(C) Daily Kos This story was originally published by Daily Kos and is unaltered. . . . . . . . . . . COVID can cause neurons to fuse together, causing some to completely stop working [1] ['This Content Is Not Subject To Review Daily Kos Staff Prior To Publication.'] Date: 2023-06-21 It’s been known for some time that SARS-CoV-2 can cause clusters of cells to form. These clusters, called syncytia, are often found in the lungs when a person contracts severe COVID-19. The cells fuse together, assisted by adhesion factors. “Most of the cells end up dying,” said the authors of a study in 2020 that specifically looked at pneumocytes in the lungs. Scientists now have found that syncytia can form among neurons, too. The findings were published this month in the article “SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity” (Science Advances, 2023). Ramón Martinez-Mármol and colleagues performed the research. Martinez-Mármol and associates found that the SARS-CoV-2 spike protein is the culprit, leading to multinucleated cells (i.e., cells with more than one nucleus) and subsequent neuronal malfunction. The authors explain that “[i]n non-neuronal tissues, enveloped viruses and reoviruses use specialized molecules called fusogens to fuse with host membranes and enter cells.” SARS-CoV-2 is an enveloped virus. Once inside the cell, the virus hijacks the cell’s machinery, creating particles that “redecorate” the membrane of the cell to allow for fusion with nearby cells. “This results in the formation of multinucleated syncytia, which allow viral propagation ‘from within,’ without the need for virion release into the extracellular space,” the authors state. In other words, the virus causes cells to fuse so that they become one cell with multiple nuclei, and these cells can then fuse with others. This allows the virus to spread in a way that may help it evade the immune system. Watch the fusion in real time: The scientists used several different methods to understand this process. They used murine (i.e., mouse)-derived brain cells that had been programmed to express human ACE2 (hACE2). (ACE2, you’ll remember, is the main entryway for the virus to enter cells via the spike protein. ACE2 is widely expressed in brain tissue.) They also utilized human embryonic stem cell-derived 3D brain organoids to observe the process in real time in material that most resembles how the virus would behave in an actual human brain. The scientists found concordant results: Similar to what was observed after infection of 2D neuronal cultures, we found that SARS-CoV-2-infected brain organoids exhibited neuronal syncytia formed by GFP [i.e., green fluorescent protein]-interconnected neurons. Hover for description of the images. Why were they using green fluorescent protein? This use of color allowed the scientists to track the movement of cellular components to see if the cells actually fused. Indeed, with the murine cells, they also had generated cells that encoded mCherry, another color-tracking protein. With these two different colors, Martinez-Mármol and colleagues were able to observe which cells contained both, which indicated fusion. They detected “the presence of both the GFP and mCherry fluorescent proteins for all the SARS-CoV-2 titers used.” Fusion is evident. Hover for description. They also performed parallel experiments with p15, a fusogen isolated from a baboon reovirus (known as BRV, baboon orthoreovirus). p15 is similar to the spike protein, except it does not require any intermediary receptor proteins as SARS-CoV-2 does. The experiments demonstrated that the spike protein behaves much in the same way as p15 does in terms of cell fusion capability. With both p15 and spike S, we observed not only neuron-neuron fusion but also neuron-glia and glia-glia fusion when the fusogens were expressed in these cell types[,] a result that mimics our observation with SARS-CoV-2 infection. p15 and spike S create similar bridges. Hover for description. (We’ll touch more on these different fusion types later.) With the parallel capacity of p15 and the spike protein in mind, the researchers performed a rather ingenious experiment where they utilized a different color-tracking scheme. I quote at length: We cotransfected neurons with the photoconvertible fluorescent protein Kaede, which shifts from green to red fluorescence upon illumination with ultraviolet (UV) light (350 to 400 nm), together with either p15 or spike S and hACE2. After identification of interconnected adjacent green fluorescent neurons, we photoconverted the green Kaede fluorophore by applying brief pulses of UV light in a small region of one neuron (donor). The newly generated red photoconverted Kaede molecules rapidly diffused to the adjacent neuron (acceptor). This diffusion was measured as a decrease in the red fluorescence within the donor neurons[,] with a concomitant increase in the acceptor neurons[,] thereby conclusively demonstrating the existence of an active cytoplasmic bridge between p15-fused neurons and between spike S—hACE2-fused neurons. “In the absence of fusion, red Kaede remained within the photoconverted neuron,” the researchers said. It was clear that, with the tracking of this color-changing protein, the cells shared molecules between each other, thus showing the formation of these bridges. Mitochondria march across the bridge. The experiments further demonstrated that these fusion bridges could bring together cells that are nearby but do not necessarily abut. Thus the fusion could occur across distance. Moreover, these bridges, which reached “variable lengths that could extend over hundreds of micrometers,” could allow very large molecules to be transferred from one cell to the next. This could even include cellular organelles, such as mitochondria. [S]haring large molecules implies a possible mechanism for the spread of toxic aggregates as observed in several neurodegenerative diseases and could also represent a mechanism of viral spreading that eludes the immune system. The scientists also found that, “[u]pon SARS-CoV-2 infection, glial cells expressing hACE2 were also positive for the spike S protein[,] and we observed additional fusion phenotypes, including neuron-glia … and glia-glia fusion.” Glia are the supporting cells of the nervous system; neurons are those that communicate using what are known as action potentials. Glia do not participate in this form of communication. This is important, as “[e]very neuron that fused with glial cells presented a complete loss of neuronal activity.” Fusion destroyed functionality in the glia-fused neurons. Importantly, neuron-neuron fusion retained some, though altered, function. After fusing differentiated neurons using p15, the researchers measured neuronal activity as demonstrated by the activity of calcium ions (Ca2+). It’s through calcium signaling that neurons are able to propagate electricity down their axons (tails) to communicate with other neurons. The majority (~90%) of fused neurons resulted in synchronized neuronal activity[,] with overlapping of Ca2+ peaks[,] whereas the remaining 10% displaced a complete loss of neuronal activity. A close evaluation of the latter subpopulation of cells revealed that it corresponded to those neurons that were fused tightly at the level of their somas. That means that those that fused at the level of their cell bodies could no longer function properly, but those that joined at other junctions could continue to be viable and somewhat functional. However, these cells lost the ability to communicate flexibly but instead could only respond as a fused unit with the whole of the syncytium. Instead of a switchboard, they became a circuit. p15 induces growth of syncytium over time compared to empty vector. Hover for description. The authors conclude, Our results indicate that viral infections, driving the expression of viral fusogens, can initiate the irreversible fusion of brain cells, causing alteration in neuronal communication and revealing a possible pathomechanism of neuronal malfunction caused by infection. They speculate that this mechanism could be a process present in many other viral infections, such as HIV, Zika virus, rabies, Japanese encephalitis, herpes simplex virus, polio, measles, cytomegalovirus, and several others. They note that “neuronal fusion can easily be missed if searching for classical multinucleated syncytia.” In other words, it’s possible that this mechanism has been there all along but had escaped the attention of science until now. At the moment, it remains to be seen what the ultimate implications of these findings are. Martinez-Mármol and his colleagues state that the fusion is permanent, though it leaves the organism with some functionality in most of the cells affected. In the context of SARS-CoV-2, the World Health Organization estimates that, through June 7, 2023, more than 103 million cases of COVID-19 have been confirmed in the United States. I should note that the researchers make a point that the spike protein that is in vaccines has been changed in conformation at the molecular level, so it cannot produce these effects. So take this as a reminder to get vaccinated and renew your vaccination when you are able: training your immune system may be the best way, in the event that you are exposed to the virus, to keep this from happening. (Paxlovid might provide some protection, too.) [END] --- [1] Url: https://www.dailykos.com/stories/2023/6/21/2176747/-COVID-can-cause-neurons-to-fuse-together-causing-some-to-completely-stop-working Published and (C) by Daily Kos Content appears here under this condition or license: Site content may be used for any purpose without permission unless otherwise specified. via Magical.Fish Gopher News Feeds: gopher://magical.fish/1/feeds/news/dailykos/