Of all of COVID-19’s symptoms, one of the most troubling is “brain fog.” Victims report headaches, trouble concentrating, and forgetfulness. Now, researchers have shown that SARS-CoV-2 can cause brain cells to fuse together, disrupting their communication. Although the study was only done in cells in a lab dish, some scientists say it could help explain one of the pandemic’s most confounding symptoms.
“This is a first important step,” says Stefan Lichtenthaler, a biochemist at the German Center for Neurodegenerative Diseases who was not involved with the work.
Researchers already knew that SARS-CoV-2 could cause certain cells to fuse together. The lungs of patients who die from severe COVID-19 are often riddled with large, multicellular structures called syncytia, which scientists believe may contribute to the respiratory symptoms of the disease. Like other viruses, SARS-CoV-2 may incite cells to fuse to help it spread across an organ without having to infect new cells.
To see whether such cell fusion might happen in brain cells, Massimo Hilliard, a neuroscientist at the University of Queensland, and his colleagues first genetically engineered two populations of mouse neurons: One expressed a red fluorescent molecule, and the other a green fluorescent molecule. If the two fused in a lab dish, they would show up as bright yellow under the microscope. That’s just what the researchers saw when they added SARS-CoV-2 to a dish containing both types of cells, they report today in Science Advances. The same fusion happened in human brain organoids, so-called minibrains that are created from stem cells.
The key appears to be angiotensin-converting enzyme 2 (ACE2), the protein expressed on the surface of mammalian cells that SARS-CoV-2 is known to target. The virus uses a surface protein called spike to bind to ACE2, triggering the virus to fuse to a cell and release its genetic material inside. Seemingly, the spike protein in infected cells may also make other ACE2 on a cell trigger fusion to a neighboring cell. When the team engineered neurons to express the spike protein, only cells that also expressed ACE2 were able to fuse with each other. The findings parallel previous work in lung cells: The ACE2 receptor seems to be critical in mediating their fusion during SARS-CoV-2 infection.
However, the neuronal syncytia seen in the lab dishes and organoids also had some peculiarities that made them stand out from those seen in lungs. When lung cells fused, only the main parts of the cell body connected to each other. Among neurons, in contrast, the fusion happened farther away from the cell body, at long, thin extensions known as dendrites and axons, which are critical for cell-cell communication.
The fusions seemed to disrupt this communication. Neurons typically fire independently, propagating signals throughout the brain. But 90% of the fused neurons fired at the same time, whereas the remaining 10% stayed silent. This massive amount of synchronous activity “is almost like a seizure,” Hilliard says. Brain fog could result when this delicate communication is disrupted, he says. Hillard’s group has previously shown that inducing neurons to fuse in the nervous system of the worm Caenorhabditis elegans blunted their ability to sense odors.
“These neurons are like Siamese twins, they are joined at the hip,” says Adonis Sfera, a psychiatrist associated with Patton State Hospital and Loma Linda University who was not involved with the study. “Can they function as neurons? Nobody knows that yet. But chances are they have lost some of that function.”
It remains to be seen whether these findings will hold up in the brains of animals infected with SARS-CoV-2, however, much less humans, says Olivier Schwartz, a virologist at the Pasteur Institute. He and others say no one has really looked for neuronal syncytia in COVID-19 patients who died. Still, he says, the work makes sense and is worth exploring further. He also says neuronal fusion may be more relevant to other viruses that infect more neurons than SARS-CoV-2 typically does, such as the rabies virus. The findings might even provide another reason rabies wreaks havoc on the brain, Schwartz says.
“We think [neuronal fusion] might be really widespread,” Hilliard agrees. “It just hasn’t been seen,” he says, “I think it’s really under our eyes.”
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June 08, 2023 at 01:04AM
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Could fused neurons explain COVID-19's 'brain fog'? - Science
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