Omicron BA. 5 Spike is bad vaccine target

And much much more.

I try to write something every day but had to deal with legal stuff today, so tomorrow I might not write anything, an FYI of some sort. Earlier today, the writer Doorless Carp commented on my yesterday’s piece with the link to the following paper. One of the few other writers I actively read, encourage you to check out.

Structural evolution of severe acute respiratory syndrome coronavirus 2: Implications for adhesivity to angiotensin-converting enzyme 2 receptors and vaccines

Two of the most important lessons I learned with the friend I collaborated with in the PAID research were: 1. Always look upstream (on molecular pathways) 2. Too much or too little of anything will cause problems. The smaller that something, an enzyme or molecule, the more problems it can cause because more at the top of the upstream pathways it is.

Here authors argue, and give plenty of reasoning (it is backed by dozens of papers in fact) in which how the Spike protein attaches to the ACE2 receptor, with such force that it basically eliminates an important stage of ACE2 “metabolism” (actually an enzyme reaction), which makes your body produce less of the byproducts of ACE2, reducing expression of Ang1,7. Ang1,7 is produced from Ang II and when/if you skip such an important step, you have higher levels of Ang II, and as we already learned here many months ago, skewing the ratio of anything inside the body is a short way to bad outcomes.

To test their hypothesis they went through various bioinformatics to build the Spikes for the BNT162b2 vaccine, alpha and omicron variant. Their findings were somewhat… intriguing.

Their findings are easy to understand. The Spike constructed by them (which is the BA. 5) had a binding affinity 63-fold compared to Alpha, which they highlight the Q498R forming a new bond. Very near this sequence is another, the Q493 mutation, one search away, as impactful as this one.

These changes in the Omicron BA. 5 Spike protein and its higher affinity and adhesivity (how strong it “glues” to the receptor) are expected to enhance Ang II, and therefore downregulate Ang1,7, which will have profound physiological effects because of how efficient Omicron BA. 5 is on both evasion and replication. And it will of course affect a vaccine designed with BA. 5 Spike (right now they are using BA. 1). Now let us connect some dots.

COVID-19, perioperative neurocognitive disorder and SARS-CoV-2-induced dysregulation of the renin-angiotensin system and kynurenine metabolism.

Hence, high Ang-II-mediated activity in SARS-CoV-2 could be a mechanism for hippocampal neurotoxicity. Importantly, increased central Ang-II induces amyloidogenesis during stress, and Aβ production is completely abolished by intracerebroventricular administration of losartan

The ACE/ACE2 ratio increases, whilst a decrease in the Ang-II/Ang (1–7) ratio occurs in AD11 and possibly in the pathogenesis of COVID-19.12 In fact, centrally acting ACE inhibitors reduce dementia and cognitive decline, and enhance memory in mild-to-moderate AD,19 and candesartan, an AT1R antagonist, diminishes the incidence of non-fatal stroke.19

Increased hippocampal expression of Ang-II and AT1R is linked with hippocampal BBB disruption as early as 6 h after surgery in aged rats, whereas AT1R antagonists restore BBB integrity by suppressing the canonical surgery-induced nuclear factor-кB activation cascade.20 Importantly, starting ACE inhibitors or AT1R blockers in the early postoperative period was associated with reduced delirium in critical care settings

Tryptophan–kynurenine metabolism

Interferon-γ and Ang-II via INF-γ induce indoleamine 2,3-dioxygenase (IDO) activity after SARS-CoV-2 infection.21 Increased expression of IDO activity and kynurenine (KYN)/tryptophan (TRP) ratio is evident in nasal epithelium after influenza type A infection.22 Altered KYN metabolism is an early marker of inflammation in SARS-CoV-2 infection, high levels of neurotoxic metabolites (3-hydroxykynurenine [3-HK] and quinolinic acid [QUIN]) with low levels of neuroprotective by-products (kynurenic acid [KYNA]). The xanthurenic acid (XA) of KYN pathways is linked with COVID-19 severity.21 In fact, high 3-HK/KYN, 3HK/KYNA, and QUIN/KYNA ratios are evident on metabolomic studies in COVID-19.21 High levels of neoptrin and low levels of XA are additional markers of severity.21 Severe COVID-19 is associated with reduced quinolinic acid phosphoribosyltransferase expression and reduced production of nicotinamide adenine dinucleotide.23 3-HK and QUIN are strong competitive agonists of glutamate.24 Contrarily, both KYNA and XA inhibit N-methyl-D-aspartate receptors. KYNA also inhibits presynaptic α7 nicotinic receptors in hippocampal neurones, but increases non-α7 nicotinic receptor expression.24 3-HK may cause reactive oxygen species formation leading to microvascular damage, increased BBB permeability, and neurotoxicity. Increased QUIN and 3-HK levels in astrocytes and neurones result from cytokines, such as INF-γ, tumour necrosis factor-α, and interleukin-1β.24 Increased QUIN and 3-HK levels can cause nerve conduction abnormalities and neurological toxicity especially in the hippocampus, striatum, and other parts of the neocortex that are sensitive to QUIN.24

We hypothesise that SARS-CoV-2 infection produces QUIN and 3-HK from olfactory epithelium that diffuses transmucosally to produce direct neuroexcitatory injury to olfactory bulb neurones, resulting in anosmia. Interestingly, direct glutamate administration at the level of olfactory bulb induces anosmia that recovers spontaneously within 2 weeks,25 the duration of anosmia usually seen in COVID-19.26 Transmucosal spread of KYN metabolites to higher-order brain structures in the olfactory–hippocampal pathway is a possibility. Systemic KYN metabolites, KYN and 3-HK, in contrast to plasma KYNA, can readily cross the BBB to generate high central QUIN levels and induce neuronal inflammation, oxidative stress, and hippocampal injury.

Similar alterations in KYN metabolism are seen in patients with neurovascular diseases.21,24 Ageing and AD are also associated with deregulated KYN metabolism. Alteration of KYN metabolism, involving tryptophan depletion along with marked increases in QUIN, but decreases in KYNA and XA plasma levels occurred in both AD and with ageing.24

In conclusion, dysregulated renin–angiotensin and KYN metabolism pathways in COVID-19 pathogenesis are similar to those in ageing, AD dementia, and PND. Studies confirming the role of these pathways in COVID-19 neurocognitive decline are urgently needed to establish targets for reducing PND in patients who had COVID-19 and are undergoing surgery. This is further highlighted by the evidence from the recent meta-analysis showing reduced risk of cognitive decline in older adults on AT1R blockers and ACE inhibitors with BBB-crossing potential.

To understand this part, or how meaningful it is, you must read the following piece, I will work on Part II and cover the IDO pathway some more. Even if it takes you 3, 4 reads, you must understand this pathway.

Kynurenine Pathway and SARS-CoV-2

The paper above is from November of 2021, and it was submitted in July of the same year, therefore the authors were not aware of the new evidence coming out by November. But here we have a few more examples of how the SARS-CoV-2 induces changes in the metabolism of Tryptophan and Kynurenine, and shifts the balance of these amino acids from protective, to toxic, their mechanism is somewhat different than the one I wrote, mine is most from a metabolic perspective alone, it is not merely a response towards inflammation and immune dysregulation, but an active byproduct of the metabolic shift the virus causes in your cells and mitochondria.

Pay attention to the third paragraph of the ANG II section, where Ang II upregulation breaks down the Blood Brain Barrier. Now, I prefer simplified and less extensive pieces for the last few months because I want people to absorb most of what I write about. This one will be old-school me.

Activation of NAD(P)H Oxidase by Tryptophan-Derived 3-Hydroxykynurenine Accelerates Endothelial Apoptosis and Dysfunction In Vivo

Mechanistically, we found that AngII-enhanced 3-hydroxykynurenine promoted the generation of NAD(P)H oxidase–mediated superoxide anions by increasing the translocation and membrane assembly of NAD(P)H oxidase subunits in endothelial cells, resulting in accelerated apoptosis and consequent endothelial dysfunction.

Angiotensin II and atherosclerosis

In vascular cells, Ang II is a potent stimulus for the generation of reactive oxygen species. As a result, Ang II upregulates the expression of many redox-sensitive cytokines, chemokines, and growth factors that have been implicated in the pathogenesis of atherosclerosis.

Angiotensin II Mediates High Glucose-Induced TGF-β1 and Fibronectin Upregulation in HPMC through Reactive Oxygen Species

The present data demonstrate that HPMC constitutively express RAS, that Ang II produced by HPMC mediates high glucose-induced upregulation of TGF-β1 and fibronectin expression, and that Ang II-induced TGF-β1 and fibronectin expression in HPMC is mediated by NADPH oxidase-dependent ROS. These data suggest that locally produced Ang II and ROS in the peritoneum may be potential therapeutic targets in peritoneal fibrosis during long-term peritoneal dialysis

Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

The present study examined the effects of ANG II on expression of a number of NF-κB-dependent pro-inflammatory genes and PPAR-α and -γ mRNA and protein expression in the vascular wall in an in vivo mouse model of atherosclerosis and aneurysm formation (10). Our data indicate that ANG II induces NF-κB-dependent pro-inflammatory genes and downregulates PPAR-α and -γ mRNA and protein expression in apoE-KO mice. Reduced PPAR expression may attenuate an important anti-inflammatory defense mechanism, thus contributing to ANG II-induced vascular inflammation.

Angiotensin II Upregulates Toll-Like Receptor 4 on Mesangial Cells

together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.

And the best for last.

Angiotensin II induces reactive oxygen species, DNA damage, and T cell apoptosis in severe COVID-19

We show that the monocytes of certain COVID-19 patients spontaneously released ROS able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs, and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, Angiotensin Converting Enzyme 2, a protease able to catabolize AngII. Accordingly, we observed in certain COVID-19 patients high plasma levels of AngII. Looking for the stimulus responsible for their monocytic ROS production, we unveiled that AngII triggers ROS production by monocytes via Angiotensin receptor I. ROS released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes.

These are but a few, and judging by the small paragraphs I shared, does any of these remind you of anything, or it is just me ?

About to take a bunch of notes (not my notebook, but I use similar, and similar pens. If you don’t use fountain pens, wth is wrong if you ?)

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