evidence that points in another direction. 

Complex interactions 

The detailed study offers insight into the complex interaction between the virus, the immune system, and brain function, shedding light on the underlying mechanisms that lead to neurological symptoms in COVID-19 patients.

One of the most perplexing aspects of COVID-19 infection has been the range of neurological symptoms that patients experience, including headaches, memory problems, and fatigue, which can persist long after the acute phase of the infection has passed.

Initially, researchers theorized that these symptoms could be due to the virus directly infecting the brain.

“We took that as our hypothesis at the start, too. But so far, there has been no clear evidence that the coronavirus can persist in the brain, let alone proliferate,” explained Dr. Helena Radbruch, head of the Chronic Neuroinflammation working group at the Department of Neuropathology at Charité. 

“For that, we would have needed to find evidence of intact virus particles in the brain, for example. Instead, the indications that the coronavirus could infect the brain come from indirect testing methods, so they aren’t entirely conclusive.”

Studying COVID and inflammation 

This lack of clarity led the Charité team to explore alternative explanations for the neurological impacts of COVID-19. 

The study involved detailed molecular biology and anatomical analyses of brain tissue from 21 individuals who succumbed to severe coronavirus infections in hospital settings, typically in an ICU. 

The analyses were compared against those of nine patients who died of other causes after ICU treatment. 

While the team did find coronavirus genetic material in the brain in some cases, they discovered no neurons infected by SARS-CoV-2.

This led to the conclusion that while the virus can be carried into the brain by immune cells, it does not infect brain cells directly.

“We assume that immune cells absorbed the virus in the body and then traveled to the brain. They’re still carrying the virus, but it doesn’t infect cells of the brain. So coronavirus has invaded other cells in the body, but not the brain itself,” explained Radbruch.

Critical insights

The research suggests that neurological symptoms may arise as a side effect from the body’s powerful immune response to the virus.

Notably, the study found significant changes in molecular processes within some brain cells of those infected with COVID-19. 

These changes included an increased activation of the interferon signaling pathway, a common response to viral infections, indicating that some neurons react to inflammation elsewhere in the body.

“Some neurons evidently react to the inflammation in the rest of the body,” said Professor Christian Conrad, head of the Intelligent Imaging working group at the Berlin Institute of Health at Charité (BIH).

“This molecular reaction could be a good explanation for the neurological symptoms we see in COVID-19 patients. For example, neurotransmitters emitted by these cells in the brainstem could cause fatigue. That’s because the brainstem is home to groups of cells that control drive, motivation, and mood.”

The role of the vagus nerve 

According to the researchers, the reactive nerve cells were found primarily in what are known as the nuclei of the vagus nerve. These cells are located in the brainstem and extend to organs such as the lungs, intestine, and heart. 

“In simplified terms, our interpretation of our data is that the vagus nerve ‘senses’ the inflammatory response in different organs of the body and reacts to it in the brainstem – without there being any actual infection of brain tissue,” explained Radbruch. “Through this mechanism, the inflammation does spread from the body to the brain in a way, which can disrupt brain function.”

Broader implications of COVID inflammation

The study not only challenges the initial hypothesis that COVID-19’s neurological symptoms are due to direct brain infection but also opens new avenues for understanding how inflammation in the body can impact brain function. 

The researchers observed that the neurons’ reaction to inflammation is temporary, with molecular changes normalizing after the acute infection phase.

However, they speculate that chronic inflammation could underlie the persistent neurological symptoms seen in some long COVID patients, a theory they plan to investigate further.

“We think it’s possible that if the inflammation becomes chronic, that could be what causes the neurological symptoms often observed in long COVID in some people,” said Conrad. 

Going forward, the team is planning to study the molecular signatures in the cerebral fluid of long COVID patients.

The study is published in the journal Nature Neuroscience. 

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