SARS-Cov-2/COVID-19 spike protein damages hematopoietic stem/progenitor cells

And is Omicron really mild ?

Before delving into this paper, first the reader needs to learn what the hell is HSPC, Hematopoietic stem, progenitor cells. From here.

Hematopoietic stem cells are immature cells found in the peripheral blood and bone marrow. They have the ability to give rise to all types of blood cells, such as white blood cells, red blood cells, and platelets, etc., through a process called hematopoiesis. Progenitor cells originate from stem cells, and they can further differentiate to create specialized cell types. They have the ability to differentiate into cells that belong to the same tissue or organ of each progenitor cell. Both HSCs and progenitor cells have applications in various cell-based therapies such as tissue regeneration and transplantation. So, this summarizes the difference between hematopoietic stem cells and progenitor cells.

They are kinda important…

At the end of the post The Case for Reverse Marek, I introduced one of my insane ideas, with marginal evidence. I suggest new subscribers read it, but here is the quote.

So months ago, while deep into researching the Reverse AIDS, sometimes we came up with uncommon pathways, that required extensive interdisciplinary research to make sense, and once in a while I usually came up with insane ideas, they were not even hypothesis.

One of those was the Protein Interaction, after your body breaks down the spike, could pieces of it interact with the rest of your body/immune system and create toxic reactions ? No, this is insanity, it’s me being crazy again haha…ha…h….

Just to be clear, this isn’t a paper, but a “letter to the editor”, sometimes when the authors think the subject is important enough, they will do this. I look forward to the paper itself.

An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner

Mounting evidence accumulates that hematopoietic stem/progenitor cells (HSPCs) and endothelial progenitor cells (EPCs) are damaged during severe SARS-Cov-2/COVID-19 infection. It has been reported that patient infected with COVID-19 are frequently presented with anemia, lymphopenia, and thrombocytopenia.

We have proposed that interaction of SP with the target cell surface receptors induces intracellular hyperactivation of Nlrp3 inflammasome which may lead to cell death by pyroptosis

Authors propose that the mere interaction of Spike Protein (SP) with cell receptors is able to hyperactivated (cause the cell to “produce” lots of Nlrp3, which is a very powerful inflammatory molecule.

Moreover, transmembrane protease 2 (TMPRSS2) cleavage of SP may augment viral entry. This facilitates its interaction with ACE2 and the subsequent fusion of viral and cellular membranes. The other receptor postulated to be involved in virus entry is toll-like receptor-4 (TLR4). Thus, this virus is using cell surface receptors that play a physiological role in the conversion of angiotensin II to angiotensin (1–7) (Ang [1–7]) as it is a case of ACE2 and TLR4 which belongs to pattern recognition cell surface receptor family and is responsible for inflammatory cytokine production and activation of the innate immunity responses. As demonstrated, both ACE2 and TLR4 are highly expressed on HSPCs and EPCs. In addition to these two receptors, SARS-CoV-2/COVID-19 may also interact with the extracellular matrix metalloproteinase inducer basigin, known as cluster of differentiation 147 (CD147) as well as recently proposed with C-type lectin receptor and Tweety family member 2

Here they mention all the different receptors that SARS-CoV-2 uses, I covered a few of them, especially the CD147, and what exactly it uses to bind to cells (CypA).

Blockage of SP interaction with cells surface-expressed ACE2 and TL4 significantly inhibited activation of Nlrp3 inflammasome downstream mediator that is caspase-1. This inhibition was even more pronounced when the interaction of SP with both receptors was blocked simultaneously, however not completely inhibited, which suggests an involvement of other receptors in Nlrp3 inflammasome activation (CD147 or other toll-like receptor family members).

The authors then design good tests to test their proposition, and by their results, I agree with their assertion, the only argument, is to level this happens.

Exposure to SP resulted in a significant increase in LDH level, which indicates the induction of pyroptosis in these cells. This effect was significantly reduced by adding rhACE2 and TAK-242, as well as after exposure to MCC950. Thus, SARS-CoV-2/COVID-19 may directly impair the viability and proliferative potential of HSPCs by hyperactivation of Nlrp3 inflammasome leading to pyroptosis. On the other hand, activation of Nlrp3 inflammasome in innate immunity cells may lead to cytokine storm and activation of the complement cascade and coagulation cascade affecting immune response against this pathogen

For laypeople, in this paragraph, the authors propose that the hyperactivation of Nlrp3 may directly impair the function of HSPCells, and also that the activation of the same inflammasome deregulates the immune system and causes a lot of the bad damage we have seen. They go on to find out which proteins are up, and downregulated when exposed to the spike protein, in my opinion, this is one of the most important steps when analyzing this virus because it generally leads to many insights (especially for me…lol). From the paper “Simultaneously, after SP exposure, we detected a decrease in expression of proteins involved in the positive regulation of cell proliferation and differentiation”, exposure to Spike Protein alone decreases the necessary proteins involved in the proliferation and differentiation, the last word means becoming other types of cells.

Therefore, HSPCs at different specification levels could be affected differently by the virus depending on expression of viral entry receptors. We and others have reported that ACE2 and TLR4 are highly expressed on the most primitive subset of HSPCs, and as demonstrated in this study, these cells are highly susceptible to SP. This study has been performed with the first available for research recombinant SP identified on SARS-Cov-2/COVID-19. Currently, there are several variants of this SP, and the biological effects of these variants need further detailed studies.

What is also important and has to be addressed is if in the case of non-productive infection the virus can survive in a latent form after entry in the long-living HSCs

This one gets complicated, and I am glad the authors are honest and don’t issue a blanket statement. At different stages, given different circumstances in regard to the HSPCells, they may be affected by the viral infection, and these cells could be a reservoir, where the virus stays in a latent form.

This entire paper is very significant for two reasons. First, is another possible reservoir of latency for the virus, something I have been saying for almost 2 YEARS. Some people, under specific circumstances, will have “chronic covid”, like people who have EBV. Second, and most important of all, the Spike Protein alone influences these important cell formation, and differentiation, causing a myriad of issues.

Why is this so significant ? Because the LNP distributes everywhere, including sources of these cells. I don’t need to explain further. Here is another piece of evidence for this, anyone following this whole vaccine saga either saw or knows someone who had iron/ferritin problems after the vaccine.

SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism

COVID-19 patients showed impaired hemoglobin biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-hemoglobin as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low serum iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity in severely ill COVID-19 patients.

This paper talks about a different type of cell and is mentioned in the paper above.

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice

Of course, this wouldn’t be me if I didn’t do this. In the case you are one of the anxious types, I already cover how to minimize all the effects of the “super flu”, including the overactivation of NLRP3 =). Here, Part 3 of my Hidden Things series.

Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice

We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC). Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 1½days of stimulation, and the best stimulators were TLR 7/8 agonist; HMGB1-DNA; TLR 9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL-17(+) memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL-17(+) T cells with "naïve" phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance.

If you want to understand what this paper means, and everything else, you should read the Reverse AIDS hypothesis posts.

As a side note, on Omicron and its apparent mild aspect.

Pulmonary lesions following inoculation with the SARS-CoV-2 Omicron BA.1 (B.1.1.529) variant in Syrian golden hamsters

The Omicron BA.1 (B.1.1.529) SARS-CoV-2 variant is characterized by a high number of mutations in the viral genome, associated with immune-escape and increased viral spread. It remains unclear whether milder COVID-19 disease progression observed after infection with Omicron BA.1 in humans is due to reduced pathogenicity of the virus or due to pre-existing immunity from vaccination or previous infection. Here, we inoculated hamsters with Omicron BA.1 to evaluate pathogenicity and kinetics of viral shedding, compared to Delta (B.1.617.2) and to animals re-challenged with Omicron BA.1 after previous SARS-CoV-2 614G infection. Omicron BA.1 infected animals showed reduced clinical signs, pathological changes, and viral shedding, compared to Delta-infected animals, but still showed gross- and histopathological evidence of pneumonia. Pre-existing immunity reduced viral shedding and protected against pneumonia. Our data indicate that the observed decrease of disease severity is in part due to intrinsic properties of the Omicron BA.1 variant.

Hamsters are a well-known and used model to test a myriad of disease, but they became a gold standard for SARS-CoV-2. So, Omicron is mild, right ? As I said weeks ago, there are only trade-offs in biology and evolution. It is mild, BUT.

In conclusion, with the continuing emergence of SARS-CoV-2 variants, models to evaluate potential phenotypic changes associated with mutations are invaluable in assessing the impact on public health. In hamsters, the currently circulating dominant SARS-CoV-2 Omicron BA.1 variant, shows reduced viral shedding and disease, recapitulating the phenotype seen in human cases. Interestingly, remaining pathogenicity in the lower respiratory tract can still be detected without being reflected in clinical manifestation.

It is doing damage, even in the lower respiratory tract, but it is keeping it at a subclinical level, that is why people are getting all sorts of weird after-effects (including me). Now I leave you with a question.

How much subclinical damage, and pneumonia you can set off before it becomes a huge problem ? Guess we will find out with the BA. 2 coming, one which will really beat the vaccinated.

Another virus post coming soon, I chose to make a different one, because it doesn’t quite fit the theme of this one, it is about an old tweet a referred to recently ;).

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