SARS-CoV-2 infecting cells without using receptor
And avoiding antibodies at the same time
I am glad I made an unspoken rule months ago of trying very hard not to publish any sort of “negative” news on weekends, and while part of this isn’t exactly “bad” or negative, it isn’t exactly sunshine and rainbows. And the second clearly is somewhat concerning from a “big picture” perspective.
For months to no end, we have explored if and how significant it would be if SARS-CoV-2 could create, travel, and interact with EV, extracellular vesicles, imagine very small cells that big cells produce for a variety of molecular uses. Since I am rather fringe (as in cutting edge) I always stated the virus did much more with EVs than previously thought, and so does other pathogens.
I never imagined the virus defying the “ligand-receptor” rule, meaning in a very simplified manner, most pathogens need the correct “lego piece” on your cell to attach and enter it. Here, it literally doesn’t, it is basically “wireless transmission”.
Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2
The authors bring up some pertinent points to the somewhat novel mechanism they found and described in this paper, with some bearing more significance than others. They also raise the point of antibody-based therapy, such as convalescent plasma, something I covered a few times and said it was a good measure for the vaccinated to develop proper immunity against other parts of the virus, which the authors state (the obvious?) that such plasma can’t help severe patients, and of course, how monoclonals are failing like nothing else. A peculiar point they raised was the following.
In addition, a recent work showed that a novel candidate receptor, the tyrosine-protein kinase receptor UFO (AXL), specifically interacted with SARS-CoV-2 S protein and promoted viral entry as efficiently as hACE-2 overexpression via “apoptotic mimicry”. Downregulating AXL was found to reduce SARS-CoV-2 infection of pulmonary cells11
Back at the time when the paper reference here was published, I couldn’t make much sense of AXL in the grand scheme of the molecular cascade, and the significance of the specific part of the virus that interacts with AXL. The NTD. Where the Galectin-fold/mimic is, among many other effects this particular section of the virus induces.
The protein that induces the creation of EVs in this research was the Envelope Protein, a structural protein for the life cycle of the virus.
Upon inserting the Envelope protein in a cell, the cell swelled to the point of “bursting” and at that point, it secreted EVs, and this was caused by the cell death, and for such, they measured specific markers finding Gasdermin E )a protein family that pole “holes” in cells and caused them to die, often via pyroptosis) to be cleaved (cut into two, therefore achieving biological function) in the presence of the Envelope Protein. Cells that go through this process, therefore, die via pyroptosis, by the name itself, a very inflammatory form of cell death.
In the context of SARS-CoV-2 infection and many of the pathologies, the Spike Protein can cause the onset of, besides ferroptosis, pyroptosis is one of the most important and impactful, and many of the analyses written in this Substack referenced it. Many of the long-term changes SARS-CoV-2 can cause in severe patients are in part because of this form of cell death.
The videos revealed three major characteristics of these EVs, including shedding, sliding and fusion, implying that the EVs may traffic from their mother cells to other cells within their immediate microenvironment as well as at a distance.
First, a large number of single-membrane vacuoles (SMVs) appeared. Second, the number of lysosomes increased significantly in cells. Last, ER, mitochondria and Golgi swelled. Closer inspection showed that the Golgi and mitochondria linked several vacuoles together
Everything discussed in the following paragraphs in the paper is of importance both from a short and also long-term perspective. The Extracellular Vesicles created by the mechanism described above could shed, slide and fuse, meaning they could both enter cells that are neighboring the mother cell (where the EV originated) but also travel within the body, an amazing dispersal technique, one that when looked from another perspective (interaction between this virus and many other pathogens) brings up many possibilities and explanations for dynamics not seen before.
Even when forming EVs, SARS-CoV-2 is directly interfering with mitochondrial function, so basically at all stages of the viral infection cycle, it is disruption mitochondrial activity, if you don’t understand why this is important just use the search feature in my Substack and either use the term mitochondria or brain.
Followed by more testing, they found that EVs formed from Envelope Protein can package (carry) SARS-CoV-2. Followed by more tests and other testing parameters, it was noticed that “the viral copies in the 2-E-EVs were higher than those in the virus-induced EVs, implying that redundant 2-E proteins may facilitate virus production, packaging, or EV secretion.”. Incredible, a redundant function in a “novel” process.
In addition to mutations, it has been reported that S protein-dependent cell-to-cell transmission may also dampen the efficacy of SARS-CoV-2 antibody50. Although more in vivo evidence is needed, our results demonstrate that CoV-2-EVs can protect the virus against neutralizing antibodies, suggesting a novel mechanism by which SARS-CoV-2 escapes from antibody neutralization.
The section speaks for itself, the virus inside EVs is protected from neutralizing antibodies, which is rather unheard of for this class of viruses, so far as we know of course.
But the most remarkable finding in the entire paper, at least for me, was the fact that EVs bearing SARS-CoV-2 can infect cells without using receptors. By using different cell lines and methods, this is exactly what they found, that independent of the presence of the most common receptor used by SARS-CoV-2 to infect cells, they could in fact infect new cells. “These results indicate that intact EVs can be taken up directly by recipient cells, suggesting a vesicle-mediated cell-to-cell transmission of SARS-CoV-2.”
Not only this is fairly uncommon for this class of virus, but SARS-CoV-2 can even travel between cells clustered inside these little cells (EVs), giving room for the potential explanation on why SARS-CoV-2 evolution defied most models, and it wasn’t merely because of the crappy non-sterilizing vaccines.
From the scope of this paper alone, this is somewhat of a groundbreaking finding, and something I wondered about since 2020, a specific function of certain pathogens called “stealth factor”, novel ways for said pathogens to evade the immune system, and sometimes be completely invisible, latent viruses have many ways of doing it. Here is the earliest and most meaningful tweet.
And indeed, one of the reasons this particular virus can do many of these novel functions, unique to SARS-CoV-2 are the “inserts” using fragments of GP120. At this point in time I have 2 orders of magnitude more knowledge than I had when I wrote that tweet, and I still wonder.
Is the GP120 the most functional protein known to science, or is the GP120 so multifunctional because it is IN SARS-CoV-2 ? Maybe one day I will have my answer, maybe not. Regardless, this particular dynamic of EVs carrying live SARS-CoV-2 is another step toward proving one of my oldest hypotheses, or observations whichever nomenclature you prefer.
That EVs can not only carry the Spike Protein, but also the entire virus, and given how the Spike/Virus can interact, deconstruct, and use the endotoxin LPS to further drive and manipulate the immune response, this is also happening with the mRNA vaccine. This could explain a lot of the skin and allergic reactions of some people near vaccinated individuals, and the immune shift (malaise) some experienced when spending time with said individuals.
Courtesy of my Twitter friend, and one of the few people doing actual good work out there.
This also completely opens up the possibility of something I and another friend have been chipping away at for as long as I proposed some of the most insane ideas from the observations I had. The interaction between SARS-CoV-2 and biofilms.
I will refer to this Substack you are reading right now because a recent paper just proved one of our points. The interaction between different pathogens with SARS-CoV-2 can and will dictate its evolution and acquiring beneficial mutations, among other elegant dynamics. I will also revisit that first paper on exosomes and mRNA, just a feeling I got right now. It falls in line with a lot of recent, yet important findings.
In summary, we now have more evidence for novel methods almost unique to SARS-CoV-2 to evade the immune system, cause sustained inflammation, and interact with other pathogens, this truly is already one of the most remarkable papers published this year. Many other papers I wrote about and linked together are impacted by this paper on itself.
Tesser on Twitter shared this extensive paper on EVs, if you want to learn the complexity and all the dynamics of this subject, I highly recommend you to read it. Rather technical but you can make sense of most of idea and get the general idea behind it.
I wanted to cover another very important paper, rather short, but I rather keep this one solely within the theme, so I will publish it tomorrow, one of my favorite subjects, protein mimicry.
I appreciate the support of those who choose a paid subscription, or who decide to buy me a coffee whenever they feel like it, and everyone who shares my Substack. This work wouldn’t be possible.
I wish the “like” button said “read” instead. Under no circumstances do I like what I read. Am I surprised? No. Was this done by design or ignorance?
It’s just weird to say “like” I press it so you know I read it. So we are in the same page.
It is really disturbing to think this is by design. I had hoped it wasn’t true.