Molecular mimicry of SARS-nCoV-2 spike to human proteins including thrombopoietin and TLR-8

High autoimmune potential shown via cross-reacting antibodies.

Please refer to the paper entitled: “Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins” published June 28, 2022 in Viruses.

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This was brought to my attention via an article I posted yesterday. They found the following.

We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients.

Figure 1: A photomicrograph of the blood showing thrombocytopenia. https://en.wikipedia.org/wiki/Thrombocytopenia

Thrombocytopenia is a coagulation disorder characterized by abnormally low levels of platelets. Thrombopoietin (TBO) regulates the production of platelets.

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The autoantibodies bind TBO to block binding to TBO receptors and subsequently inhibit platelet production. Interestingly, heparin-induced thrombocytopenia is the most common drug-induced, antibody-mediated thrombocytopenic disorder.

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The authors summarize a list of motifs that share this potential for induction of autoimmunity from other proteins. There are a total of 16 human proteins identified as 3D mimics based on an RMSD (Root Mean Square Deviation - small differences between values) of at most 1 Å (Ångstrom) listed in Table 1. Of these is thrombopoietin - a regulator of platelet production, and Toll-Like Receptor 8 (TLR-8). TLR-8 is a receptor that recognizes single stranded RNA (ssRNA) and when it does, it recruits MyD88 and leads to activation of the transcription factor NF-κB (DNA transcription) to initiate an antiviral response. TLR-8 recognizes ssRNA viruses such as HIV and HCV, and since coronaviruses are also ssRNA viruses, it likely recognizes them too.

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It is also interesting to note that TLR-8 expression levels are also significantly elevated in individuals with severe and critical COVID-19.

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This implies that cross-reactivity, if possible, would be more likely to ensue.

Figure 2: 3D-mimics found for SARS-nCoV-2 spike. Table 1 from paper.

These are alarming findings, but I think I can add to the alarm, if I am correct that is. One of the motifs implicated in autoimmune reactions via molecular mimicry found in SARS-nCoV-2 and human thrombopoietin, namely: TQLPP, is not found in SARS-nCoV. Now, where have I heard this kind of story before? Furin cleavage site? Other inserts? Hmm. One of the clinical manifestations of SARS-nCoV-2 that appears distinct from SARS-nCoV is this bleeding/clotting/vascular component. What if the antibodies generated against this motif in the spike protein of SARS-nCoV-2 are going after human thrombopoietin and via cross-reactivity inducing down-stream signaling to modify platelet production?

The implications of this are quite staggering because it is highly unlikely (some genius out there can calculate the likelihood - ahem: Jikky (his fan account got erased from Twitter today again)) that this motif would ‘arise’ in the SARS-nCoV-2 version ‘naturally’. It’s another brickky in the wall. In my opinion, it’s statistically impossible for all of these unique SARS-nCoV-2 motifs to naturally arise.

Figure 3: X-ray crystal structure of SARS-nCoV-2 spike protein with TQLPP motif highlighted in yellow spheres. https://www.rcsb.org/structure/7CWM

Figure 4: X-ray crystal structure of SARS-nCoV-2 spike protein with TQLPP motif highlighted in yellow spheres aligned with X-ray crystal structure of SARS-nCoV lacking this motif. https://www.rcsb.org/structure/7CWM; https://www.rcsb.org/structure/5X58

Basically, this is further evidence that the original SARS-nCoV-2 was constructed, and it was constructed by very intelligent people. They must have known that this molecular mimicry was possible and the implications of autoimmune responses. We are seeing ITP, TTP and all sorts of thrombocytopenias in VAERS and in life.

Figure 5: VAERS reports of thrombocytopenia as of July 1, 2022 normalized to CDC age-stratified dose 1 data.

By the way, there’s also this.

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Results:

SARS-CoV-2 spike glycoprotein was found to share 41 minimal immune determinants, that is, pentapeptides, with 27 human proteins that relate to oogenesis, uterine receptivity, decidualization, and placentation. All the shared pentapeptides that we identified, with the exception of four, are also present in SARS-CoV-2 spike glycoprotein-derived epitopes that have been experimentally validated as immunoreactive.

We’re really up the creek without a paddle on this one.

1. Nunez-Castilla, J.; Stebliankin, V.; Baral, P.; Balbin, C.A.; Sobhan, M.; Cickovski, T.; Mondal, A.M.; Narasimhan, G.; Chapagain, P.; Mathee, K.; et al. Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins. Viruses 2022, 14, 1415. https://doi.org/10.3390/v14071415.

2. Kuter DJ, Gernsheimer TB. Thrombopoietin and platelet production in chronic immune thrombocytopenia. Hematol Oncol Clin North Am. 2009 Dec;23(6):1193-211. doi: 10.1016/j.hoc.2009.09.001. PMID: 19932428; PMCID: PMC2789970.

3. https://www.news-medical.net/news/20210816/SARS-CoV-2-Spike-may-trigger-production-of-antibodies-that-cross-react-with-human-thrombopoietin-to-induce-thrombocytopenia.aspx

4. https://rarediseases.org/rare-diseases/immune-thrombocytopenia/

5. https://en.wikipedia.org/wiki/Toll-like_receptor_8

6. Kayesh MEH, Kohara M, Tsukiyama-Kohara K. An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants. Viruses. 2021 Nov 18;13(11):2302. doi: 10.3390/v13112302. PMID: 34835108; PMCID: PMC8622245.

7. Dotan A, Kanduc D, Muller S, Makatsariya A, Shoenfeld Y. Molecular mimicry between SARS-CoV-2 and the female reproductive system. Am J Reprod Immunol. 2021;86(6):e13494. doi:10.1111/aji.13494.