I think it'll be good to do a complete thread explaining why SARS-CoV-2 is so dangerous and why it is so hard to fight off this virus with the help of the ⁦ @khanacademy⁩. To do so will require an understanding of both the virus and immunology. https://www.khanacademy.org/video/helper-t-cells
I will annotate the tweets in this thread with as many scientific literature as possible, so you don't have to take my word for any of this. You can read the same papers I read and make up your own mind.
The cleavage site is "furin-like" instead of simply being called a furin cleavage site because the canonical cleavage sequence for furin is Arginine-X-Arginine or Lysine-Arginine. The X means any amino acid. The sequence in the virus is backwards.

This is what Arginine-Alanine-Arginine-Arginine looks like with the assistance of https://pepdraw.com .

This is what furin should cut normally if the sequence was canonical.
This is what the actual sequence is in the original SARS-CoV-2 virus is: Arginine-Arginine-Alanine-Arginine.

As you can see, it's nearly identical. You can't do this with all amino acids. It's highly likely that it has to be this exact sequence to convey high pathogenicity.
Inevitably, some of the spike protein will get cleaved into inactivate non-functional S1 and S2 subunits regardless of the fact the sequence is backwards. But instead of impeding the virus when the cell bursts, it contributes to the highly pathogenic nature of this virus.
This is because the S2 subunit sits in the membrane of the virus, it does absolutely NOTHING for B-cells to make antibodies against the S2 subunits. It wastes valuable B-cells and energy.

Making antibodies against the S1 subunit... is what makes this virus so dangerous.
To fully understand the grim nature of this virus, you have understand how this virus enters and infects a cell.

And this will inform why having a furin-like cleavage site between the S1 and S2 subunits makes this virus so very, very dangerous.
This is the full trimeric complete spike protein thanks to @RommieAmaro and collaborators.

The host machinery makes 3 spike monomers, and the 3 monomers come together to form a complete functional spike protein for the virion membrane.

https://twitter.com/rommieamaro/status/1241810976866840577?s=21 https://twitter.com/RommieAmaro/status/1241810976866840577
The final assembled trimeric spike protein is heavily glycosylated by glycans. Antibodies don't like sugars. Antibodies are proteins, and they like to bind other proteins, not sugar. The glycosylated nature of the spike protein protects the virus from attack by host antibodies.
A similiar thing happens with the HIV binding protein in glycosylation. Indeed, the spike protein shares another grim similarity with HIV.

SARS-CoV-2 also protects its furin-like cleavage site with conformational changes to the spike protein.
In order for SARS-CoV-2 to infect a cell, a protease on the surface of the host cell has to cut off one of the spike monomers. This is theory: The unstable trimer of two complete monomers and a remaining S2 subunit is likely what initiates membrane fusion between host and virus.
And this is an important part. This can happen with direct virus to host membrane fusion with the virus outside the cell or endosome or lysosome escape. This part is not entitely clear and will require more research. https://www.nature.com/articles/cr200815
And now we move on to the grimmest aspect of SARS-CoV-2 and why this virus is so very, very dangerous. But to understand fully, we have to understand immunology, and how the immune system functions with the help of the @khanacademy. https://www.khanacademy.org/video/b-lymphocytes-b-cells
A good starting point is to elucidate exactly what furin is, and which cells in the human body has furin.

And the answer to that question to quote Terminator 2... 😅 "All of them I think."

Well, not really all of them, but it might as well be.

Deleting furin in embryos is a lethal mutation. This is why people with COVID-19 often suffer heart damage. Both ACE2 and furin are in heart tissue. SARS-CoV-2 is not just a respiratory disease. It is a virus that can infect your heart.

In the rat brain, furin expression is localized especially to the ventricles (the choroid plexus and ependymal cells), the islands of Calleja, the hippocampus, and the pineal gland.

Any brain cells with both ACE2 and furin on the surface are vulnerable.

This is because hypoxia, one of the hallmarks of COVID-19, causes the blood brain barrier to break down.

SARS-CoV-2 is not just respiratory illness. It can be an encephalitis virus.

Because furin in T-cells is involved in cytokines, this makes T-cells especially vulnerable the antibody dependent enhancement of an antibody attached to the ACE2 RBD. The furin cleavage site is exposed, so any white blood cell with furin can be infected.

B-cells are also vulnerable. Especially the ones with membrane bound antibodies that bind to the ACE2 RBD because those antibodies will behave just like ACE2 in anchor the virus to the B-cell until a surface furin cleaves the spike protein.

This means you get absolutely NO B-cell effector proliferation let alone B-cell memory proliferation of the ACE2 RBD from live viruses. The only proliferation comes from pieces of the spike protein floating around that weren't assembled into the virus.
And most of those spike proteins are already cleaved into the S1 and S2 subunits. So the only way to get an antibody to the furin-like cleavage site is for the B-cell to mutate the antibody to half of the cleavage site on its own until it finds the prefect match.
That's bad enough on its own, but remember something binding to the ACE2 receptor binding domain (RBD) of the spike protein causes a conformational change in the spike protein that exposes the furin-like cleavage site. So once a B-cell lineage does start making antibodies...
That antibody that binds to the ACE2 RBD will activate the spike protein. The receptor is no longer ACE2. The receptor is now furin. ANY cell with furin on the surface unfortunate enough to bump into a virus with the ACE2 antibody can become infected.

This includes T-cells.
This is most dangerous phase of the disease. Now that the furin-cleavage site is exposed by a bound antibody, any B-cell with the right antibody to bind the furin-cleavage cleavage can do so. But remember that that B-cell can also be infected if it is super unlucky.
None of this matters if all your B-cells that can recognize the furin-like cleavage site that were floating around in your blood are already dead. Your bone marrow will have to make new ones. And that is time you simply do not have.

You need to inhibit furin as soon as possible.
Also natural killer T-cells don't just make cytokines to kill infected cells. They also burst out cytokines when they die. This is likely where the cytokine storm of COVID-19 comes from. It's just lots and lots of white blood cells dying.
Luteolin is another treatment option is a molecule known to inhibit furin although the exact mechanism of action is not entirely clear. Perhaps luteolin is also a zinc ionophore and zinc chelating agent like hydroxychloroquine.

The following is a list of all molecules that can possibly treat COVID-19.

It is highly likely that quercetin and luteolin are furin inhibitors since they only differ in a single OH group. You'll likely have to take some zinc supplements with them.

The reason that luteolin and quercetin are super safe is that they are metabolized by the human body quickly. They have very little side effects if any for precisely that reason.

But this also means that their bioavailability might be low.
A common dosage for quercetin seems to be 1000mg. That's one gram. Make sure to not overdose on any of these treatments even the super duper safe ones because often they haven't be studied extensively because they were very important.
Absolutely do NOT take lycorine though even though it works really well. It's poisonous.

Making antibodies against this virus is really, really difficult, but not impossible. People have been doing it even without taking furin inhibitors. I'm not entirely sure how. Maybe it's an antibody that binds to the side of the spike protein that blocks both ACE2 and furin?
If an antibody binds to the spike and doesn't cause significant conformational changes to the spike protein that exposes the furin-like cleavage site, that single monoclonal antibody will be neutralizing for the virus. Maybe that is why someone people are having mild disease.
But in order for it to work, the target of the serine protease has to be uncleaved and outside the bacteria. That's gotta be pretty rare. Your immune system has to lyse the bacteria and the target of the serine proteases have to remain intact.
But really tho. You should take a serine protease inhibitor with the BCG vaccine. This is safer than a vaccine with just spike protein because your body won't make antibodies against the ACE2 receptor binding domain. So you won't have an antibody dependent enhancement right away.
And when your body does make anybodies against the ACE2 RBD, you'll already have antibodies against at least 1 of the 3 cleavages sites in the spike protein. That antibody might just be big enough to block enzyme access to all 3 cleavage site including the furin-like cleavage.
So the BCG vaccine should work, but you likely have to give the vaccine to someone twice, 7 days apart. Or 3 times. First two 7 days apart. And last shot 21 days later.

Kudos to whoever figured out that the BCG vaccine was the childhood vaccine that gave cross-reactivity.
Some bad news about vaccines for this virus that I was trying to avoid.

Memory B-cells get reactivated when a pathogen bumps into their membrane-bound antibody.

Remember that something binding to the ACE2 RBD on the spike causes conformational changes to the spike protein.
If you still have the furin-like cleavage site neutralizing antibodies in your blood, memory B-cells with the ACE2 RBD antibody can reactive into plasma cells without dying.
Unfortunately, the most likely scenario is that you will be reinfected with this virus and get sick again. This time though, you'll have a much better chance of survival. There should be furin-like cleavage site neutralizing memory B-cells in your blood. Lots of them.
Some of those memory B-cells with the furin-like cleavage site antibodies will get reinfected and die, but while they're dying, they'll make more antibodies. Other B-cells that are clones of them will survive because of that sacrifice.
This means that if you get re-infected with this virus, you most likely should retake furin inhibitors again. Yeah... That's not really "immunity" to a virus.

But it is what it is.

That's what happens when a virus uses furin as part of the way it infects cells.
Well, whoever makes the first successful vaccine for this virus will be hella rich. It's likely you need to reactivate memory B-cells into effector B-cells every 7 months. That means a booster shot every 7 months if you want "immunity." Yeah... That sucks.

But it is what it is.
Remember not to take artemisinin with anything else at the same time. Artemisinin is almost completely metabolized in the liver in about 2 to 3 hours, and its peroxide bonds are inactivated. So it's safe, but...

But one of the main mechanisms of action for artemisinin is iron breaking the peroxide bonds in artemisinin and turning the artemisinin into a free radical. If you take any other drugs before or after artemisinin, those drugs can be alkylated by artemisinin.
So you should time artemisinin intake so that you are not taking anything else 3 hours before you take artemisinin and 3 hours after artemisinin.

Food is okay. Zinc is okay. Just nothing that is a drug and will be in your body at the same time as artemisinin. Zinc is an atom.
Artemisin itself is completely safe. Its inactivated form without the peroxide bonds might even be therapeutic against COVID-19.

Its those random new molecule that are created when the artemisinin in free radical form makes with other molecules that might cause minor toxicity.
But remember not to overdose on artemisinin just like you don't want to overdose on chloroquine. If artemisinin is indeed a furin inhibitor, overdosing on it will probably kill you. Remember that furin is in your heart muscles. It absolutely does something important.
You can overdose on water. I mean if you drink way too much water, and your electrolytes go out of balance, you can die from drinking too much water. I am so not kidding.

Be careful and @Google everything. ❤️
In my defense tho, the interleukin-6 receptor looks absolutely NOTHING like the ACE2 enzyme.

Don't judge a book by its cover right?

Don't judge an enzyme until you've taken a look at its active site.

Tocilizumab is a humanized monoclonal antibody. It inhibits the human IL-6 receptor. There are two main ways to inhibit an enzyme. You either cause conformational changes to the enzyme, or you bind to the active site of the enzyme.

The interleukin-6 receptor binds to interleukin-6. That's why it was called interleukin-6 receptor. 🧐

Interleukin-6 itself is a protein.

But key part is this:

"Recently, a heptapeptide (N- to C-terminus: LSLITRL), designated as I6P7, which can specifically bind to IL-6R, has been proved to inhibit the binding between IL-6 and IL-6R, thereby retarding the tumor growth (Sturzu and Heckl)"

That means angiotensin(1-7) is a competitive inhibitor of the interleukin-6 receptor. And the only way it can do that is the active site of the IL-6 receptor is nearly identical to the active site of ACE2, the intended target of angiotension(1-7).
This means that Tocilizumab is an antibody that binds to things that like to bind to things that bind to ACE2.

Oh my God... That was hard to say.
Long story short, the antibody Tocilizumab will bind to the antibodies your body made against the ACE2 receptor binding domain of the spike protein. Tocilizumab will stop the antibody dependent enhancement of your own body's antibodies.
In your body, Tocilizumab is functioning as an antibody that binds to another antibody at its active site. Specifically, it'll bind to the antibodies your own body made against the spike ACE2 RBD that is causing the antibody dependent enhancement that is killing you.
Yeah, so you shouldn't take Tocilizumab at all at first if you have mild symtoms. You want those antibodies at first, so your body can learn to make antibodies against the furin-like cleavage site with the site exposed from conformational changes the ADE antibody causes.
If you started taking a furin inhibitor right away, you probably don't even have to take any Tocilizumab at all.

But for someone wasn't treated with hydroxychloroquine + zinc from the beginning, Tocilizumab will definitely help. LIKE A LOT.
So besides lowering your fever, Tocilizumab will most likely help save your life if you let your disease deteriorate that far by not taking a furin inhibitor to begin with.

Don't do that. Take the furin inhibitors as soon as you are diagnosed as positive for SAR-CoV-2.
Remember that all furin inhibitors will have a fatal dose amount. Even quercetin , which is super safe.

This is because if they are indeed furin inhibitors, if you take enough of it, it WILL stop your heart.

It's same reason that SARS-CoV-2 causes problems with your heart.
SARS-CoV-2 kills heart cells with furin on the surface.

Furin inhibitors inhibit the normal function of heart cells that need furin on their surfaces.

The effect is temporary for furin inhibitors because your cells can always make more furin later on.
The effect SARS-CoV-2 have on your heart cells is a little more permanent.

Things that are dead don't usually come back to life.

It only ever happened to one dude that I know of. 😇 I think the @Pontifex can back me up on that one.
A little note on the anedoctal evidence coming out of South Korea that people are becoming re-infected with SARS-CoV2.

That is to be expected honestly.

Remember that I said that T-cells are ALMOST completely useless in the fight against COVID-19 because of their furin.
I said ALMOST because T-cells aren't useless. They're actually essential. If they weren't completely necessary, we wouldn't have T-cells at all.

In this case, the T-cell we need are T helper cells that tell B-cells to live for a long, long time.
Like Sal Khan from the @khanacademy so eloquently explained here, B-cells can fight all on their own.

But they don't live for very long if you don't "stimulate" them with help from helper T-cells.

The reason is to prevent autoimmune diseases.
As I've already mentioned, this virus specializes in killing T-cells along with almost all the other cells in your body.

This means that it is extremely likely that if you didn't take any furin inhibitors and recover on your own, you probably don't have any memory B-cells.
It is still possible that some helper T-cells survived and helped the right B-cells form memory B-cells, so not everybody will have this problem.

But you really, REALLY want to take a furin inhibitor like the hydroxychloroquine + zinc combination as early as possible.
Oh yeah, by the way... Nobody has done a paper about this yet, but I'm pretty sure SARS-CoV-2 can use the Interleukin-6 receptor as an anchor just like it uses ACE2. Maybe not well.

But the receptor is only in specific cell lines, so it's not super bad.

Still pretty bad tho.
By the way, if anybody with access to genomic databases can confirm this from @rickilewis, that would be awesome.

"COVID-19’s spike gene shares a 39-base insertion with a type of soldierfish that swims in the South China Sea."

You know... Octopuses, squid, and cuttlefish can edit their RNA. If an RNA virus somehow ended up in one of them, it's totally conceivable that it starts to pick up RNA fragments using the octopus machinery. Maybe even from fish the octopus swallowed.

I'm just saying... @hughlaurie (Dr. Gregory House, M.D.) would've been proud of me. 😇

Maybe it WAS lupus. Or a drug that treats lupus... 😁
The protein atlas says that there is no TMPRSS2 in brain cells, heart cells, or white blood cells.

They are not "both essential."

It's much more likely they can both independently get the virus in.

This means you have to inhibit BOTH separately.

https://twitter.com/biorxivpreprint/status/1250655315751768065?s=21 https://twitter.com/biorxivpreprint/status/1250655315751768065
If TMPRSS2 is required heart cells, brains cells, and white blood cells would barely get infected at all.

No, the TMPRSS2 is the orginal SARS-CoV pathway that SARS-CoV-2 ALSO uses.
This probably means that furin inhibition alone won't stop the virus from infecting cells that the original SARS-CoV infects if the furin inhibitor you picked doesn't also inhibit TMPRSS2.
The empirical clinical evidence simply does not suggest that SARS-CoV-2 is just SARS-CoV.

The furin-like cleavage site allows the virus to infect a lot more different kinds of cells that the original SARS-CoV cannot.
If you look at the protein atlas for TMPRSS2, it shows that if TMPRSS2 is REQUIRED or ESSENTIAL, people should have no heart symptoms at all.

The empirical evidence does not support the theory that this virus doesn't infect the heart.

There have been people who start off with cardiovascular symptoms BEFORE they have the respiratory symptoms that create the hypoxic conditions thst would cause cardiovascular damage.
More very important information:

https://twitter.com/jexpmed/status/1250789550865121287?s=21 https://twitter.com/jexpmed/status/1250789550865121287
I would like to dedicate this tweet to @TwoPaddocks.

"They're moving in herds.... They DO move in herds."

Artemisinin should work better than hydroxychloroquine.

Moreover, artemisinin should permanenently akylate spike protein.

I would just like to point out that luteolin is in orange peel. People don't usually eat orange peel, but they do add it to tea.

I don't know if @SirPatStew drinks Earl Grey, but Captain Jean Luc Picard is definitely not dying from SARS-CoV-2. 😝
One good thing tho. You can probably use subtilisin, the secreted enzyme, as a treatment option. It'll inactivate the virus by cutting off spike proteins on active virus. I don't know how long before your body starts making antibodies against subtilisin tho.

Only works once.
I think people should seriously consider this. Nattokinase and other subtilisins will behave like Lorena Bobbit towards SARS-CoV-2.

Each specific subtilisin will only work once. Your body will start to make antibodies against them pretty quickly.

But it'll clear your blood of active virus and leave inactivated virus and cleaved S1 sections of the spike protein. For people who weren't treated early with a furin inhibitor, it might just buy them the time they need for their immune systems to recover enough to fight back.
I'm just imagining @LisaEdelstein saying: You want to inject poop juice into the patient's veins?!?

And @hughlaurie answering: That's exactly what I want to do.

Specifically, the secreted enzyme subtilisin from the probiotic bacillus subtilis from your gut.
Pretty sure subtilisin will cut off the spike protein from active virus. If not, there will be other secreted serine proteases that will work.

That's the big gun I think. It'll work better than anti IL-6 receptor antibodies like tocilizumab as the big gun, the last thing to try.
"positive regulation of type B pancreatic cell apoptotic process"

Dude... We just can't catch a break.

By the way, if you're going to treat with artemisinin, luteolin, and nattokinase together, you should space them all out about 3 hours.

Luteolin is a serine protease inhibitor. Nattokinase is a serine protease. It's not rocket science. 😉
More computer modeling evidence that quercetin works.

Potential Inhibitor of COVID-19 Main Protease (Mpro) from Several Medicinal Plant Compounds by Molecular Docking Study

Antibody dependent enhancement is very, very rare. Vaccines are usually very,
very safe. And most of time, vaccines actually give you cross-reactivity protection.

In fact, that's what people are hoping for with the BCG vaccine: cross-reactivity.
A very good explanation of the ADE that happens with SARS-CoV-2:

It also explains why some people get very, very sick, and some people have mild disease. It's all just... luck sadly.

It's like what @jentaylortown said about @SteveDownes117 in @Halo: Luck. https://twitter.com/natrevimmunol/status/1252648686166913026
So in the future when you're playing Dungeons and Dragons, always, ALWAYS max out your points in LUCK. 😇

Sure you can max out charisma, but charisma can't save your from a piano falling on your head or save you from SARS-CoV-2.
There is any TMPRSS2 expression in B-cells and dendritic cells. So... pretty darn sure that furin-like cleavage site in SARS-CoV-2 made it so you didn't need TMPRSS2 cleavage anymore.

There wouldn't be any lymphocytopenia in patients otherwise.

This thread is almost all bad news. Let me add some good news to it.

The survivors of the mild form of this horrible virus will likely live for a long, long time like the survivors of the 1918 pandemic flu. Like um... 20 to 30 years more maybe.
Your body will make two antibodies to this virus that are pretty cool. You'll actually make thousands of different kinds of antibodies, but two in particular will prolong your life.

The first one is an antibody with an affinity to angiotensin.
The antibody wasn't design for angiotensin. It was design for the ACE2 receptor binding domain on the spike protein of SARS-CoV-2, but it'll have an affinity to angiotensin.

So much so that for the rest of your life, you'll have softer arteries. That alone is pretty cool.
The second antibody though. That's an antibody against the furn-like cleavage site.

That antibody will prevent you from getting certain forms of cancer. Prevent cancers from metastasizing.

That antibody will prevent at least one cause of Alzheimzer's.
This virus, however horrible,
is for all intents and purposes, a longevity vaccine.

It'll make you live sooo much longer.

That is, of course, you survive it at all.

Small caveat. 🤣 But good newes nonetheless.
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