We have long known that certain viruses have the potential to infect the brain (e.g., the measles, polio, and herpes simplex viruses), but we have not understood why this happens in some patients and not in others, and in most cases, we don’t yet have a complete understanding of how viruses do this (fortunately, our brains have extra protections from infection than the rest of our body parts). Certain viruses, such as Epstein-Barr virus, rabies, and herpes simplex can infect neurons (nerve cells, of which there are a number of types).
If you have followed my blog for the past few years during the pandemic, then you may recall that when a virus infects you, there are a number of immune protections that go rapidly into effect. The first set of responses is from the innate immune system, the part of the immune system that is like throwing a hand grenade at the enemy – it is thrown in the general direction of the enemy, it is not specifically directed at a target (compare with the images we see from precision-guided missiles), and it blows up anything in the immediate area, whether desirable or not.
If the virus can avoid this barrage of non-specific attacks for a few days, then the body’s next attack is antibodies, like a precision-guided missile attack in that the antibodies are targeting a specific protein of the virus as their point of attack. (We do sometimes see the equivalent of friendly fire if the targeted protein of the virus is very similar in structure to one of the body’s own proteins (a concept referred to as mimicry) resulting in auto-antibodies (antibodies against ourselves), in fact, we previously have discussed that many people suffering from Long COVID or PASC (Post-Acute Sequelae of COVID-19), have autoantibodies that may contribute to the chronic inflammation seen in some of these patients.
If the virus can withstand the attack by antibodies (as is happening to some degree with the newer SARS-CoV-2 variants that have acquired immune evasion capabilities), and gain entry into cells, then they no longer face risk from antibodies while in the cell, because antibodies cannot get inside of cells.
However, cells have additional defenses against viruses attempting to enter them, (as well as once the virus is in the cell). Once viruses are detected, genes are activated that produce a chemical messenger called interferon. Interferon sends a message to all the neighboring cells that they need to go on lockdown, so to speak. When I lived in Houston, we would get hurricane warnings. That meant we would secure our doors and cover our windows with boards. That was not a guarantee that wind and rain would be kept out, but it significantly reduced the chances. Similarly, cells make modifications in the presence of interferon to make it harder for viruses to enter them in response to this interferon warning.
When we allow basically unfettered transmission of viruses, especially RNA viruses, like SARS-CoV-2, we allow viruses to use humans as laboratories to determine which mutations in the virus (these occur while the virus is replicating in the cells and producing offspring viruses), confer advantages to the virus, especially when we do not as a society work to protect immunocompromised patients from getting infected. Why would that be? Let’s imagine that I give you a puzzle of some kind to solve, that you have no familiarity with. If I give you 15 minutes and all the tries or guesses that you can make in that time, you are more likely to solve it than if I give you only 5 minutes. Now, in most healthy people, it appears that we can clear the virus in a matter of days to weeks. On the other hand, if immunocompromised patients (e.g., those being treated with chemotherapy for cancer, those on medications to treat an autoimmune disease, and those who have what are called primary immune deficiencies because a part of their immune system is not formed or working (e.g., there are people who don’t make many antibodies or do not make certain types of immune cells or who make the immune cells, but they don’t work well) are infected, they take much longer to clear the virus, and we have reports of such patients being infected for more than a year. This simply allows the virus to keep making new mutations and discovering in real time in an actual host which mutations give the virus the greatest advantage – increase in transmissibility, immune evasion, etc. When the virus is passing through healthy people, we can generally easily follow the progression of mutations, because they are generally few as healthy people generally don’t give the virus access to their body as a laboratory for very long. This is what we saw in the progression from the original virus to Alpha and to Delta. However, when Omicron first appeared, there were a huge number of new mutations that could not be predicted from the natural evolution of the virus that was circulating in the population. This led to the consensus that Omicron likely had been the result of infection of one or more immunocompromised patients from long ago that had developed many new mutations over the course of that patient’s infection before that person then transmitted it into the general population.
To continue my puzzle analogy, not only can I increase your chances of successfully solving the puzzle by giving you more time and more tries, but imagine that I allowed you to have one million people on your team to try to help solve the puzzle. As the saying goes, two heads are better than one, and for viruses, the more people we allow to be infected, the more opportunities there are to learn how to infect people better.
For SARS-CoV-2, we have seen improvements in the virus’ ability to evade innate immunity (that early part of the immune system that I analogized to a hand grenade), the ability of the virus to escape antibodies, and more recently, the virus has learned how to tell the gene that produces interferon as a warning to neighboring cells that there is nothing to see here, just relax and don’t send out that warning.
Now, the aim of viruses is to make more viruses (progeny). To do this, the virus must infect and enter cells, because the virus comes with all the instructions to make new viruses, but none of the equipment to do so. The virus basically hijacks the cells machinery that it uses to make proteins that the cell needs to function and instead commandeers the production line to follow its instructions and produce more viruses just like it. Now, if you want to make a lot more viruses, you have to infect more cells. And, essentially, that is what happens when a virus invades a cell, takes over the production line, makes more viruses, then those viruses burst through or are carried out of the cell to go find new cells to infect.
But remember when we were kids and we played tag? We had a safe location that we called “home” where if you could get there before being tagged, you were safe and could not be tagged. Well, as far as antibodies go, when the virus gets inside a cell, it has reached home and is safe (only from antibodies, but that is a whole other story that we are not going to go into right now). So, the problem for viruses is that they make new viruses, but then they spit them out right into the waiting arms of antibodies circulating in the space outside of and around cells (aptly named the extracellular space).
Hopefully by now, you are getting the concept that the body has a lot of different mechanisms to protect itself from viruses, but the more time and opportunities we give viruses to infect us, the more viruses evolve ways to get around these defenses. Well, some variants of SARS-CoV-2 (I saw this for the first time with Delta back in the fall of 2021) have developed a new trick called fusogenicity (the ability to fuse something together). And, what it was that the virus fused were cells! What that meant was that new viruses did not have to be produced, get expelled from the cell, and try to avoid antibodies long enough to invade new cells, rather this mutation basically allowed viruses to move from one cell to another (we saw this in the lungs) with impunity from antibodies without ever leaving the cell! By analogy, imagine that you are a burglar. You want to get a big haul. You pick out a house, break in, get what you want, but if you want more, now you have to go and break into another house, greatly increasing the chances that someone will see you, an alarm will go off, and the police will catch you. But with fusogenicity, it is as if breaking into one house, you now have instant tunnels to each of the neighbors’ houses and you no longer have to worry about going outside and being seen, setting off an alarm or getting caught by the police. Instead, you now can move freely between houses.
Further, while it was not the viruses’ intention (remember, viruses are not sentient beings, I am just taking liberties in simplifying a very complicated subject) to make patients’ sicker (once a virus gets the opportunity and has gone through all the work of infecting its host, it doesn’t do the virus any good to kill its host because then there are no longer living cells to enable it to reproduce and make more viruses), but these fused cells in the lungs are called syncytia (if you want to talk about this at your next family gathering, it is pronounced “sin-sich-a”) and they appeared to significantly worsen the ability of lung cells to do their job of exchanging oxygen and other gases, and may very well be why we saw many more people on ventilators at that time of the pandemic.
With all that in mind, you are now ready to understand this new and disturbing article: SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity | Science Advances.
I already explained how earlier variants of SARS-CoV-2 developed the ability to fuse lung cells to promote viral replication and spread, but at the unintended consequence of impairing the functioning of the lung cells, which sometimes killed or contributed to the death of its host. Since the early days of SARS-CoV-2, during which we mostly saw the virus manifest itself in the lungs, by producing a viral pneumonia and acute respiratory distress syndrome picture, we have seen more and more neurological sequelae, some that had onset during the acute illness, but many manifestations that did not appear until after the patient appeared to have recovered from their infection. Like lung cells, neurons (brain cells) operate as single cells, but unlike lung cells, they are also part of neural networks of coordinated activity. What if SARS-CoV-2 could cause fusion of brain cells and the formation of syncytia in the brain as it has done in the lungs?
The problem in answering this question is that we can’t use the brains of living people for the experiment and we can’t use the brains from deceased individuals at autopsy, because the virus needs living cells. Therefore, these researchers first used mice to demonstrate that in fact SARS-CoV-2 is fusogenic in brain cells (neurons and in supporting brain cells called glia). But, mice and humans are different, so the researchers then used method in which human stem cells are directed to make neurons in a collection that is referred to as an organoid (a miniature model of a brain, if you will). When they infected the nerve cells of the organoid with SARS-CoV-2, it did in fact induce fusion between nerve cells and created syncytia.
To, I think, the surprise of many (I can certainly speak for myself), not only did adjacent nerve cells fuse following infection with SARS-CoV-2, but nerve cells, including neurons and glial cells fused into syncytia. Concerningly, those neurons that fused at their body (soma, where the cell nucleus is located; this accounted for about 10% of the cells that fused, whereas 90% fused at the part of the neuron that resembles a tail) completely lost neuronal activity. In addition, those neurons that fused to glial cells (these are cells that support the health and function of neurons) also completely lost their neuronal activity.
As far as we know, this fusion and syncytia formation is irreversible. How clinically significant (the severity of signs and symptoms) this process is likely depends upon the viral load (the amount of virus that infects the brain) and the exact parts of the brain that are impacted. In addition, just as syncytia help protect the viability of virus from the immune system, there is concern that syncytia formation in the brain might provide a mechanism for viral persistence in the brain. Viral persistence is one of many postulated causes of Long COVID and PASC, and further raises concern for those patients’ long-term health. We have recently discovered that prior Epstein-Barr virus infection can result in multiple sclerosis decades later. Prior herpes simplex virus infection can be associated with the later development of Alzheimer’s disease. HIV infection has been associated with the development of Parkinson’s disease. Parkinson’s like signs and symptoms have already been described in some patients following COVID. Further, we see acceleration of dementia following COVID and we see a wide-range of neurologic signs and symptoms during infection and following COVID.
While we are only beginning to understand the long-term health consequences of SARS-CoV-2 infection and the pathogenesis of these complications, we should be reminded that the SARS-CoV-2 is not just a cold or flu virus and it appears that it can cause very serious complications in some people. Until we understand more, it makes sense, not to live your life in a protective bubble, but not to be complacent, either. If you have not yet been infected, you are not alone. Try to postpone that initial infection as long as you can. If you have been infected, try to delay a reinfection as long as you can.
In the meantime, we need to protect the immunocompromised for their sake and our own. Further, we should protect the children. Sure, they are far less likely to be hospitalized or die than someone my age, but on the other hand, I am not likely to be around 20, 30 or 40 years from now if that is how long it takes for some of these health consequences to manifest; but these children will be at what should be the prime of their lives.
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