Infectious diseases affecting the nervous system can be caused by various factors, including bacteria, fungi, parasites, and viruses belonging to different families such as the rabies virus, herpes simplex virus, EBV, Zika virus, euthero virus, and SARS-CoV-2. Viral brain infections manifest in a range of neurological symptoms, including headache, fever, confusion, seizures, and loss of taste or smell.
In severe cases, viral brain infections can lead to encephalitis, meningitis, and potentially irreversible neuronal defects like paralysis and death. While these clinical signs can be attributed to the death of infected neurons, some viral infections do not kill host cells. Consequently, the chronic neurological sequelae associated with these infections cannot be explained solely by neuronal death. This suggests the presence of other neuropathic mechanisms of viral infection that result in brain dysfunction.
On June 7, 2023, researchers from the University of Queensland published a paper titled "SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity" in Science Advances.
This study is the first to demonstrate that SARS-CoV-2 infection in the brain leads to fusion between neurons and between neurons and glia. This abnormal cellular fusion disrupts neuronal activity, resulting in chronic neurological symptoms. These findings provide new insights into the mechanisms by which SARS-CoV-2 and other viruses impact the nervous system, altering its function and leading to neuropathology. Additionally, they offer a potential explanation for the persisting neurological effects observed in SARS-CoV-2 infection, commonly referred to as long-term COVID-19.
In non-neuronal tissues, enveloped and eutherian viruses fuse with host cell membranes by utilizing specialized molecules called fusogens. These viruses then hijack cellular machinery to produce viral components. The newly synthesized viral fusogens modify the cell membrane, enabling fusion with neighboring cells. This fusion leads to the formation of multinucleated syncytia, facilitating viral spread within the tissue without the need to release viral particles into the extracellular space.
Indeed, in April 2021, a research paper was published in Cell Death & Differentiation by the team of researchers, Qiang Sun from the Military Medical Research Institute, Professor Hongyan Huang from Capital Medical University, and Professor Liang Liu from Tongji Medical College of Huazhong University of Science and Technology. This study identified the prevalent presence of a heterogeneous cell-in-cell structure formed by multinucleated syncytia and lymphocytes in the lung tissue of COVID-19 patients. It was shown that this unique structure resulted from the fusion of lung epithelial cells and internalization of lymphocytes mediated by the spike protein (S protein) during SARS-CoV-2 infection.
In the nervous system, which consists of discrete neurons functioning as individual units, development and information exchange rely on biological, chemical, and electrical signals rather than intercellular fusion. The independent function of neurons is crucial for the normal operation of the nervous system. However, it remains unknown whether viral infections and subsequent viral fusogens can induce neuronal fusion, leading to the formation of multinucleated syncytia capable of permanently altering neural circuits and function.
In this recent study, researchers from the Queensland Brain Institute at the University of Queensland investigated how viruses impact neurological function. They discovered the presence of SARS-CoV-2 in the brains of long-term COVID-19 patients several months after infection. These viruses induce a previously unknown process of cell fusion in brain neurons. Once infected, the S protein appears on the neurons, and upon fusion, the neurons do not die but either start firing synchronously or cease functioning altogether.
The team specifically observed SARS-CoV-2-induced fusion between neurons and between neurons and glia in mouse and human brain-like organoids. This fusion was mediated by a viral fusogen that could be replicated by expressing the S protein or the unrelated fusogen p15 from the baboon orthoreovirus.
Furthermore, the team demonstrated that this virus infection-induced neuronal fusion is a progressive event leading to the formation of multicellular syncytia and the spread of macromolecules and organelles within them.
Finally, using Ca2+ imaging techniques, the team revealed that these neuronal fusions severely impair neuronal activity.
To illustrate the impact, the team drew an analogy between neurons and wires connecting light switches in a kitchen and bathroom. When neurons fuse, it is similar to turning on both the kitchen and bathroom lights simultaneously or not being able to turn on either, which is clearly undesirable.
This discovery also offers a potential explanation for the persistent neurological effects observed in individuals infected with SARS-CoV-2.