The coronavirus that causes COVID-19 can infiltrate star-shaped cells in the brain, triggering a chain reaction that can disable and even kill nearby neurons, according to a new study.
The star-shaped cells, called astrocytes, perform many functions in the nervous system and provide fuel for neurons, which transmit signals throughout the body and brain. On a laboratory plate, the study found that infected astrocytes stopped producing essential fuel for neurons and secreted an “unidentified” substance that poisoned nearby 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 fogs” and psychiatric problems that seem to accompany some cases of COVID-19, the authors wrote.
That said, the new study, published on February 7 in the prepress database medRxiv, has not yet been peer-reviewed, and an expert told Live Science that “these data are very preliminary” that still need to be verified with additional research, especially with regard to neuron death seen on laboratory plates.
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“The main message of the newspaper is that the virus can get there, [into astrocytes]”, said study author Daniel Martins-de-Souza, associate professor and head of proteomics at the Department of Biochemistry at the State University of Campinas in Brazil.” It doesn’t get there every time, but it can get there. “
Other studies have found that the coronavirus can also directly infect neurons, although the exact route of the virus to the brain is still under investigation, Live Science previously reported. The new study may 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 extracted data from three sources: cells in laboratory plates, brain tissue from deceased patients and brain scans from living patients who recovered from mild COVID-19 infections.
Given the striking differences between each arm of the study, “I find it difficult to compare the mild illness portion of the study with the severe illness cohort,” said Dr. Maria Nagel, professor of neurology and ophthalmology at the University of Colorado School of Medicine, who did not participate in the study. In other words, the brain changes seen in mild infections may not be driven by the same mechanisms as those seen in tissues of people who died of COVID-19, she told Live Science by email.
To assess the 81 patients with mild infections, the team did MRI scans of their brains and compared them with scans from 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 – showed significant differences in thickness between the two groups.
“It was surprising,” said the study’s author, Dr. Clarissa Lin Yasuda, assistant professor in the Department of Neurosurgery and Neurology at the State University of Campinas.
MRI scans were done about two months after the diagnosis of each patient with COVID-19, but “in two months, I wouldn’t expect such changes”, assuming that the patients ‘brains once looked more like the participants’ not infected, said Yasuda. Usually, only persistent long-term insults cause changes in the thickness of the cortex, she added. Chronic stress, drug abuse and infections, such as HIV have been associated with changes in cortical thickness, for example, said Nagel.
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In COVID-19 patients, regions of the cortex located just above the nose showed significant thinning, suggesting that the nose and related sensory nerves may be an important route for the virus in the brain, said Yasuda. That said, the virus is unlikely to invade everyone’s brain; but even in those who avoid direct brain infection, immune responses like inflammation it can sometimes damage the brain and thin the cortex, said Yasuda. This particular study cannot show whether direct infection or inflammation drove the differences; it just shows a correlation between COVID-19 and the thickness of the cortex, noted Nagel.
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 of COVID-19, finding brain damage in five of the 26.
Damage included patches of dead brain tissue and inflammation markers. Notably, the team also detected the genetic material SARS-CoV-2 and the virus “peak protein, “which stands out from the surface of the virus, in all five patients’ brains. These findings indicate that their brain cells were directly infected by the virus.
Most of the infected cells were astrocytes, followed by neurons. This suggests that once SARS-CoV-2 reaches the brain, astrocytes may be more susceptible to infection than neurons, said Martins-de-Souza.
For the lab
With these new data in hand, the team went to the laboratory to conduct experiments with human astrocytes derived from stem cells, testing how the coronavirus breaks down in these cells and how they react to infection.
Astrocytes do not carry ACE2 receptors, the main port that the coronavirus uses to enter cells, the authors found; this confirmed several previous studies showing a lack of ACE2 in the star-shaped cells. Instead, astrocytes have a receptor called NRP1, another entry that the spike protein can penetrate to trigger the infection, the team found. “It is known among coronavirus researchers that ACE2 is not only necessary for the virus to enter cells,” and that NRP1 sometimes serves as another portal, said Nagel.
When the researchers blocked NRP1 in laboratory experiments, SARS-CoV-2 did not infect astrocytes. As soon as the virus enters the astrocyte, the star-shaped cell begins to function differently, the authors found. In particular, the cell begins to burn glucose at a higher rate, but, strangely, the normal by-products of this process decrease in number. These by-products include pyruvate and lactate, which neurons use as fuel and to build neurotransmitters – the brain’s chemical messengers.
“And this, of course, will affect all the other functions that neurons play in the brain,” said Martins-de-Souza.
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The data on deceased patients from COVID-19 confirmed what they saw in the laboratory; for example, infected brain samples also had unusually low levels of pyruvate and lactate, compared to SARS-CoV-2 negative samples.
Back in the lab, the authors also found that infected astrocytes secrete “an unidentified factor” that kills neurons; they found this by placing neurons in a medium where astrocytes had previously been incubated with SARS-CoV-2. Dying neurons could explain, at least partially, how the cerebral cortices became so thin in COVID-19 patients with mild infections, the authors noted.
“This could somehow connect with the beginning of the story – that we saw these changes in living people,” said Martins-de-Souza. But this is only a hypothesis, he added.
“We still don’t know whether mild patients with COVID-19 have a viral infection in the brain,” so it is speculative to link changes in cortical thickness to astrocyte-related neuronal death, said Nagel. In addition, “the results on a plate may be different from those in the brain at Vivo, “then the findings need to be verified human brains, she added.
Next steps
Looking ahead, Martins-de-Souza and his team want to investigate how glucose metabolism goes wrong in infected astrocytes and whether the virus somehow diverts that extra energy to feed its own replication, he said. They are also investigating the unidentified factor that causes neuron death.
The team will also monitor live patients in the study, collecting more MRI scans to see if the cerebral cortex remains thin over time, said Yasuda. They will also collect blood samples and data on any psychological symptoms, such as mental confusion, memory problems, anxiety or depression. They have already begun to study how the observed changes in cortical thickness can relate to how brain cells send signals or build new connections with each other, according to a statement.
“We are very curious to see if these changes, both clinical and neuropsychological, are permanent,” said Yasuda. Additional studies of people with moderate to severe infections will help determine how these individuals differ from those with mild illnesses.
And in the long term, the team will monitor any new brain-related conditions that may arise in their patients, such as dementia or other neurodegenerative diseases, to determine whether COVID-19 has somehow increased its likelihood.
“I hope I don’t see that,” said Yasuda. “But everything was so surprising to us, that we may see some of these unwanted problems in the future.”
Originally published on Live Science.