One of my favorite songs never officially release, great to list while reading this article.
For a few weeks, I have been struggling with presenting the information you are about to go through, alongside fate presenting more and more information that connected many dots. Not by merely jest, in this Substack, we deal with very complex, often interconnected subjects since biological systems are the paramount examples of complex systems. On average sometimes the subjects are already complex but here, things get tricky. So this will be presented in parts the usual science, part essay-ish.
To understand the importance of what we are about to discuss, we must go back in time and explain a “time-culture-memetic” concept from Quantum Physics and Science Fiction. Nexus points. A nexus point is a point in time where “fate” interconnects, it branches out into multiple pathways, these are usually moments in life that can define your next few years, your next decade, or your entire life. Nexus points are only observed in retrospect, years after the fact.
One of my nexus points was when I and my dear friend-mentor figure deconstructed the mRNA vaccine immunological response and partially the platform to a very precise degree, at the same time tracing parallels with the viral response. Our goal was solving the puzzle, what we would later say “our small part of the puzzle”, no single human being can figure all of this out, alone.
In this herculean task, one of my deep instincts was always to find the common denominator, what linked viral Spike, mRNA, and the deluge of harm that would come, both virus and vaccine alike. Kynurenines, Endotoxin, anti-cholinergic effects, the list goes on, they all belong to different branches, but no single one explains or links all of them especially because the missing link would have to possess a double effect. Inside and outside the cell (most of our discussions in the last 3 years are always one or the other, very few things have effects in and out). This “thing” would have to act as a glue that keeps everything together theoretically.
Sometimes the truth stares at your face, you just need some pieces of the puzzle to see the picture. You can also scroll down in the following article and see all mentions of CypA.
A quote from the article.
CypA also influences Liver fibrosis, cardiovascular diseases, viral infections, neurodegeneration, cancer, rheumatoid arthritis, sepsis, asthma, periodontitis, and aging. Among others.
Host cyclophilin A facilitates SARS-CoV-2 infection by binding and stabilizing spike on virions
Cyclophilin A (CypA from here on) is a very important protein, because it is present in numerous cells, and it is both a cytoplasmic (inside) and secretory (outside the cell) protein. This means not only it plays multiple roles, but the place it finds itself will change its function, it is essential for protein folding and trafficking (moving protein around).
A CypA inhibitor has been proposed as an inhibitor for SARS-CoV-2 infection since late 2020, but no mechanism has been concretively found, therefore so far it has been disputed as a valid mechanism by a portion of clinicians and researchers. Here the researchers had hypothesized that CypA could facilitate SARS-CoV-2 infection by binding and regulating the Spike Protein of the virus, a significant amount of evidence has pointed to this so far.
Here they used a mutated Spike Protein so they could test and measure the possible effects of CyPA on the entire S protein, not just the cleaved parts. They found in their tests that the Spike Protein formed a complex with CypA and ACE2, given that ACE2 can’t interact with CypA directly, Spike probably recruits CypA. Another rather significant aspect was that S glycosylation can inhibit CypA+Spike interaction. Glycosylation is the addition of sugar molecules to proteins, something many viruses love to do to escape the immune system.
CypA doesn’t bind that well to the S2 part of the Spike but binds very well to the full-length Spike, which implicates the S1 part. The authors cite this recent paper where another group found that the Receptor Binding Domains (in the S1 part) bind to CypA. We will get back to this later.
They next found that CypA depletion did not decrease ACE2 levels, and CypA directly affects the infectivity of the virus by affecting Spike function, which directly affects transmission. The absence of CypA in these cells results in weaker infectivity of the virus, indicating CypA’s role in the production of the virus.
Lastly, CypA is involved in cell-to-cell viral transmission, a strategy used by coronaviruses to directly infect neighboring cells, and very important in many aspects not only for transmission of the virus but syncytia formation also participates in many different diseases and infections. The absence of CypA impairs the formation of large, multinucleated cells (syncytia), disrupting virus transmission.
The short of it, CypA, a protein expressed “everywhere” interacts with the Spike Protein, it increases its membrane fusion, and it participates and helps infectivity, and transmission of the virus. So, to this point, we know CypA participates negatively in many diseases, it is expressed inside and outside cells and in the regard of outside, usually in response to inflammatory responses and oxidative stress, and the Spike Protein of SARS-CoV-2 interacts with it.
Cyclophilin A, its favorite receptor, and their roles in other diseases
Why CypA is important goes beyond just the interaction above. CypA has a widely known receptor. Basigin. EMMPRIN (Extracellular Matrix Metalloproteinase Inducer). But most commonly known as CD147. Some of the cells that express this protein are Hepatocytes, Endothelial Cells, Erythroid (Red Blood progenitor) cells, monocytes, granulocytes, epithelial cells, and mostly activated T-Lymphocytes, B Cells, and dendritic cells.
CypA is also significant in the development of many types of cancer, another example, especially under hypoxic conditions, which directly make your body produce more of it. You can find a list and quite an awesome review on CD147 and its role in cancer here, the list of cancers is both quite extensive and…peculiar. The interaction between soluble CypA (floating around) and CD147 can both create and accelerate cancer. It also plays a role in neurodegeneration, and Alzheimer’s. Coronary Arterial (heart) diseases. It can augment thrombosis and its cascading inflammation. Kidney disease. Lung disease. Endothelial cell activation and dysfunction.
Before going further I want to reiterate that exposure to Endotoxin (LPS) increases the expression of both CypA and CD147 and “forces” some cells to secrete CypA (therefore becoming “soluble”).
Early in the pandemic, a few researchers were proposing the interaction of CD147, CypA, and the virus, especially its N-Protein, but no person was earlier or more accurate than Aneta Molenda, who proposed many of the mechanisms we would later discover early on 2020, including what we are discussing here.
Here is a late 2020 paper discussing the disruption of cardiac pericytes and endothelial cells through the CD147 receptor (it caused an uproar back in the day). It was later published and revised.
Here is a recent paper on SARS-CoV-2 using alternative receptors to induce kidney damage, and one of them is CD147. The other is TLR4, it will be important in a few minutes. Here we have a recent paper demonstrating that human motor neuron cells (created from pluripotent stem cells) are susceptible to SARS-CoV-2 infection by…CD147.
Another recent paper on how two specific molecules inhibit SARS-CoV-2 entry into Megakaryocytes by targeting CD147. This one is especially significant because recently a team of researchers found another potential reservoir in Long Covid patients. The bone marrow (where the megaka cells are produced, this paper will be present in my Covid Persistence part 3).
So not only does Cyclophilin A “glue” itself to the Spike if there aren’t many small sugars there, but we now have good evidence one of its favored receptors participates in much of the uncharacteristic damage the infection does. So far, it explains a lot of the “odd damage” from viral infection or vaccine-derived Spike Protein, via other mechanisms. Still, doesn’t explain it all. It is about to get a little bit complicated, so bear with me.
I have hinted at this in my “Covid-induced cognitive deficit 1 year after infection”, an unofficial Part II of my Covid Brain articles. RAGE, Receptor for Advanced Glycation End-Products. AGEs are byproducts of sugar that are reduced nonenzymatically such as cooking via interacting with proteins and fats (the process called glycation). They are also abundant under hyperglycemic and hyperlipidemic states (obesity, diabetes, metabolic syndrome).
Deep down we knew RAGE was potentially a CypA receptor because it would explain so many more “oddities”, especially because of the role these 3 play in endothelial health, inflammation, and thrombosis (Clots). A quote direct from the authors.
We propose RAGE as a hitherto unknown receptor for CyPA mediating leucocyte as well as platelet activation. The CyPA–RAGE interaction thus represents a novel mechanism in thrombo-inflammation.
RAGE engagement by SARS-CoV-2 enables monocyte infection, and together with all the information presented here, we have more than one plausible mechanism for not only the infection of monocytes but also a reason why some researchers sometimes find pieces of the Spike Protein inside monocytes, but also Lymphocytes.
As I wrote at the start, I would get back to S1 binding to CypA. We have evidence for the RBD interacting with CypA, but now I will go further, and propose something…unsavory for the scientific inclined. And something that kept pestering my brain for years.
The NTD is considered to be a “super-site”, it has a big importance because neutralizing antibodies are very attracted to it, but it has hidden significance. The NTD is also referred to as “Galectin-Fold” because it resembles pretty closely the human Galectin-3, and also mimics closely one of the HIV proteins (it is one of the “inserts”), but the NTD arose naturally, it is present in other coronaviruses.
But not entirely natural since its shape has indications of very precise manipulation, which led me to question why would someone change it. To make matters worse Galectin-3 induces clustering of CD147 and Integrins, thus modifying cell behavior, which theoretically could facilitate what we discussed here.
At first, my thought was “evil bioweapon”, but nuance is important, balance is important and the more I learned the more I understood many of these pathways are compensatory. Double-edge. The Galectin-fold has many downsides but why it is so “present”, and so biologically potent ?
I guess this would be a necessary step to prevent every living organism you passaged your FCS virus (which mimics one of the most potent toxins known to science) not dying. Unforeseen/unintended consequences are quite something. The same parts of the virus that exert a myriad of novel effects, were there as probably a protective method while researching a highly pathogenic virus. FCS, Galectin-Fold, RBD.
The fact that CypA, CD147, RAGE, and the Galectin-fold all interact, all participate, and all create negative feedback loops is not only remarkable, but concerning, since these are all Spike-bound, and they are shared by both virus and vaccines. While sharing many common denominators the biggest of all remains the same.
Toxins. Especially Endotoxin. There is no better source for the complexity and how absurdly powerful and deep the effects of Endotoxins go than Geoff Pain’s Substack.
To not overly complicate and let give me more research time and let the hypothesis simmer, these mechanisms are also how viral fragments from any source become “eternal”. Similar to the Aryl Hydrocarbon Receptor that binds to things that “shouldn’t”, CypA binds and forms complexes to the weirdest stuff, such as tau and α‐Synuclein.
Hopefully, I did a good enough job for you to understand the significance of these mechanisms. These complex interactions are likely one of the roads toward the viral persistence we have and will discuss. I will also get back to RAGE, and CypA soon.
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I have two addendum unrelated to the article, but in regards to this Substack. First, Substack is a gigantic newsletter company, so it sends an absurd amount of e-mails every hour, and some of my articles may end up in your spam folder sometimes, I have no control over this.
And I also have no control over the following. Something banks simply deny you becoming a paid subscriber and your payment. I also have no control over this and none of the companies involved (Substack, Stripe, the banks) give you a reason to why.
See you all soon. Have a great week.
Ugh. So is there hope for a solution to fix this? Should we all be drinking Indian snakeroot or taking reserpine?
My mind does not want to believe that this is permanent for everyone, that everyone is damaged in some way even though it may not be obvious at the moment.
I was thinking that with, say, loss of smell and taste, it was due to destroyed cells - a one time bomb of destruction, which may or may not be repaired. But this sounds more like it is an ongoing attack - and not confined to just one organ.