An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations

Preprint. 2020 May 21

Any extracts used in the following article are for non commercial research and educational purposes only and may be subject to copyright from their respective owners.

---

Good find by @smallervoice

https://gab.com/smallervoice/posts/108114228794995392

I've covered the histopathology of cytokines in detail previously, such as IL-6. Focused on infections locally for a short period they are highly beneficial, but if expressed systemically for a time or overexpressed can lead to immune impairment, autoimmune disorders, tumorigenesis, organ damage, osteoporosis, neuronal damage & feedback loops leading to toxic shock.

Spike protein (inc vax) induced immunodeficiency & carcinogenesis megathread #26: Interleukin-6 (IL-6) induced pathology

Background:

Superantigens

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system.[1] Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells.[2] Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens (and can activate up to 100% of T cells).

The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg thus undermining one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More importantly, the large number of activated T-cells secrete large amounts of cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma in turn activates the macrophages. The activated macrophages, in turn, over-produce proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. TNF-alpha is particularly important as a part of the body's inflammatory response. In normal circumstances it is released locally in low levels and helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels (due to mass T-cell activation resulting from the SAg binding), it can cause severe and life-threatening symptoms, including shock and multiple organ failure.

Direct effects

SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of Th1 T-helper cells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon (IFN-γ), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1).[15]

This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in rashes, fever, and can lead to multi-organ failure, coma and death.[8][10]

Deletion or anergy of activated T-cells follows infection. This results from production of IL-4 and IL-10 from prolonged exposure to the toxin. The IL-4 and IL-10 downregulate production of IFN-gamma, MHC Class II, and costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation.[16][17]

One mechanism by which this is possible involves cytokine-mediated suppression of T-cells. MHC crosslinking also activates a signaling pathway that suppresses hematopoiesis and upregulates Fas-mediated apoptosis.[18]

IFN-α is another product of prolonged SAg exposure. This cytokine is closely linked with induction of autoimmunity,[19] and the autoimmune disease Kawasaki disease is known to be caused by SAg infection.[12]

SAg activation in T-cells leads to production of CD40 ligand which activates isotype switching in B cells to IgG and IgM and IgE.[20]

To summarize, the T-cells are stimulated and produce excess amounts of cytokine resulting in cytokine-mediated suppression of T-cells and deletion of the activated cells as the body returns to homeostasis. The toxic effects of the microbe and SAg also damage tissue and organ systems, a condition known as toxic shock syndrome.[20]

If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a severely compromised immune system.

Superantigenicity independent (indirect) effects

Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection.[1]

One such effect is vomiting. This effect is felt in cases of food poisoning, when SAg-producing bacteria release the toxin, which is highly resistant to heat. There is a distinct region of the molecule that is active in inducing gastrointestinal toxicity.[1] This activity is also highly potent, and quantities as small as 20-35 μg of SAg are able to induce vomiting.[8]

SAgs are able to stimulate recruitment of neutrophils to the site of infection in a way that is independent of T-cell stimulation. This effect is due to the ability of SAgs to activate monocytic cells, stimulating the release of the cytokine TNF-α, leading to increased expression of adhesion molecules that recruit leukocytes to infected regions. This causes inflammation in the lungs, intestinal tissue, and any place that the bacteria have colonized.[21] While small amounts of inflammation are natural and helpful, excessive inflammation can lead to tissue destruction.

One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment the effects of endotoxins in the body. This is accomplished by reducing the threshold for endotoxicity. Schlievert demonstrated that, when administered conjunctively, the effects of SAg and endotoxin are magnified as much as 50,000 times.[7] This could be due to the reduced immune system efficiency induced by SAg infection. Aside from the synergistic relationship between endotoxin and SAg, the “double hit” effect of the activity of the endotoxin and the SAg result in effects more deleterious that those seen in a typical bacterial infection. This also implicates SAgs in the progression of sepsis in patients with bacterial infections.

More:

https://en.m.wikipedia.org/wiki/Superantigen

CD28

CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins (IL-6 in particular).

CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins. When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen-presenting cells (APCs). The CD86 expression on antigen-presenting cells is constitutive (expression is independent of environmental factors).

More:

https://en.wikipedia.org/wiki/CD28

Toxic shock syndrome

Toxic shock syndrome (TSS) is a condition caused by bacterial toxins.[1] Symptoms may include fever, rash, skin peeling, and low blood pressure.[1] There may also be symptoms related to the specific underlying infection such as mastitis, osteomyelitis, necrotising fasciitis, or pneumonia.[1]

TSS is typically caused by bacteria of the Streptococcus pyogenes or Staphylococcus aureus type, though others may also be involved.[1][2] Streptococcal toxic shock syndrome is sometimes referred to as toxic-shock-like syndrome (TSLS).[1] The underlying mechanism involves the production of superantigens during an invasive streptococcus infection or a localized staphylococcus infection.[1] Risk factors for the staphylococcal type include the use of very absorbent tampons, and skin lesions in young children characterized by fever, low blood pressure, rash, vomiting and/or diarrhea, and multiorgan failure.[1][4][5] Diagnosis is typically based on symptoms.

More:

https://en.wikipedia.org/wiki/Toxic_shock_syndrome

---

Highlighted below the key toxins/superantigens. As above, explains the risk of what is identical to toxic shock syndrome. I'm concerned a cytokine storm could be one eventual outcome of VAIDS as each reinfection persists for longer with higher viral loads & quasispecies swarms. I need hardly explain the gross negligence of using full length spike protein expressing mRNA gene therapies with these motifs.

Aegrescit medendo

“The remedy (cure) is worse than the disease”.

And we already have case studies:

Autoantibody Release in Children after Corona Virus mRNA Vaccination: A Risk Factor of Multisystem Inflammatory Syndrome?https://doorlesscarp953.substack.com/p/autoantibody-release-in-children?s=w

Note the reference to HIV glycoprotein GP-120, another superantigen, neurotoxic and also of lab origin:

Absolute proof: The Gp-120 sequences prove beyond all doubt that "COVID-19" was man-made

The "missing link" was there in Pradhan's paper all along, we just needed to ask the right question: "where are the genome sequences for the Gp-120 inserts"

Dr Ah Kahn Syed

Apr 10, 2022

https://arkmedic.substack.com/p/absolute-proof-the-gp-120-sequences?s=r

---

"The insertion PRRA together with the sequentially preceding seven amino acids and succeeding Arg (fully conserved among β-coronaviruses) have been pointed out to form a motif, Y674QTQTNSPRRAR685, homologous to that of neurotoxins from Ophiophagus (cobra) and Bungarus genera, as well as neurotoxin-like regions from three RABV strains (21) (Fig. 2C). We further noticed that the same segment bears close similarity to HIV-1 glycoprotein gp120 superantigenic motif F164-V164."

"This dodecapeptide sequence within the SEB shows strong conservation among a broad range of staphylococcal and streptococcal SAgs "

"This led to the identification of the nine sequence stretches including three Botulinum neurotoxin type D or G precursors, and two motifs that have a high similarity with the intercellular adhesion molecule 1 (ICAM-1). Comparative analysis with SARS-CoV-2 spike sequence revealed that seven of these sequence motifs are conserved between SARS-CoV and SARS-CoV-2."

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations (2020)

Abstract

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors (TCRs). Here, we used structure-based computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a high-affinity motif for binding TCR, interacting closely with both the α- and β-chains variable domains’ complementarity-determining regions. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any other SARS coronavirus), which is highly similar in both sequence and structure to bacterial superantigens. Further examination revealed that this interaction between the virus and human T cells is strengthened in the context of a recently reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from a motif shared between the SARS viruses from the 2003 and 2019 pandemics, which has intracellular adhesion molecule (ICAM)-like character. These data suggest that the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.

Keywords: Covid-19, Superantigen, SARS-CoV-2 Spike, Toxic shock syndrome, Cytokine

Figure 2:

Sequence and structural properties of the insert “PRRA” motif.

A–B SARS-CoV-2 encodes both a cleavage site (1) and neurotoxin motifs (21) near the insertion PRRA that distinguishes it from SARS-CoV. (A) Sequence alignment of SARS-CoV-2 and multiple SARS-CoV and Bat SARS-like CoV strains (1) near the insertion PRRA. (B) Structural alignment of SARS-CoV-2 and SARS-CoV at the same region. The PRRARS motif is shown in red sticks. (C) Sequence similarity between neurotoxin motifs and the close neighborhood of the PRRA insert, reported earlier (21) as well as HIV-1 gp120 SAg motif (22) in the last row. (D) SARS-CoV-2 S trimer composed of S1 subunits only. The protomers are colored orange, red and gray, and displayed in van der Waals format. The protruding motifs E661-R685 are highlighted in white, green, red, and blue representing the hydrophobic, hydrophilic, acidic, and basic residues…

CONCLUSION

An understanding of the immunopathology leading to severe manifestations of COVID-19, in both adults and children, is of critical importance for effective management and treatment of the disease. MIS-C shows remarkable similarity to pediatric TSS (5–9). Using in silico modeling and analysis, we found that SARS-CoV-2 encodes a superantigen motif near its S1/S2 cleavage site. This region is highly similar in structure to the SEB SAg motif that interacts with both the TCR and CD28 (23) and mediates TSS. SEB enables large-scale T cell activation and proliferation (13), resulting in massive production of pro-inflammatory cytokines including IFNγ, TNFα and IL-2 from T cells as well as IL-1 and TNFα from APCs (13). This cytokine storm leads to multi-organ tissue damage similar to what is now observed in MIS-C. We therefore propose that MIS-C observed in COVID-19 patients may be mediated by superantigen activity of the SARS-CoV-2 S protein…

Full paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263503/