A research paper published last week in Science Advances, and a related story about it in Science, reported a previously unknown effect that SARS-CoV-2, the virus that causes COVID-19, has on brain cells. This effect might explain why some infected individuals experience brain fog. In particular, earlier strains of SARS-CoV-2 seem to expose affected individuals to higher risks for depression, brain fog, and substance abuse as far out as a year post-infection.
The paper in Science Advances, published by researchers at the University of Queensland in Brisbane, Australia, along with colleagues at Macquarie University in Sydney and the University of Helsinki, Finland, revealed that SARS-CoV-2 can cause different types of brain cells to fuse together. They showed that following infection, neurons fused with other neurons. They also fused with glial cells, a major cell type in the brain responsible for neuronal homeostasis, which maintains a chemical and physiological environment that supports healthy neuronal function. Glial cells fused with each other, and neurons and glial cells also fused.
This formed large masses of continues cell ‘blobs’ called syncytia, which allowed structures inside the cells (organelles) to ‘flow’ from one cell to another in ways that should not occur. The scientists also showed that neuronal signaling was affected. Importantly, astrocytes, one of three types of glial cells in the brain, have the ability to cross talk with neurons, in addition to their homeostatic roles, and may also participate in information processing. So the pathological effects of cell fusion caused by SARS-CoV-2 infection could possibly affect information processing in the brain in both neurons and astrocytes.
It is important to note though that these studies were done using cells in a laboratory setting in isolated cells in a dish and in human-derived brain organoids. Brain organoids are self-organizing structures that share certain anatomical and functional properties with the intact brain. They are derived from induced stem cells that become neurons and glial cells. Because of the restricted and limited nature of the experiments, additional work needs to be done to understand if and how the effects observed in a dish translate to clinical effects experienced by humans. Neuronal syncytia have not yet been identified in patients that have passed away from COVID-19.
Prior studies suggested that SARS-CoV-2 can induce the fusion of other cells types. In some cases, autopsies of COVID-19 patients have shown syncytia in the lungs, which likely contribute to respiratory symptoms. Similar to other viruses, SARS-CoV-2 induced cell fusion may facilitate the spread of the virus within an organ without the need for it to infect new cells. Similar to how cellular structures are able to move between fused cells, the virus could spread without the need for additional infections.
To investigate whether cell fusion occurred in brain cells, the researchers genetically modified two populations of mouse neurons in a dish. One group expressed a red fluorescent molecular marker, while the other expressed a green one. When SARS-CoV-2 was introduced, the cells fused, appearing yellow, a mix of the red and green. Similar results were observed when they repeated the experiments in brain organoids.
A critical factor in the cellular fusion processes seems to be the binding of spike proteins on SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2), a ubiquitous protein found on the surface of mammalian cells. Binding to ACE2 seems to trigger fusion between cells.
However, the structure of the neuronal syncytia were different from those observed in the lungs. Fusion in lung cells occurred between the cell bodies themselves, but fusion between neurons seemed to occur primarily along dendrites and axons, the parts of the neuron responsible for integrating incoming signals from other neurons (the dendrites) and the cable-like process that passes action potential electrical signals to other downstream neurons (the axon).
The fusion that occurs seems to disrupt normal signaling and communication between neurons. Individual neurons are self-contained tiny computational machines onto themselves. Neurons activate and fire electrical signals to other neurons independently from whatever other neurons are doing. But when neurons fused neurons after exposure to SARS-CoV-2, 90% fired simultaneously, while the remaining 10% did not fire at all. Such synchronization between neurons resembles a seizure, and could disrupt signaling and information processing sufficiently to manifest clinically as brain fog.
Although more research is needed, these results offer a plausible pathophysiological explanation for the effects of SARS-CoV-2 on the brain that might account for the cognitive effects of long-COVID. And beyond COVID-19, scientists pointed out that neuronal fusion could be a relevant mechanism that other viruses that infect the brain take advantage of also, such as for example the rabies virus.
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