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The coronavirus that causes COVID-19 can infiltrate star-shaped cells in the brain, triggering a chain reaction that can turn off and even kill neighboring neurons, according to a new study.
Star-shaped cells, called astrocytes, fulfill many roles in the nervous system and provide fuel for neurons, which carry signals throughout the body and brain. In a lab box, the study found that infected astrocytes stopped producing essential fuel for neurons and secreted an “unidentified” substance that poisoned neighboring neurons.
If infected astrocytes do the same in the brain, it could explain some of the structural changes seen in patients’ brains, as well as some of the “brain fog” and psychiatric problems that appear to accompany some cases of COVID-19, the authors said. written.
That said, the new study, published Feb. 7 in the Pre-Print Database medRxiv, has not yet been peer reviewed, and an expert told Live Science that “this is very preliminary data” which has yet to be verified by further research, particularly with regard to concerns the death of neurons observed in laboratory dishes.
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“The main message from the newspaper is that the virus is capable of doing this, [into astrocytes]”said study author Daniel Martins-de-Souza, associate professor and head of proteomics at the Department of Biochemistry at the University of Campinas in Brazil.” He doesn’t always succeed, but he can. “
Other studies have shown that the coronavirus can also directly infect neurons, although the exact route of the virus through the brain is still under investigation. Previously reported Live Science. The new study could add astrocytes to the long list of cells that SARS-CoV-2 attacks, but many questions about COVID-19 and the brain remain unanswered, the authors said.
In the brains of COVID-19 patients
The new study pulled data from three sources: cells in lab dishes, brain tissue from deceased patients, and brain scans from living patients who had recovered from mild COVID-19 infections.
Given the stark differences between each arm of the study, “I think it’s difficult to compare the mild illness portion of the study to the severe illness cohort,” said Dr Maria Nagel, professor of neurology and of ophthalmology at the University of Colorado. School of Medicine, which did not participate in the study. In other words, the brain changes seen in mild infection may not be due to the same mechanisms seen in tissues of people who have died from COVID-19, she told Live Science in an email. .
To assess the 81 patients with mild infections, the team performed magnetic resonance imaging (MRI) scans of their brains and compared them with scans of 145 volunteers with no history of COVID-19. They found that certain regions of the cerebral cortex – the wrinkled surface of the brain responsible for complex processes like memory and perception – had significant differences in thickness between the two groups.
“It was surprising,” said study author Dr Clarissa Lin Yasuda, assistant professor in the Department of Neurosurgery and Neurology at the University of Campinas.
MRI scans were taken approximately two months after each patient was diagnosed with COVID-19, but “in two months I would not expect such changes”, assuming that patients’ brains once looked like those of non-participants. infected, Yasuda said. Usually, only long-term persistent insults cause changes in the thickness of the cortex, she added. Chronic stress, drug addiction and infections such as HIV have been associated with changes in cortical thickness, for example, Nagel said.
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In COVID-19 patients, regions of the cortex just above the nose showed significant thinning, suggesting that the nose and associated sensory nerves could be an important pathway for the virus to the brain, Yasuda said. However, the virus probably does not invade everyone’s brain; but even in those who avoid direct brain infection, immune responses like inflammation can sometimes damage the brain and thin out the cortex, Yasuda said. This particular study cannot show whether direct infection or inflammation drove the differences; it only shows a correlation between COVID-19 and the thickness of the cortex, Nagel noted.
To better understand how often and to what extent SARS-CoV-2 invades the brain, the team collected brain samples from 26 patients who died from COVID-19, finding brain damage in five of the 26.
The damage included plaques of dead brain tissue and markers of inflammation. Notably, the team also detected genetic material of SARS-CoV-2 and the virus “spike protein, “which sticks to the surface of the virus, in all five of the patients’ brains. These results indicate that their brain cells were directly infected with the virus.
The majority of infected cells were astrocytes, followed by neurons. This hinted that once SARS-CoV-2 reaches the brain, astrocytes may be more susceptible to infection than neurons, Martins-de-Souza said.
In the laboratory
With the new data in hand, the team went to the lab to conduct experiments with human astrocytes derived from stem cells, testing how the coronavirus enters these cells and how they respond to infection.
Astrocytes do not carry ACE2 receptors, the main gate the coronavirus uses to enter cells, the authors found; this confirmed several previous studies showing a lack of ACE2 in star shaped cells. Instead, astrocytes have a receptor called NRP1, another entry that the spike protein can penetrate to trigger infection, the team found. “It is known among coronavirus researchers that ACE2 is not just necessary for the virus to enter cells,” and that NRP1 sometimes serves as an additional gateway, Nagel said.
When researchers blocked NRP1 in lab experiments, SARS-CoV-2 did not infect astrocytes. Once the virus slips inside an astrocyte, the star-shaped cell begins to function differently, the authors found. In particular, the cell begins to burn through glucose at a higher rate, but oddly enough, the normal byproducts of this process decrease in number. These byproducts include pyruvate and lactate, which neurons use for fuel and to build neurotransmitters – the brain’s chemical messengers.
“And that will affect, of course, all the other roles that neurons play in the brain,” Martins-de-Souza said.
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Data from deceased COVID-19 patients confirmed what they saw in the lab; for example, infected brain samples also exhibited abnormally low levels of pyruvate and lactate, compared to samples negative for SARS-CoV-2.
Back in the lab, the authors also discovered that infected astrocytes secrete “an unidentified factor” that kills neurons; they discovered it by placing neurons in a medium where astrocytes had already been incubated with SARS-CoV-2. Dying neurons may explain, at least partially, how the brain cortices have become so thin in COVID-19 patients with mild infections, the authors noted.
“It could kind of connect to the beginning of the story – that we saw these alterations in living people,” Martins-de-Souza said. But that’s just a guess, he added.
“We still don’t know if patients with mild COVID-19 have a viral infection of the brain,” so it’s speculative to link changes in cortical thickness to astrocyte-related neuronal death, Nagel said. In addition, “the results of a dish may be different from those of the brain in vivo, “therefore the results must be archived human brains, she added.
Next steps
For the future, Martins-de-Souza and his team want to study how glucose metabolism goes wrong in infected astrocytes and whether the virus somehow diverts this extra energy to fuel its own replication, has he declared. They are also studying the unidentified factor causing neuron death.
The team will also follow up with the living patients in the study, collecting more MRIs to see if the cerebral cortex remains thin over time, Yasuda said. They will also collect blood samples and data on any psychological symptoms, such as brain fog, memory problems, anxiety or depression. They have already begun to study how changes seen in cortical thickness may be related to the way brain cells send signals or make new connections with each other, according to a statement.
“We are very curious to see if these alterations, both clinical and neuropsychological, are permanent,” said Yasuda. Further studies of people with moderate to severe infections will help determine how these people differ from those with mild illness.
And in the long term, the team will monitor any new brain-related illnesses that may appear in their patients, such as dementia or other neurodegenerative diseases, to determine if COVID-19 has somehow. increased their probability.
“I hope I don’t see this,” Yasuda said. “But it was all so surprising to us, that we might see some of these unwanted issues in the future.”
Originally posted on Live Science.
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