The novel coronavirus' spike protein plays additional key role in illness

md_a

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Scientists have known for a while that SARS-CoV-2's distinctive "spike" proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that they also play a key role in the disease itself.


The paper, published on April 30, 2021, in Circulation Research, also shows conclusively that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a cellular level. The findings help explain COVID-19's wide variety of seemingly unconnected complications, and could open the door for new research into more effective therapies.

"A lot of people think of it as a respiratory disease, but it's really a vascular disease," says Assistant Research Professor Uri Manor, who is co-senior author of the study. "That could explain why some people have strokes, and why some people have issues in other parts of the body. The commonality between them is that they all have vascular underpinnings."

Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.

While the findings themselves aren't entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There's been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.
In the new study, the researchers created a 'pseudovirus' that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model—proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.

The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2's molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.


Previous studies have shown a similar effect when cells were exposed to the SARS-CoV-2 virus, but this is the first study to show that the damage occurs when cells are exposed to the spike protein on its own.

"If you remove the replicating capabilities of the virus, it still has a major damaging effect on the vascular cells, simply by virtue of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID," Manor explains. "Further studies with mutant spike proteins will also provide new insight towards the infectivity and severity of mutant SARS CoV-2 viruses."

The researchers next hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.
 

LeeLemonoil

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Can this in part explain vascular side effects of the vacines like thrombosis and so forth?
 

Giraffe

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ENGLISH - wodargs Webseite!

Dangerous side effects of genetically induced production of SARS CoV-2 spike proteins
Wolfgang Wodarg 15.3.2021

Neither Coronaviruses nor their spikes do enter blood in uncomplicated infections. In more than 90% of all corona-infections immune barriers in the upper respiratory tract or local mucosa immunity will prevent this. This is the result of T-cell driven cross-immunity. (1)

We do not find such an immunity by analyzing antibodies, instead we would have to analyze many T- cell epitopes of corona viruses (2), which is an effort to big to be used for preventive public health reasons.

No matter, which new mutation of a virus will come, the cellular memory of the local immune system is able to recognize tens of different typical epitopes of each respiratory virus species, even then, when some of them have changed by mutations (2).

This seems to be true for all mild respiratory infections and not just for coronaviruses*.

In rare cases of insufficient local immunity, or by medical manipulations (intubation!) viruses happen to enter the blood and become targets of a stronger and more generalized immune defence with humoral and cellular traces (e.g. antibodies) and symptoms like fever or even hampered organ function (less than 1%) (3).

If coronaviruses reach blood, the effect of corona-Spikes within the blood system is well known to be the reason for complicated or deadly Corona infection courses. Some of them are seen as a direct effect in reaction with certain cell receptors, others are reported as secondary effects, happening when infected cells start reproducing new viruses.

All those reactions take place or start within some days or in the first weeks after the infection. Those effects may be the reason for the fact that even some younger patients are dying each year with atypical pneumonia, heart or central nervous complications after some infection with different flu viruses like Influenza A or B, Parainfluenza, human Metapneumovirus, RS-Virus, Coronavirus and many others.

It is well known that also virus-virus synergism as well as superinfections with bacteria or nosocomial infections may play an important role in those rare complications among children and younger adults. Very often there are other pathogenetic factors that lead to complications. All those cases have to be distinguished from elderly victims, where frailty und chronic diseases weaken the resistance against any additional infectious stress.

No matter, where those corona-spikes come from, whether they are part of whole viruses or just spike-proteins, produced by genetically programmed cells, in both cases dangerous reactions may result, if they reach the patient’s blood vessels.

Again, a normal acute respiratory infection without fever or severer symptoms (> 99%) does not come along with corona-spike protein reaching the blood and does not initiate risky generalized immune alarms.

However when genetically engineered vectors or particles are injected into the upper arm muscle, natural immune barriers or systems of defence are bypassed.

There are not enough competent immune cells in the tissue of the m. deltoideus. And as soon as some closer cells in the muscle start to produce and present spike protein, there should be a strong and more and more generalizing local immune reaction with swellings and pain. This fits well with observed side effects of the ongoing experimental use of all genetically modifying injections.

It is unknown where the new self-made spike proteins remain, or whether parts of them could go with the blood. As there are many blood vessels in the muscle, it may happen often and easily, that part of the injected dose reaches the blood already during injection.

If this happens, the complications may be similar to those, coming along with hematogenous sowing during a complicated infection.

In such cases there are three possible risks of vaccination, that can have similar serious consequences and even may happen in combination with each other:


1.
after intramuscular injection, it must be expected that at least in some cases the injected genetic information may leave the injection site by mistake or accidentally and more or less enter the bloodstream to be spread throughout the body [1].

In such cases, it must be also expected that the genetic information will be distributed in the bloodstream and taken up by endothelial cells in different parenchymatic organs. Endothelic cells are those cells, with which blood vessel walls are lined. It can be assumed, that such uptake in endothelial cells occurs particularly at sites with slow blood flow. This will presumedly happen, where the contact time is long enough, such as during capillary passage or in the venous system following with low pressure and orthostatic narrow venous network.

When this happens, the injected genetic information will cause those endothelial cells to produce portions of spike proteins and present them on their surfaces to passing blood cells.

Many healthy individuals have CD8 lymphocytes that patrol the blood and recognize such corona spike peptides, which may be due to previous COVID infection but also to cross-reactivity with other coronavirus types [6; 7] [8].

We must assume that these CD8 lymphocytes launch an attack on the corresponding cells upon contact. This can lead to vascular wall damage at countless sites in the body with subsequent triggering of blood clotting by activation of platelets (thrombocytes). This is what happens when the vaccine itself enters the blood.


2.
when such spike proteins, genetically engineered from our cells, enter the blood, they directly bind with the ACE2 receptors of platelets, which also leads to blood clotting and thrombosis [9][10]. This has also been observed with whole coronaviruses entering the blood in rare cases. Thrombocytopenia so developed has also been reported in vaccinated individuals [11][12][13].

3.
In addition: the ability of the SARS-CoV-2 spike proteins to initiate cell fusions is very strong. The resulting giant cells can also lead to vasoobstruction, inflammatory responses, and microthrombosis. (14)


Manifestations of all three risks

On blood tests, it can be seen by a drop in platelet count and the appearance of D-dimers (fibrin degradation products) in the blood. Clinically, there can be innumerable damages as a result of circulatory disorders throughout the body, including the brain, spinal cord and heart. Because of such consumption of clotting factors and platelets, hemorrhage can also occur in various organs and have fatal consequences, for example, in the brain.

Importantly, for all of the above possibilities that can lead to disseminated intravascular coagulation (DIC), all three vaccines lack evidence that those risks have been excluded by the EMA prior to their approval for use in humans.

*Patients admitted to hospitals with atypical viral infections usually also have multiple infections (12), but unfortunately, especially in times of fixation on Covid-19, these are rarely clarified by differential diagnosis.

**The first two questions presented have also been submitted to the European Medicines Agency by an international group of scientists on 2/28/2020.
 

StephanF

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Yes, Giraffe, I listened to the Corona-Ausschuss sessions, some international ones are in English, and Dr. Wolfgang Wordag explains in detail the effect of the spike protein. This holds for both, during an active Coronavirus infection and the presence (or production, in the case of the mRNA ‘vaccine’) of the spike protein in the vaccines.

Symptoms like severe headaches right after a vaccination may indicate a narrowing of the veins in the brain. He explained that if the needle injures a vein at the injection site, that the mRNA can cause inflammation of the cells in the brain’s veins. Since the head is above the heart, there is a negative pressure between the heart beats and that the veins collapse. If the cells are now producing the spike proteins, this can lead to closures of these veins.

The only criticism I have with this theory is the timing. Even if the mRNA enters the blood stream, this proposed process doesn’t occur instantly. The negative reactions like headaches right after the injection must therefore come from the adjuvants.

I have watched now sessions 38-50 and I must say this is the most interesting, educational ’show’ that I have watched. A pity that it doesn’t have English subtitles.

In the session 38, one person mentioned that in session 22, the lawyer Dr. Fuellmich attacks the PCR test. This will be the next session I am going to watch!
 

PxD

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This sounds troubling, given that mRNA vaccines are specifically designed to turn the recipient's body into a spike protein factory.
 

cedric

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Could masks (intermittent hypoxia/reoxygenation) be responsible for COVID? Is oxygen/"respirator" making "viral" entry?

J Cell Mol Med
. 2018 Mar;22(3):1873-1882.
doi: 10.1111/jcmm.13471. Epub 2018 Jan 24.

ACE2-EPC-EXs protect ageing ECs against hypoxia/reoxygenation-induced injury through the miR-18a/Nox2/ROS pathway​

Cheng Zhang 1 2, Jinju Wang 1, Xiaotang Ma 3, Wenjun Wang 2, Bin Zhao 3, Yanfang Chen 1, Can Chen 3, Ji C Bihl 1

Abstract​

Oxidative stress is one of the mechanisms of ageing-associated vascular dysfunction. Angiotensin-converting enzyme 2 (ACE2) and microRNA (miR)-18a have shown to be down-regulated in ageing cells. Our previous study has shown that ACE2-primed endothelial progenitor cells (ACE2-EPCs) have protective effects on endothelial cells (ECs), which might be due to their released exosomes (EXs). Here, we aimed to investigate whether ACE2-EPC-EXs could attenuate hypoxia/reoxygenation (H/R)-induced injury in ageing ECs through their carried miR-18a. Young and angiotensin II-induced ageing ECs were subjected to H/R and co-cultured with vehicle (medium), EPC-EXs, ACE2-EPCs-EXs, ACE2-EPCs-EXs + DX600 or ACE2-EPCs-EXs with miR-18a deficiency (ACE2-EPCs-EXsanti-miR-18a ). Results showed (1) ageing ECs displayed increased senescence, apoptosis and ROS production, but decreased ACE2 and miR-18a expressions and tube formation ability; (2) under H/R condition, ageing ECs showed higher rate of apoptosis, ROS overproduction and nitric oxide reduction, up-regulation of Nox2, down-regulation of ACE2, miR-18a and eNOS, and compromised tube formation ability; (3) compared with EPC-EXs, ACE2-EPC-EXs had better efficiencies on protecting ECs from H/R-induced changes; (4) The protective effects were less seen in ACE2-EPCs-EXs + DX600 and ACE2-EPCs-EXsanti-miR-18a groups. These data suggest that ACE-EPCs-EXs have better protective effects on H/R injury in ageing ECs which could be through their carried miR-18a and subsequently down-regulating the Nox2/ROS pathway.

Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells​

Highlights​



Hypoxia downregulates SARS-CoV-2 receptors ACE2 and TMPRSS2 and inhibits viral entry

Hypoxic signaling inhibits SARS-CoV-2 replication and particle genesis via HIF-1α

HIF prolyl hydroxylase inhibitors are a potential therapeutic option for COVID-19[...]
We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19."

Telmisartan protects chronic intermittent hypoxic mice via modulating cardiac renin-angiotensin system activity[...]​


Results​

Cardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment.

Conclusions​

CIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts.[...]
However, a key component of RAS, angiotensin converting enzyme 2 (ACE 2), inhibits RAS and exhibits vasodilatatory and anti-proliferative functions [3]. Currently, the effects of ACE 2 on the cardiovascular system have been investigated in diabetic animal models. However, the expression and function of ACE 2 in the hearts of CIH animals has not, to date, been explored. Previously, we reported that we successfully generated a CIH mouse model and studied the potential mechanisms by which CIH impaired cardiovascular function [4]. In our published work, we also investigated the protective effects of an angiotensin receptor blocker (ARB), telmisartan (TERT), that both has vasodilatory and anti-oxidative activity and is widely used clinically as an antihypertensive [5,6,7]. We found that CIH increased oxidative stress in the mouse hearts, as evidenced by increased levels of 8-hydroxy-2′-deoxyguanosine/8-hydroxyguanosine (8-OHdG/8-OHG), malondialdehyde (MDA), and NADPH oxydase p47, which were suppressed by TERT treatment [4]. In the present study, we investigated the mechanisms by which CIH affects the RAS. Furthermore, we explored whether TERT could protect against CIH-induced cardiac damage via modulating the activity of the RAS. Our goal was to elucidate the mechanisms by which TERT, and more generally, ARB, may act in the treatment of SAS."

Event 201?
 

cedric

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md_a

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Can this in part explain vascular side effects of the vacines like thrombosis and so forth?
 
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