Courtesy of Yale Medicine

Yale researchers found that the coronavirus can directly infect brain cells, potentially eliciting neurological symptoms — such as the loss of taste or smell — observed in 40 to 60 percent of COVID-19 patients.

The preprint of a study led by Professor of Immunology Akiko Iwasaki and Director of Yale Center for Genome Analysis Kaya Bilguvar was released on the server bioRxiv earlier this month. In the paper — first-authored by Eric Song MED ‘22 GRD ‘22 and Ce Zhang MED ‘22 GRD ‘22 — they report that several neurological symptoms of COVID-19 could be tied to coronavirus invasion of the central nervous system.

A second study, led by Assistant Professor Shelli Farhadian and also first-authored by Song, was released as a preprint just days after Iwasaki and Bilguvar’s paper. Their findings suggest that immune responses to the coronavirus in the central nervous system could occur independently from the rest of the body.

“The biggest thing about our study is that it has shown people the possibility of neuroinvasion,” Song, who was involved with both projects, said.

Before their findings, Song and Zhang explained, many dismissed the possibility of neuroinvasion because it had not been experimentally substantiated. Now that this idea is supported by evidence, Song says that specialists might feel more encouraged to look into consequences that could stem from this phenomenon.

To explore whether SARS-CoV-2 could invade brain cells, Iwasaki and Bilguvar’s group used mouse models, post-mortem brain tissue from COVID-19 patients and brain organoids –– artificially-grown mini brains.

“I think that with a combination of the three methods, you can kind of piece together the whole picture as best as possible, especially for an organ like the brain, where you can’t take samples readily,” Song said.

According to Song, the three models complemented each other. While organoids have the limitation of not accounting for all cell types found in the brain, the mouse model is more physiologically representative. But the limitation to the mouse model is that mice probably will not react to the virus in the same way that humans would. Post-mortem brain tissue of patients who died due to COVID-19 served as a way to verify whether observations from the other models made sense — but only provided insight into the brains of critically ill patients at the moment of death.

This three-pronged approach provides compelling evidence for the scientific community to potentially accept the theory of neuroinvasion. It also allowed the Iwasaki and Bilguvar group to see that the virus is able to use ACE2 receptors –– surface proteins that serve as the coronavirus’s molecular gateway into human cells –– to infect brain cells and co-opt their reproductive machinery to multiply itself. They also observed that cerebral vasculature in mice rearranged itself in response to oxygen deprivation.

Song and Zhang said that one of their most surprising findings was that infection of specific neurons affected surrounding brain cells, resulting in their death.

“We found that once the virus infects the cell, the cell that’s infected actually doesn’t die, [but] rather the neighboring cells around it die,” Zhang said. “We hypothesize that this is because we found that the cell that’s infected with the virus undergoes sort of a hypermetabolic state in which it’s using nutrients that the other cells around it need to survive.”

According to Song, the group hypothesizes that, due to viral infection, neurons adapt and modify some metabolic pathways. The neurons respond in ways similar to what you would see in strokes, where tissues die due to oxygen deprivation.

He also told the News that the group faced challenges acquiring post-mortem COVID-19 brain tissue. Song said that pathologists had refrained from extracting brains from corpses because bone saws are required to crack skulls open and can aerosolize the coronavirus, posing contamination hazards. Due to those challenges, Song added that collaboration with professionals in France, who “graciously shared” some samples, was pivotal.

At the Yale School of Medicine, collaboration was also fundamental in bringing this study into fruition. The partnership between Song and Zhang, for example, budded from a text message and a casual conversation about their research interests.

“I think this is a lesson for people going into science … to share your research with your peers, because you never know, one day [someone] can ask you for help on something that could lead to a big collaboration like this,” Zhang said.

The second study aimed to investigate whether the immune system could play a role in prompting neurological symptoms associated with coronavirus infection.

According to Farhadian, a neuroinfectious disease doctor, understanding localized immunological impacts of the virus on the nervous system is essential to guaranteeing that COVID-19 patients expressing neurological symptoms are treated for processes occurring within the brain.

“In this study, we were specifically asking whether the immune system itself may be driving some of the neurological symptoms that have been reported in patients with COVID-19,” Farhadian said.

Upon examining biological samples from patients and using a mouse model to simulate infection, the group observed that immunological responses in the central nervous system differed from those coursing through the rest of the body — suggesting that brain-specific treatments might be warranted for diseases like COVID-19.

After looking at immune responses against COVID-19 in the brain, Song explained, the team found anti-SARS-CoV-2 antibodies in the cerebrospinal fluid of all the patients they sampled. According to Song, this made the group believe that “you [might be] having some sort of COVID-specific immune response in the central nervous system in a lot of patients.”

Farhadian told the News that it remains unknown whether coronavirus neuroinvasion can happen in asymptomatic COVID-19 patients. She explained that in HIV, for example, even the cerebrospinal fluid of those who don’t manifest overt neurological symptoms still show evidence of effects of the virus within the brain. However, as of yet, the same has not been studied or proven when it comes to the coronavirus.

Overall, Farhadian said that the study is important because it emphasizes that people can’t hope to understand what is happening in the brain simply by studying reactions in the rest of the body.

According to Song, the “million-dollar” question that remains is how the virus makes its way towards the brain in the first place.

Each study approaches neuroinvasion through a different angle. Together, they shed light on pressing scientific unknowns — heralding a new direction for research on COVID-19’s neurological effects.

More than 995,000 people across the globe have died due to COVID-19 at time of writing.

Maria Fernanda Pacheco | maria.pacheco@yale.edu