COVID Transmissions for 5-5-2021
Understanding the role of the spike protein in causing COVID-19
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 534 days since the first documented human case of COVID-19. In 534, King Athalric of the Ostrogoths died at age 18 from tuberculosis, one of many things that have killed a lot of people.
We’ve conquered a lot of those diseases, and we can beat COVID-19 too.
Today I’m going to walk through a scientific paper about how SARS-CoV-2 causes disease, shared with me by a friend and reader. I have a few of these queued up, and there have been some really interesting results lately.
As usual, bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
Spike protein alone may be sufficient to cause lung and vascular damage in SARS-CoV-2 infection
Now that we are in the second year of the pandemic we are starting to see work that explains the pathogenicity of SARS-CoV-2; in other words, we are starting to see research that tells us how the virus causes the disease that we call COVID-19.
One such paper was shared with me recently: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.318902
In this paper, the authors developed a model for SARS-CoV-2 infection. This is something that is very common to do in emerging disease research when a pathogen is restricted for reasons of biosecurity, as SARS-CoV-2 has been for this past year.1
The model that these researchers created involved making a “pseudovirus” that has the SARS-CoV-2 S protein on its surface. A pseudovirus is not that different from the viral vectors that are used in some vaccines for COVID-19. Specifically, the machinery of another virus is used to create a simulated virus particle that can mimic the target you are interested in studying, but that is not a competent, disease-causing, communicable entity. A few platforms can be used for the generation of pseudoviruses, and this article that I found from The Scientist explains more about how they are made: https://www.the-scientist.com/news-opinion/what-pseudoviruses-bring-to-the-study-of-sars-cov-2-68457
Anyway, the authors have here created a model which contains the S protein but not other components of SARS-CoV-2. The person who shared this article with me noticed the similarity between this model and certain vaccines, and wondered if the effects seen here could be seen with vaccines. I think the answer is no, but I’ll explain why after we talk through the results.
The authors took their new tool and applied it to use in an animal model, the Syrian hamster. Syrian hamsters are frequently used in laboratory studies. They are used to study many conditions, but in the past they have been used as a model for human lungs in the study of lung damage and respiratory illnesses, including lung cancer and infectious diseases. In March 2020, not long into the pandemic, they were identified as a good model for SARS-CoV-2 infection.
Something to keep in mind here is that this work is being done with a pseudovirus in an animal model. This isn’t a study of SARS-CoV-2 in humans; it’s a study of a laboratory construct in a hamster. So I would not make too much of its conclusions too quickly, but it can still be informative.
OK, so we have our cast of characters: a pseudovirus and a hamster. The pseudovirus may only be a model, but it is interesting because it allows the study of the S protein in isolation. That in mind, the authors “infected” animals with this construct and were able to demonstrate that on its own, the S protein-bearing pseudovirus was able to cause lung damage in the hamster model.
The authors then looked at what was happening in the damaged lung tissue. To do this, they examined the gene regulation changes, relative to normal, that occurred during exposure to the pseudoviruses. A living system, with its many thousands of genes, is like a vast machine with many thousands of levers that carefully calibrate its machinery. Changing gene regulation tugs on these levers to subtly change the way the machine works. Literally what is happening with changes in gene regulation is that more, or less, of a specific piece of machinery is made, to help each cell respond to whatever is going on.
In the hamster model, they found that exposure to the pseudovirus brought about changes in specific genes in the damaged lung tissue. These genes are part of a cluster that controls expression of ACE2, the receptor for SARS-CoV-2, but also, tellingly, they found changes in expression of a gene that functions not in lung tissue itself, but in lung vasculature.
For quite some time, there has been a movement to characterize COVID-19 as a disease of the vasculature, and these results seem to support that concept.
Specifically, the hamster results indicated to the authors that S protein alone was able to cause damage to lungs by harming vascular endothelial cells—the cells that line blood vessels. They extended this work by looking at the effects of their pseudovirus on human vascular endothelial cells grown in tissue culture—another model system, but one that allows for more targeted molecular exploration. They found the same gene expression changes in this model system as well, suggesting a reliable molecular biological process happening in response to S protein.
To make a long story short, the authors traced the effects of the S protein to impacts on mitochondria in these cultured cells. Mitochondria are a cell’s metabolic center, not just producing energy, but responding to sources of stress and serving as a central communications hub for stress signals. Normally, they have an oblong shape. Using microscopy, the authors showed that exposure to spike protein changed mitochondrial shape:
OK, so what we are looking at here is some pretty fluorescent microscopy that is a representative image of many experiments. The researchers have counted the shape of mitochondria in their many experiments, and determined that the presence of the S protein increased mitochondrial fragmentation, and fewer tube-shaped, typical mitochondria were seen. Mitochondrial fragmentation is a sign of cell stress, and an indication that cell death processes may be going on here.
The authors investigated further and determined that they saw similar effects on mitochondria when they manipulated ACE2 levels within their model cells—without exposure to the S protein.
They took this together to imply that by reducing ACE2 levels, the S protein on its own is able to cause damage to vascular cells. In lung vascular cells, they anticipated that this could contribute to, or even be a major cause of, the lung damage that they observed in their animal model.
This is a good scientific story, but there is more work to be done. I am not convinced that the effects seen by directly manipulating ACE2 levels are he same thing that is happening with exposure to the S protein. There could be more to the story, and the effects are just similar. Also, I am not sure that these effects are the only cause of the lung damage that was observed in the hamster model. Then, finally, I am not sure how these models relate to disease in humans.
That said, given the evidence that SARS-CoV-2 has effects on human vasculature, this is an interesting result that gives us more clues about how the virus can cause serious disease. I’m interested to learn more about this potential disease mechanism.
Now, I want to turn to the question of whether the vaccines can have this kind of effect. There are a number of reasons that I believe the answer is no. First and foremost, I have not heard of any reports of lung damage of any kind in people who have received COVID-19 vaccines. That would be the first thing that I would look for.
There are a number of other reasons, though. Importantly, the vaccines are not injected into the lungs. They are injected into muscle tissue, which is intentional. Muscle tissue does not have great connections to vasculature, and vaccine materials injected there are not likely to circulate in the body. I do not expect there to be a way for the vaccines to get into the lung vasculature. Additionally, the amount of vaccine material that is delivered is very small, so even if this material could somehow get to the lung, I do not think it could have anything close to the effects of a full-blown infection. Then there is the fact that we are talking about a mechanism here that was demonstrated in two model systems and not in humans directly.
I also want to mention that it’s not clear that most of the vaccines are even competent to do something like this. The S protein that was used in this paper is one that is fully functional. In the mRNA and J&J vaccines, the S protein used has been modified in a way that compromises its functions. I cannot guarantee that this modification compromises the specific function explored here—and I wish that the authors had looked at the vaccine constructs too—but it seems to me that it almost certainly would. The modification really limits the S protein’s function to where it cannot enter cells. So, I wouldn’t worry about this effect happening with vaccines at all.
Anyway, I think this is a really interesting study that may explain one way that SARS-CoV-2 can cause disease. In a practical sense, if this really does tell us something about disease, it could also tell us something about how to treat it. I’ll be keeping an eye on this particular story to see if any new results are forthcoming.
What am I doing to cope with the pandemic? This:
Watching: The Bad Batch
You may have heard that I’m a Star Wars fan at some point. Maybe someone wrote about it in this space, in fact. I won’t corroborate this at the moment, but I will mention that yesterday a new Star Wars TV series showed up on the Disney+ streaming service. It focuses on some outcast clone soldiers, a very small part of the much bigger universe, and seems to combine Star Wars with elements of the A-team. I watched the first episode, and while I found some aspects of it uneven, I’m interested to see where it goes! There’s a lot of potential.
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See you all next time.
Always,
JS
This is might change now that there is an effective vaccine, but it may take some time.
Steve Novella disagrees with you about the mRNA vaccines, specifically the Pfizer vaccine. He says it does in fact contain a complete and functional spike protein. (He doesn't say "functional," but I think he implies it.) https://sciencebasedmedicine.org/spike-proteins-covid-19-and-vaccines/?utm_source=rss&utm_medium=rss&utm_campaign=spike-proteins-covid-19-and-vaccines