Viruses such as SARS-CoV-2, the virus that causes COVID-19, can induce fusion between neurons, which can lead to ongoing problems in the brain, according to new research published in Science Advances. The study provides new insights into the neuropathological mechanisms underlying viral brain infections and their impact on neuronal circuitry and function.
The researchers conducted this study to investigate how viral infections can affect the nervous system and cause neurological symptoms. They focused on understanding the mechanisms by which viruses can infect neurons and potentially alter the normal functioning of the brain.
“Fusogens are very fascinating molecules that are necessary in every organism to merge cells, which is a common occurrence in a number of normal developmental processes, such as fertilization (sperm-egg fusion), formation of the placenta (fusion of thousands of cells), muscle development, and others,” explained study author Massimo A. Hilliard (@HilliardLab), a professor and NHMRC Investigator at the Clem Jones Centre for Ageing Dementia Research at The Queensland Brain Institute.
“In some species, such as the nematode worm C. elegans, fusogens are present in the nervous system and are utilized to sculpt some dendritic arbours, as well as to repair severed axons upon injury where they function as a molecular glue to stitch the two separated fragments back together. We have been interested in how fusogens are regulated in neurons, and in 2020 discovered that if they are deregulated – i.e. expressed in higher amounts or in the wrong place and time – they can cause neurons to fuse.”
“Importantly, the fusogens present in our body and in other animals are originally derived from viruses, and thus we decided to test whether viruses themselves, such as SARS-CoV-2, as well as their viral fusogens alone, such as the Spike S protein, can cause neurons to fuse, which they invariably do,” Hilliard said.
To conduct the study, the researchers used various methods and techniques. They obtained DNA sequences of specific viruses from a database and designed plasmids to study the viral proteins. They cultured different types of cells, including human embryonic kidney cells and neuronal cells, in the laboratory. They also used mouse models and brain organoids derived from human embryonic stem cells.
In their experiments, the researchers infected the cultured cells and brain organoids with the SARS-CoV-2 virus, which causes COVID-19. They examined the effects of the virus on the neurons, including whether it could cause neuronal fusion and the formation of syncytia (multinucleated cells). They also performed genetic modifications on certain viral proteins to better understand their role in viral infection.
The researchers found that the SARS-CoV-2 virus was able to infect neurons and cause fusion between neighboring cells, resulting in the formation of syncytia. Multinucleated syncytia are structures formed when multiple cells fuse together, resulting in a single large cell with multiple nuclei.
“Perhaps, one of the surprising elements in our findings is that fused neurons do not die,” Hilliard told PsyPost. “Instead, they either start functioning in synchrony or stop functioning altogether.”
This fusion allows the viruses to spread within the neurons without the need for release into the extracellular space. The presence of viral fusogens, molecules that facilitate fusion, can potentially lead to the permanent alteration of neuronal circuitry and function.
According to the researchers, many other viruses cause cells to fuse in other parts of the body but can also infect the nervous system and cause similar problems. “These viruses include HIV, rabies, Japanese encephalitis, measles, herpes simplex virus and Zika virus,” said co-author Ramon Martinez-Marmol in a news release. “Our research reveals a new mechanism for the neurological events that happen during a viral infection. This is potentially a major cause of neurological diseases and clinical symptoms that is still unexplored.”
“The take home message from our study is that viral infections can cause neurons to fuse, resulting in their malfunction,” Hilliard explained. “This, on its own, represents a new neuropathological mechanism. Moreover, based on our results, we predict that this effect of neuronal fusion is not limited to SARS-CoV-2 virus, but potentially expands to a variety of other viruses that impact the brain. Preventing viral infection is thus extremely important to minimize these new pathological consequences.”
The findings contribute to the knowledge of viral pathogenesis in the brain and may have implications for the development of treatments and interventions for viral brain infections.
“This discovery opens a number of important questions and challenges. First and foremost, can we detect fusion occurring in patients’ brains? This will already be difficult on donated brains, but even more so in a non-invasive manner in living people,” Hilliard told PsyPost.
“Second, can fusion be reversible? We think this is a non-reversible process, but we do not have yet solid evidence on this aspect. Can toxic aggregates, such as those observed in neurodegenerative diseases, spread between neurons via fusion?”
“Finally, as residuals of past infections, we carry in our genome a large number of silent viral genes, including those encoding fusogens,” Hilliard added. “Is the reactivation of these viral genes with consequent neuronal fusion a still unexplored cause of brain disease? I imagine the next few years to be characterized by a steep growth of interest in this field of biology and medicine, and that we will have answer to many of these key questions.”
The study, “SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity“, was authored by Ramón Martínez-Mármol, Rosina Giordano-Santini, Eva Kaulich, Ann-Na Cho, Magdalena Przybyla, Md Asrafuzzaman Riyadh, Emilija Robinson, Keng Yih Chew, Rumelo Amor, Frédéric A. Meunier, Giuseppe Balistreri, Kirsty R. Short, Yazi D. Ke, Lars M. Ittner, and Massimo A. Hilliard.
