Spike Protein causes endothelial inflammation independently

And an annoucement

First, I wish everyone a good weekend ahead. While I deeply value the feedback of my subscribers, I decided to follow my gut and create another Substack. The majority of my readers are here for the health/science aspect of it, some for the deeper analysis. I still need to set up and finalize an introductory post, but for the most part, the new Substack will cover what the Beyond Mathematical Odds series covered, but more, it will give me the freedom to write whatever I want, such as Cognitive Warfare, the many recent uses of AI, etc. Such change will enable me to use this Substack solely for Science and Medicine, and explore any subject I see fit in the other one.

I will not shill the other Substack (shilling means pushing it often), nor I will bring my current e-mail list there, so if you are interested in the other side of things I write, similar to what I did on Twitter, you should subscribe. With this out of the way, to more pertinent matters.

At this point in time, if you are one of my readers, it should be no surprise how the Spike Protein from SARS-CoV-2 can interact with a couple of dozen receptors on its own. No virus is needed, just Spike to achieve many pathological effects. This one will be short and bittersweet.

Given the subject of the last article, both the presence of vaccine Spike, and SARS-CoV-2 RNA in the central nervous system downregulating ACE2, by being “stuck” around perycites and affecting endothelial cells, the following is a significant find. Before delving any further, a little summary.

ACE2 is a very important part of the RAAS (Renin-Angiotensin-Aldosterone System) it plays a fairly complex role in the hormonal system to regulate blood pressure, fluid balance (salt and water), and electrolyte levels in the body.

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication

Given the importance of the enzyme ACE2 on human physiology and its significant role in all levels of infection and sequelae of SARS-CoV-2, the authors here attempted to investigate if the Spike Protein binding to ACE2 induces endothelial inflammation and to determine the role of ACE2 in the process. Human endothelial cells were exposed to the S1 subunit (here named rS1p) and cell signaling and inflammation were assessed.

Endothelial cells were also exposed to SARS-CoV-2. rSP1 increased production of IL-6, MCP-1, ICAM-1 and PAI-1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury.

Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS-CoV-2 virus did not exhibit viral replication. We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID-19- associated endotheliitis.

What is the significance of these findings ? In simpler terms, IL-6 is a well-known inflammatory protein, one of the most powerful ones and here its increased production means endothelial cells are responding to the S1 part of the Spike Protein and releasing IL-6, which signals the body to produce inflammation. MCP-1 (Monocyte Chemoattractant Protein-1), as per the implies, is a protein that attracts monocytes, meaning the endothelial cells are “calling” immune cells towards the area. ICAM-1 (Intercellular Adhesion Molecule-1) is an adhesion molecule, and it functions by facilitating different cells “gluing” together. PAI-1 (Plasminogen Activator Inhibitor-1) is a protein that regulates both clotting and tissue remodeling (this is a fancy word to describe healing from an injury, here at a molecular level, increased levels of PAI-1 indicates more propensity towards clotting, not a surprise so far as many other authors throughout the last 3 years demonstrated the ability of the Spike alone to induce clotting.

Among the many tests in the paper on the proteome (most or the entire groups of proteins expressed in cells, or in organisms) the following quote bears more significance to me.

biological process enrichment showed proteins from major signalling pathways and cellular processes, such as translational, virus transcription, cell–cell adhesion, NFκB signalling, oxidation–reduction process, MAPK cascade, T-cell receptor signalling, suggesting that rS1p induced endothelial cell inflammation and proliferation

Most of the signaling pathways and cellular processes here are shared by both the S1 and Endotoxins (LPS), and so do all of the previously discussed proteins/markers. While LPS is a highly complex and substantial subject, it has been demonstrated that lung exposure to LPS leads to the downregulation of ACE2. In their own words “In addition, TLR activation itself may be an additional mechanism of spike protein-induced inflammation.”



The authors propose 3 possible mechanisms for this effect on endothelial cells by the Spike Protein alone, inducing inflammation and damage.

• Hypothesis 1, in simpler terms, the interaction between the virus and ACE2 may not only allow the virus to enter cells but also trigger inflammation as a result of this interaction. The moment the virus uses ACE2 as a receptor, it often internalizes the virus with ACE2, leading to a systemic shift in ACE2 levels.

• Hypothesis 2, ACE2 loses its enzymatic activity, leading to the loss of balance between important molecules such as Angiotensin II (AngII) and Angiotensin-(1-7) (Ang-(1-7)).

• Hypothesis 3, ACE2 might play a role in directly regulating cell signaling pathways, suggesting ACE2 is more than a receptor, it can actively change how the body responds to inflammation.
  
  There is a case to be made for all 3 in fact, but the most pertinent to our discussion would be Hypothesis 2. The Spike used here was the Wuhan Spike (as it has often been in the past 12 months), and the author left “in the air” the potential for the current strains to induce this level of dysfunction, given the virus collects dozens of mutations per new “variant”. A little over a year ago, I was sent a paper by DoorlessCarp and wrote the following.

Omicron BA. 5 Spike is bad vaccine target

The Spike Protein from Omicron BA. 5 had an incredibly strong binding strength to ACE2, capable of “tilting” the RAAS(ystem) into producing abundant quantities of a protein that increases blood pressure, coagulation, and affects the kidney. ACE2 is highly expressed in the gut, and per the Substack referred above, the dysregulation of this protein will inevitably lead not only to other complications but an indirect shift on the Tryptophan-Kynurenine pathway.

This interaction with ACE2 will potentially affect the tryptophan absorption capacity of the body, thus it can lead to changes in the microbiome, since the microbes in the gut are largely responsible for metabolizing tryptophan, and this can affect systemic immune function by changing how Aryl Hydrocarbon Receptor

By the mechanism described here alone, without adding any of the other mechanisms I covered in the last 20 months, the Spike Protein alone, especially the S1 section can induce systemic inflammation and changes in many immune and cellular functions, let alone adding Endotoxins and its extraordinary cascade effects to this equation. Once more we are presented with evidence that the Spike alone can interact and signal cells, it is a biologically active protein with dozens of physiological functions (mostly detrimental to anyone). Endothelial inflammation and damage, especially aided by ACE2 dysfunction will directly induce NETosis. (One of the main “players” in damage induced by Spike Accumulation in the brain)

Source

Do you want to know what else can create pathologic Neutrophils and contribute to NETosis ? HERVs.

Now would be a good time to remind my readers of this article.

SARS-CoV-2 hijacks the Kynurenine Pathway

As covered recently persistence of viral fragments or the virus will induce continuous downregulation (less production of) ACE2, therefore tilting the entire body into a dysfunctional immune state, where both inflammation and immune dysfunction persist. Partially at the core of these effects lies the KP, and endotoxin also plays a substantial role in this. Dysregulation of the KP (which one could also refer to as Tryptophan Dysfunction) will also “feed” cancer growth, and will induce immune suppression and tolerance.

Higher levels of Kynurenine metabolites (byproducts) are present in HHV-6 encephalophathy, some researchers proposed because certain Herpesvirus infections and neurodegenerative diseases share similar pathways, this shared dysfunctional response could be how these latent infections contribute to neurodegeneration.

Everything discussed here and the substacks referred to here will be significant in the next one, which is about prions, amyloids, and protein (mis)folding.


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