The many faces of the Spike Protein of SARS-CoV-2

Molecular mimicry bro !

This is a very extensive version of the one below, which is simple, small, and to the point, the image below also comes from the said piece.

Plagued by Design II

Since the focus of this will be parts molecular mimicry, parts hidden functions. Here is a fair description of Molecular Mimicry. “Molecular mimicry can be defined as the structural similarity between foreign (microbial) and self-molecules of the mammalian host.” When the peptides (structure of) an antigen (little Y thingies that bind to your immune cells) are similar to one of yourself (literally called self) your body momentarily (sometimes forever, this is when you get actual autoimmunity) gets fixated in those antigens and attack whatever harbors that sequence.

Another concept to bear in my is immune tolerance. “Immune tolerance is the state of unresponsiveness of the immune system to substances or tissues that have the potential to induce an immune response. Self tolerance to an individual's own antigens is achieved through both central tolerance and peripheral tolerance mechanisms.”

When this paper was published it was heavily overlooked by many as “too out there”, and “the potential for this is minimal”.

To not make this overly complex, more than it already will be, you can search for each of these antibodies + SARS-CoV-2+mRNA and you will find at the very least 2, 3 published papers about how the Spike Protein in the vaccine set of an autoimmune disease related to said antibody, I myself covered a few here (Type 1 Diabetes especially).

And there are even newer ones not listed here, the list of autoimmune diseases that the mRNA vaccines can induce is abnormally big. One of the most widely acknowledge “mimics” in SARS-CoV-2 is the Staphylococcal enterotoxin B (SEB), which isn’t the point of this article. The following is.

Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins

Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes.

This entire paper is a fairly interesting (yet complex) read, but from all the mimicry in the Spike, two caught my eye within the first 20 minutes of reading this paper.

Kynureninase (motif EELDK), and Tryptophan-tRNA ligase (motif GNCDV).

Here, the predominant intermolecular contacts are formed between charged-apolar, polar-apolar, and apolar-apolar residues (Table S4). In COVID-19, stronger antibody responses to the epitope containing the ELDKY motif have been recorded for severe (requiring hospitalization) vs. moderate cases, while fatal cases had a weaker response than surviving cases [16]. A synthetic epitope containing the ELDKY motif has also been shown to elicit antibody production following COVID-19 immunization [70]. Together with the 3D mimics identified here, these results suggest interesting possibilities for the ELDKY motif from the perspective of both protective immunity and an autoimmune response

Not only did the researchers demonstrate using previous evidence this is a reactive motif, and there is an immune response it also dictates the severity of disease in many cases, or at the very least is correlated. Why Kynurinenase is important ?

Kynureninase is a very important enzyme to your body, which catalyzes (breaking down) Kynurenine into Anthranilic acid. It is the second step in the Kynurenine pathway, arguably really important because of the metabolites it forms. You can read most of my arguments on the KP below.

Kynurenine Pathway and SARS-CoV-2

Even a transient autoimmune reaction, meaning you stay within tolerance, but your body attacks the enzyme, would mean a disruption in the breakdown of tryptophan and imbalance of the KP. You can read some of my arguments above on how I think the virus/spike is inducing such dysfunction of the Kynurenine Pathway, but now we have evidence of another mechanism, which actually explains more.

Hydroxykynureninuria or Kynureninase deficiency is the name for a rare genetic disorder of tryptophan metabolism. “The clinical phenotype is highly variable, ranging from asymptomatic or mild cases presenting with jaundice and vomiting, with subsequent normal development and growth, to more severe cases with manifestations which include intellectual disability, cerebellar ataxia, pellagra, progressive encephalopathy with muscular hypotonia, global developmental delay, stereotyped gestures and/or congenital deafness” Kynureninase is often responsible for downregulation inflammation in aneurysm setting. The lack of kynureninase in cultured macrophages enhanced the expression of interleukin-6 and indoleamine 2,3-dioxygenase 1 (IDO).

Does any of this remind you of any symptoms in a subset of people ? You will understand a sizable portion of the dysregulation of the KP can do in Part II of the piece above. The second one that got my attention is even more remarkable, Tryptophan-tRNA ligase, also called WRS. The following article is massive, I do recommend the people interested to read it, I will just quote the most meaningful parts. (This enzyme is also called synthetase sometimes, they are the same enzyme)

Unique roles of tryptophanyl-tRNA synthetase in immune control and its therapeutic implications

As you can see, this enzyme is not only incredibly important for the uses of Tryptophan but it has a clear immune controlling capacity. The transient loss (or deficiency) of this enzyme would lead to the reverse of what the highlighted text above describes, therefore loss of immune tolerance, senescence, loss of protective protein synthesis for immune cells, more activation of CD4+ T Cells, and less activation of CD8+ cells. It will also work as a tryptophan reservoir for your cells, and now after reading my aforementioned piece of the KP, and many others.

Does this remind you of anything ? WRS in fact has a novel (non-canonical…heh) recently discovered capabilities. Would you believe me if I told you it is a novel damage-induced cytokine ?

The major challenges of most adult stem cell-based therapies are their weak therapeutic effects caused by the loss of multilineage differentiation capacity and homing potential. Recently, many researchers have attempted to identify novel stimulating factors that can fundamentally increase the differentiation capacity and homing potential of various types of adult stem cells. Tryptophanyl-tRNA synthetase (WRS) is a highly conserved and ubiquitously expressed enzyme that catalyzes the first step of protein synthesis. In addition to this canonical function, we found for the first time that WRS is actively released from the site of injury in response to various damage signals both in vitro and in vivo and then acts as a potent nonenzymatic cytokine that promotes the self-renewal, migratory, and differentiation capacities of endometrial stem cells to facilitate the repair of damaged tissues. Furthermore, we also found that WRS, through its functional receptor cadherin-6 (CDH-6), activates major prosurvival signaling pathways, such as Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. Our current study provides novel and unique insights into approaches that can significantly enhance the therapeutic effects of human endometrial stem cells in various clinical applications.

Source

WRS (TrpRS here) can also be one of the mechanisms for neurodegeneration and mitochondrial disease via its deficiency. Tryptophan will play a big role in my upcoming Inflammaging piece, it is what I call a “primordial” amino acid (scientifically they call it an essential, but it goes beyond that in my opinion).

So far, in summary, the Spike can make your body attack for a moment two very important enzymes for both energy generation, systemic immune, and “disease checkpoint” therefore contributing to the massive cascade of issues we have been experiencing for ages. Arguably from my PoV these are among the top important mimicry sites given the systemic importance of what they target and explain much of the mental change we have been experiencing over the last 18 months. Psychological war takin virological form in a crude way. You may be asking, which would be the top ones.

Well, I am glad you did ask. Since early 2020 I have been asking every person I saw as a competent immunologist/virologist/molecular biologist why the following proteins were in the Spike, and if they were functional, or they were molecular clamps (basically a way to keep things that shouldn’t be together, glued to each other). These are one of the most used molecular clamps in laboratories all over the world.

The following finding would not be possible without the help of the same person who I researched the PAID hypothesis.

Credit to whoever marked the sites because I don’t remember who it was.

We go from the simpler function to OMFG one.

Source

Insert 3 is a novel cleavage site for the Spike Protein, facilitating infection using Cathepsin L. Insert 2 is what they are calling “NTD supersite” a part of the virus that can severely impact for good or for bad the neutralization of antibodies, and it is mostly a site that antibodies bind aggressively to neutralize the virus. Many of the new mutations in the new variants are all around this NTD supersite.

The third one, and the most impactful and important one, is the secondary reason to write this after the KP-related mimics. A friend on Twitter brought the following to my attention.

The S1 Subunit of the SARS-CoV-2 Spike Protein Activates Human Monocytes to Produce Cytokines Linked to COVID-19: Relevance to Galectin-3

The mechanisms responsible for this CRS remain poorly understood, yet hyper-inflammatory features were also evident with predecessor viruses within the β-coronaviridae family, namely SARS-CoV-1 and the Middle East Respiratory Syndrome (MERS)-CoV. It is further known that the spike protein (S) of SARS-CoV-2 (as first reported for other β-coronaviruses) possesses a so-called galectin-fold within the N-terminal domain of the S1 subunit (S1-NTD). This fold (or pocket) shows structural homology nearly identical to that of human galectin-3 (Gal-3). In this respect, we have recently shown that Gal-3, when associated with epithelial cells or anchored to a solid phase matrix, facilitates the activation of innate immune cells, including basophils, DC, and monocytes

In that paper citation section, you have one paper analyzing the NTD and its homology towards Galectin. The title is Role of the GTNGTKR motif in the N-terminal receptor-binding domain of the SARS-CoV-2 spike protein. That would be Insert 1.

I will make an ENTIRE post about Galectin 3, so you understand how meaningful this is.

Source

Identification of galectin-3 as an autoantigen in patients with IgG4-related disease

IgG4 galectin-3 autoantibodies are present in a subset of patients with IgG4-RD and correlate with galectin-3 plasma levels. The marked increases in levels of circulating IgG4 and IgE observed clinically are, at least in part, caused by the development of IgG4- and IgE-specific autoantibody responses.

The shift in mRNA elicited immunity

IgG4, Long Covid, and the road to Rome

I did say Galectin-3 would be incredibly important… In case you are worried about all of this, yes the stack and things I recommend most people to take already take care of these mechanisms, I will expand on that in the Galectin-3 piece.

I wish everyone a great Sunday.

Massive appreciation to all supporters here and on Kofi !!!