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A leaky blood–brain barrier and inflammation might account for some of the cognitive symptoms of COVID-19.
Loss of smell, headaches, memory problems: COVID-19 can bring about a troubling storm of neurological symptoms that make everyday tasks difficult. Now new research adds to the evidence that inflammation in the brain might underlie these symptoms.
Not all data point in the same direction. Some new studies suggest that SARS-CoV-2, the virus that causes COVID-19, directly infects brain cells. Those findings bolster the hypothesis that direct infection contributes to COVID-19-related brain problems. But the idea that brain inflammation is key has gotten fresh support: one study, for example, has identified specific brain areas prone to inflammation in people with COVID-191.
“The whole body of literature is starting to come together a little bit more now and give us some more concrete answers,” says Nicola Fletcher, a neurovirologist at University College Dublin.
When researchers started looking for a culprit for the brain problems caused by COVID-19, inflammation quickly became a key suspect. That’s because inflammation — the flood of immune cells and chemicals that the body releases against intruders — has been linked to the cognitive symptoms caused by other viruses, such as HIV. SARS-CoV-2 stimulates a strong immune response throughout the body, but it was unclear whether brain cells themselves contributed to this response and, if so, how.
Severe COVID could cause markers of old age in the brain
Helena Radbruch, a neuropathologist at the Charité – Berlin University Medicine, and her colleagues looked at brain samples from people who’d died of COVID-19. They didn’t find any cells infected with SARS-CoV-2. But they did find these people had more immune activity in certain brain areas than did people who died from other causes. This unusual activity was noticeable in regions such as the olfactory bulb, which is involved in smell, and the brainstem, which controls some bodily functions, such as breathing. It was seen only in the brains of people who had died soon after catching the virus.
To Radbruch, these observations suggest that inflammation caused by COVID-19 outside the brain triggers an immune response in specific brain areas early during infection, which could contribute to neurological symptoms. The team suspects that if neuroinflammation persists, it could result in the brain symptoms linked to long COVID, the complex constellation of symptoms that can last for months or years after infection. The findings were published in Nature Neuroscience1.
But how would molecules from the rest of the body influence inflammation in the brain? Research from neuroscientist Matthew Campbell and neurologist Colin Doherty at Trinity College Dublin has found that the blood–brain barrier, which separates the brain from the rest of the body, can break down during SARS-CoV-2 infection.
The team found that this barrier is more permeable in people with both long COVID and ‘brain fog’ — problems with memory, concentration and decision-making — than in uninfected people or people who have long COVID but not brain fog. The results, reported in Nature Neuroscience2, point to a clear route for immune molecules to enter the brain, where they could lead to brain fog.
The team found that these individuals’ blood was teeming with inflammatory molecules, which could potentially cross into the brain through the leaky barrier.
Although most evidence points to neuroinflammation as the source of symptoms, some studies back the direct-infection theory.
For instance, a different team at University College Dublin has found that human neurons and other brain cells in laboratory dishes can become infected with SARS-CoV-2, and even release infectious virus into their surroundings. The researchers also found that blocking a particular protein on brain cells protected them from SARS-CoV-2 infection. The virus needs to bind to this very same protein to infect other cell types, including lung cells. “This supports a model where the virus is able to directly affect the brain,” Fletcher says. The work was posted on the bioRxiv preprint server3 and has not yet been peer reviewed.
Another team successfully infected dopaminergic neurons, which use the signalling molecule dopamine to communicate. Neuroscientist Shuibing Chen at Cornell University in Ithaca, New York, and her team found that infection triggered these neurons, but not others, to enter a state called senescence, which is associated with ageing and has a characteristic gene-activity pattern that prompts cells to release immune molecules.
When the researchers analysed autopsy tissue from people who had died of COVID-19, they again saw the senescence-related gene pattern in a brain area riddled with dopaminergic neurons. Chen thinks that senescence and the resulting secretion of inflammatory factors from these cells might underlie COVID-19-induced brain damage and possibly neurological effects. The study was published in Cell Stem Cell4.
But only a small number of brain cells became infected in the lab dishes, and conclusive evidence of viral infection of the brain in people with COVID-19 is lacking.
Even Fletcher, whose study provides support for direct neuron infection, recognizes the significant contribution of immune cells. “There are data to support both theories,” she says, but “the symptoms that people are experiencing would fit with the inflammatory response.”
Ultimately, all of these studies point to potential therapeutic targets and biomarkers. For example, the diabetes medication metformin blocked viral-induced senescence in neurons in Chen’s study, making it a possible therapeutic option. But COVID-19’s brain symptoms are probably caused by a combination of factors, which would complicate treatment of cognitive problems, particularly in long COVID. “There are multiple things occurring at once,” says Campbell. “I just don’t think there’s a golden bullet.”
Sourced from Nature
