THIS IS BIG. WOW. New paper in PLOS Pathogens has findings about:
- the effect of the SARS-CoV-2 spike protein on cardiac cells (and mitochondrial dysfunction!),
- a treatment to be investigated, and
- how this is NOT caused by mRNA vaccines!
Buckle up, we're diving in...
1/
[This paper is an uncorrected proof; it's been peer-reviewed, but not copyedited yet.]
A bit of background: syncytia (sin-sih-sha) are giant cells with multiple nuclei that form from the fusion of multiple cells. Viral infections are a common cause of syncytia.
2/
The authors had two motivations for this study:
1. Cardiac complications are a major feature of COVID.
2. Patients with heart failure tend to experience very poor outcomes from COVID.
Really, it hasn't been entirely clear *how* COVID leads to heart failure... until now?
3/
Syncytia form when the spike protein present on the surface of one cell makes contact with another cell.
This study went a step further by looking at how *extracellular* vesicles containing the spike protein can fuse cells... *without* active infection.
4/
Why do syncytia matter?
They're a potential route for the spike protein to cause damage even AFTER an active infection has subsided.
Like some other viruses, SARS-CoV-2 can cause cell senescence—which is when the cell replication cycle stops, and the cells degrades.
5/
So before we dive into results, what is the headline?
Although cytokine storm has long been thought the cause of COVID-related cardiac issues, this study found that the SARS-CoV-2 spike protein "led to profound cardiac fibrosis without affecting baseline cariac function."
6/
Moreover, they found a drug target that may be able to prevent "the downregulation of mitochondrial metabolism," and it has shown potential promise in treating heart failure overall.
It would treat the "increased risk of developing heart failure and sudden cardiac death"!
7/
Let's dive in to the results! I'm going to jump around a bit, because this paper is EXTENSIVE.
First up, when they cultured cells expressing the spike (S) protein and the ACE2 receptor in a 1:1 ratio, the cells started fusing within four hours. Basic premise confirmed!
8/
In the cultures with SARS-2-S syncytia, the cells secreted more senescence-related cytokines, including IL-6, IL-8, and IL-2, compared to the cells exposed to a mutant spike protein that can't cause senesense!
They found similar syncytia formation in other cell types.
9/
They also tested the spike from four Omicron variants (BA.1, BA.5, BA.2.75, BA.2.75.2). Previous work has found BA.1 has a 5x reduction in ability to fuse cells (compared to wild-type), but the others have a 1.2-1.7x reduction.
All formed syncytia, just a bit more slowly.
10/
Here's where it gets REALLY concerning: Extracellular vesicles—little packets, emitted by cells, containing a protein or some other type of small molecule—have been found carrying the S protein in patients' blood long after initial infection...
11/
...and they found that these extracellular vesicles, once taken up by a cell, can cause the cell to fuse to another ACE2-expressing cell.
The fused cells then showed signs of senescence (including increased transcription of TNF, IL6, IL8, and CDKN1A genes).
Not great!
12/
What about the mRNA vaccines—they produce a spike protein, so can they also cause this problem? Nope!
The spike design used in the vaccines has a couple of tweaks to make it more stable, and those changes prevent it the vaccine-based spike protein from causing cell fusion!
13/
To be really sure that the S protein can cause this type of syncytial senescence to occur in real organs, they injected mice with a virus that causes them to express human ACE2 in their livers.
When injected with the wild S protein, it induced senescence in their livers!
14/
Next up, they looked at mitochondrial regulation.
Long story story, MAVS (mitochondrial antiviral signaling) proteins, which detect foreign double-stranded RNA, cause mitochondrial senescence in response to the SARS-2-S syncytia.
15/
Jumping ahead a bit, they found that "senescent SARS-2-S syncytia exhibit [shrunken] morphology, leading to the activation of WNK1," which is a molecule involved in regulating cell senesence.
It is activated by the fused cells losing their volume.
16/
They found WNK1 activation led to significantly decreased "mitochondrial oxidative capacity of the cocultured cardiomyocyte"
But "inhibition of WNK1 via WNK463 [which prevents down-regulation of metabolic enzymes] was sufficient to rescue impaired mitochondrial respiration"
17/
Jumping ahead again, we're getting to the headline experiments.
They administered the SARS-2-S protein to some mice that express the human ACE2 receptor, and syncytia formed, as expected.
18/
They concluded that "SARS-2-S promotes fibrosis without causing baseline cardiac abnormalities," and in the mice with pre-existing heart failure, it "exacerbated heart failure progression"
"fibrosis without causing baseline cardiac abnormalities"... not great!
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Finally, they examined if WNK1 inhibition can "alleviate heart failure exacerbated by SARS-2-S through rescuing metabolic dysfunction." They found positive results, "further supporting the notion that senescent SARS-2-S syncytia contribute to exacerbated heart failure."
20/
What do they conclude?
The S protein can contribute to heart failure. This is important for acute infections AND long-term complications, because the "persistence of circulating SARS-2-S protein ... increase the likelihood of cell-cell fusion in uninfected cells."
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They also note that syncytia expressed senescence-related cytokines, including TNF-alpha, IL-6, and IFN-gamma, among others, and these seem related to the metabolic regulation.
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And, importantly, the mRNA vaccines CANNOT cause cellular senescence using this mechanism, as they have a couple of mutations which "effectively inhibit the formation of syncytia, mitigate cellular senescence, and prevent the release of" senescence-relate signals.
23/
Because patients with heart failure show elevated ACE2 expression, while those with Long COVID exhibit "persistent circulating SARS-2-S and EVs harboring SARS-2-S," this combination "may increase the likelihood of syncytium formation."
24/
This is very much a basic research paper and doesn't have anything directly *usable* in clinical practice. However, it really illuminates the pathophysiology of cardiac complications of SARS-CoV-2 infection—EVEN ASYMPTOMATIC INFECTIONS.
Paper:
25/25journals.plos.org/plospathogens/…
AFAIK, it’s totally a non-issue with the non-mRNA vaccines, because they don’t even have a full spike protein.
And I think their statements about how mRNA vaccines with a different design could have more complications was a veiled reference to one of China’s vaccines
26/25
No idea what to do about denialism at this point, other than continuing to educate and hope it gets through!
That's the goal with my threads: Hopefully, they can help give people the knowledge and language they need to discuss the science directly!
27/25
At this point, it's a *potential* treatment that still needs further study, but it's a solid lead!
- Inhibiting the *WNK1 molecule* with a *WNK463 molecule* is the new option uncovered here
- Two existing preventative drugs should be investigated
28/25
Glad you asked, because I was conflating previous vector vaccines with ones under development!
It seems that Novavax and Janssen use the same STABILIZED spike protein as Pfizer and Moderna:
But oddly enough...
29/25
pubs.acs.org/doi/10.1021/ac…
...it seems that a bunch of Russian viral vector vaccines—and AstraZeneca—used the regular spike protein!?
So that kind of explains the issues with the AstraZeneca vaccine! Weird.
30/25 ncbi.nlm.nih.gov/pmc/articles/P…
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