[ExI] COVID Bradykinin hypothesis

[Dave Sill]

Interesting results from  my workplace.

https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63

A Supercomputer Analyzed Covid-19 — and an Interesting New Theory Has
Emerged

Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in
Tennessee set about crunching data
<https://spectrum.ieee.org/the-human-os/computing/hardware/has-the-summit-supercomputer-cracked-the-covid-code.amp.html>
on more than 40,000 genes from 17,000 genetic samples in an effort to
better understand Covid-19 <https://coronavirus.medium.com>. Summit is the
second-fastest <https://www.top500.org/> computer in the world, but the
process — which involved analyzing 2.5 billion genetic combinations — still
took more than a week.

When Summit was done, researchers analyzed the results. It was, in the
words of Dr. Daniel Jacobson, lead researcher and chief scientist for
computational systems biology at Oak Ridge, a “eureka moment
<https://www.forbes.com/sites/cognitiveworld/2020/08/05/your-lungs-can-fill-up-with-jell-o-scientists-discover-a-new-pathway-for-covid-19-inflammatory-response/#1c4172e824be>.”
The computer had revealed a new theory about how Covid-19 impacts the body: the
bradykinin hypothesis
<https://www.the-scientist.com/news-opinion/is-a-bradykinin-storm-brewing-in-covid-19--67876>.
The hypothesis provides a model that explains many aspects of Covid-19,
including some of its most bizarre symptoms
<https://elemental.medium.com/every-covid-19-symptom-we-know-about-right-now-from-head-to-toe-bd1d47584096>.
It also suggests 10-plus potential treatments, many of which are already
FDA approved. Jacobson’s group published their results
<https://elifesciences.org/articles/59177> in a paper in the journal *eLife*
in early July.

According to the team’s findings, a Covid-19 infection generally begins
when the virus enters the body through ACE2 receptors in the nose, (The
receptors, which the virus is known to target
<https://www.wired.com/story/meet-ace2-the-enzyme-at-the-center-of-the-covid-19-mystery/>,
are abundant there.) The virus then proceeds through the body, entering
cells in other places where ACE2 is also present: the intestines, kidneys,
and heart. This likely accounts for at least some of the disease’s cardiac
and GI symptoms.
But once Covid-19 has established itself in the body, things start to get
really interesting. According to Jacobson’s group, the data Summit analyzed
shows that Covid-19 isn’t content to simply infect cells that already
express lots of ACE2 receptors. Instead, it actively hijacks the body’s own
systems, tricking it into upregulating ACE2 receptors in places where
they’re usually expressed at low or medium levels
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186534/>, including the
lungs.

In this sense, Covid-19 is like a burglar who slips in your unlocked
second-floor window and starts to ransack your house. Once inside, though,
they don’t just take your stuff — they also throw open all your doors and
windows so their accomplices can rush in and help pillage more efficiently.

The renin–angiotensin system (RAS) controls many aspects of the circulatory
system, including the body’s levels of a chemical called bradykinin, which
normally helps to regulate blood pressure. According to the team’s
analysis, when the virus tweaks the RAS, it causes the body’s mechanisms
for regulating bradykinin to go haywire. Bradykinin receptors are
resensitized, and the body also stops effectively breaking down bradykinin.
(ACE normally degrades bradykinin, but when the virus downregulates it, it
can’t do this as effectively.)

The end result, the researchers say, is to release a bradykinin storm — a
massive, runaway buildup of bradykinin in the body. According to the
bradykinin hypothesis, it’s this storm that is ultimately responsible for
many of Covid-19’s deadly effects. Jacobson’s team says in their paper that
“the pathology of Covid-19 is likely the result of Bradykinin Storms rather
than cytokine storms,” which had been previously identified
<https://elemental.medium.com/this-is-how-your-immune-system-reacts-to-coronavirus-cbf5271e530e>
in Covid-19 patients, but that “the two may be intricately linked.” Other
papers <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267506/> had
previously identified bradykinin storms as a possible cause of Covid-19’s
pathologies.

Covid-19 is like a burglar who slips in your unlocked second-floor window
and starts to ransack your house.

As bradykinin builds up in the body, it dramatically increases vascular
permeability. In short, it makes your blood vessels leaky. This aligns with
recent clinical data, which increasingly views Covid-19 primarily as a
vascular disease
<https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2>,
rather than a respiratory one. But Covid-19 still has a massive effect on
the lungs. As blood vessels start to leak due to a bradykinin storm, the
researchers say, the lungs can fill with fluid. Immune cells also leak out
into the lungs, Jacobson’s team found, causing inflammation.
Coronavirus May Be a Blood Vessel Disease, Which Explains Everything
Many of the infection’s bizarre symptoms have one thing in common
elemental.medium.com
<https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2>

And Covid-19 has another especially insidious trick. Through another
pathway, the team’s data shows, it increases production of hyaluronic acid
(HLA) in the lungs. HLA is often used in soaps and lotions
<https://www.allure.com/story/what-is-hyaluronic-acid-skin-care> for its
ability to absorb more than 1,000 times its weight in fluid. When it
combines with fluid leaking into the lungs, the results are disastrous: It
forms a hydrogel, which can fill the lungs in some patients
<https://www.azolifesciences.com/news/20200729/Supercomputer-analyses-point-to-a-new-pathway-for-COVID-19-inflammatory-response.aspx>.
According to Jacobson, once this happens, “it’s like trying to breathe
through Jell-O
<https://medicalxpress.com/news/2020-07-gene-pathway-covid-inflammatory-response.html>
.”

This may explain why ventilators have proven less effective
<https://www.statnews.com/2020/04/21/coronavirus-analysis-recommends-less-reliance-on-ventilators/>
in treating advanced Covid-19 than doctors originally expected, based on
experiences with other viruses. “It reaches a point where regardless of how
much oxygen you pump in, it doesn’t matter, because the alveoli in the
lungs are filled with this hydrogel,” Jacobson says. “The lungs become like
a water balloon.” Patients can suffocate even while receiving full
breathing support.

The bradykinin hypothesis also extends to many of Covid-19’s effects on the
heart. About one in five hospitalized Covid-19 patients
<https://www.scientificamerican.com/article/heart-damage-in-covid-19-patients-puzzles-doctors/>
have damage to their hearts, even if they never had cardiac issues before.
Some of this is likely due to the virus infecting the heart directly
through its ACE2 receptors. But the RAS also controls aspects of cardiac
contractions and blood pressure. According to the researchers, bradykinin
storms could create arrhythmias and low blood pressure, which are often
seen in Covid-19 patients.

The bradykinin hypothesis also accounts for Covid-19’s neurological effects
<https://elemental.medium.com/what-covid-19-did-to-my-brain-2c8ee0b64c6e>,
which are some of the most surprising and concerning elements of the
disease. These symptoms
<https://www.health.harvard.edu/diseases-and-conditions/covid-19-basics>
(which include dizziness, seizures, delirium, and stroke) are present in as
many as half of hospitalized Covid-19 patients.
<https://www.medpagetoday.com/infectiousdisease/covid19/86926> According to
Jacobson and his team, MRI studies in France revealed that many Covid-19
patients have evidence of leaky blood vessels in their brains.

Bradykinin — especially at high doses — can also lead to a breakdown of the
blood-brain barrier
<https://www.sciencedirect.com/science/article/abs/pii/0169409X9500004Q#:~:text=Bradykinin%20is%20a%20very%20powerful,-brain%20barrier%20%5B34%5D.>.
Under normal circumstances, this barrier acts as a filter
<https://qbi.uq.edu.au/brain/brain-anatomy/what-blood-brain-barrier>
between your brain and the rest of your circulatory system. It lets in the
nutrients and small molecules that the brain needs to function, while
keeping out toxins and pathogens and keeping the brain’s internal
environment tightly regulated.

If bradykinin storms cause the blood-brain barrier to break down, this
could allow harmful cells and compounds into the brain, leading to
inflammation, potential brain damage, and many of the neurological symptoms
Covid-19 patients experience. Jacobson told me, “It is a reasonable
hypothesis that many of the neurological symptoms in Covid-19 could be due
to an excess of bradykinin. It has been reported that bradykinin would
indeed be likely to increase the permeability of the blood-brain barrier.
In addition, similar neurological symptoms have been observed in other
diseases that result from an excess of bradykinin.”

Increased bradykinin levels could also account for other common Covid-19
symptoms. ACE inhibitors — a class of drugs used to treat high blood
pressure
<https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480>
— have a similar effect on the RAS system as Covid-19, increasing
bradykinin levels
<https://cvpharmacology.com/vasodilator/ACE#:~:text=ACE%20inhibitors%20produce%20vasodilation%20by%20inhibiting%20the%20formation%20of%20angiotensin%20II.&text=ACE%20also%20breaks%20down%20bradykinin,vasodilator%20action%20of%20ACE%20inhibitors.>.
In fact, Jacobson and his team note in their paper that “the virus… acts
pharmacologically as an ACE inhibitor” — almost directly mirroring the
actions of these drugs.
By acting like a natural ACE inhibitor, Covid-19 may be causing
<https://www.bmj.com/content/368/bmj.m406/rr-27> the same effects that
hypertensive patients sometimes get when they take blood pressure–lowering
drugs. ACE inhibitors are known to cause
<https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/ace-inhibitors/art-20047480>
a dry cough and fatigue, two textbook symptoms of Covid-19. And they can
potentially increase blood potassium levels, which has also been observed
in Covid-19 patients
<https://medium.com/beingwell/in-some-patients-with-covid-19-the-blood-potassium-levels-are-high-f1ef9f65e9cf>.
The similarities between ACE inhibitor side effects and Covid-19 symptoms
strengthen the bradykinin hypothesis, the researchers say.

ACE inhibitors are also known to cause a loss of taste and smell
<https://coronavirus.medium.com/a-new-study-explains-why-covid-19-causes-a-loss-of-smell-e3f9e7082bdd>.
Jacobson stresses, though, that this symptom is more likely due to the
virus “affecting the cells surrounding olfactory nerve cells” than the
direct effects of bradykinin.

Though still an emerging theory, the bradykinin hypothesis explains several
other of Covid-19’s seemingly bizarre symptoms. Jacobson and his team
speculate that leaky vasculature caused by bradykinin storms could be
responsible for “Covid toes
<https://www.nytimes.com/2020/05/01/health/coronavirus-covid-toe.html>,” a
condition involving swollen, bruised toes that some Covid-19 patients
experience. Bradykinin can also mess with the thyroid
<https://pubmed.ncbi.nlm.nih.gov/1665827/> gland, which could produce
the thyroid
symptoms
<https://elemental.medium.com/the-coronavirus-may-mess-with-thyroid-levels-too-87f94e45c5c9>
recently observed in some patients.

The bradykinin hypothesis could also explain some of the broader
demographic patterns of the disease’s spread. The researchers note that
some aspects of the RAS system are sex-linked, with proteins for several
receptors (such as one called TMSB4X) located on the X chromosome. This
means that “women… would have twice the levels of this protein than men,” a
result borne out by the researchers’ data. In their paper, Jacobson’s team
concludes that this “could explain the lower incidence of Covid-19 induced
mortality in women.” A genetic quirk of the RAS could be giving women extra
protection against the disease
<https://coronavirus.medium.com/why-do-men-fare-worse-with-covid-19-a5debff87dc1>
.

The bradykinin hypothesis provides a model that “contributes to a better
understanding of Covid-19” and “adds novelty to the existing literature,”
according to scientists Frank van de Veerdonk, Jos WM van der Meer, and
Roger Little, who peer-reviewed the team’s paper
<https://elifesciences.org/articles/59177>. It predicts nearly all the
disease’s symptoms, even ones (like bruises on the toes) that at first
appear random, and further suggests new treatments for the disease.

As Jacobson and team point out, several drugs target aspects of the RAS and
are already FDA approved to treat other conditions. They could arguably be
applied to treating Covid-19 as well. Several, like danazol, stanozolol,
and ecallantide, reduce bradykinin production and could potentially stop a
deadly bradykinin storm. Others, like icatibant, reduce bradykinin
signaling and could blunt its effects once it’s already in the body.

Interestingly, Jacobson’s team also suggests vitamin D
<https://elemental.medium.com/what-black-people-need-to-know-about-vitamin-d-and-covid-19-5bf5885d5288>
as a potentially useful Covid-19 drug. The vitamin is involved in the RAS
system and could prove helpful by reducing levels of another compound,
known as REN. Again, this could stop potentially deadly bradykinin storms
from forming. The researchers note that vitamin D has already been shown to
help those with Covid-19
<https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484>. The vitamin
is readily available over the counter, and around 20% of the population is
deficient
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126987/#:~:text=vitamin%20D%20deficiency-,The%20prevalence%20of%20mild%2C%20moderate%20and%20severe%20vitamin%20D%20deficiencies,%25%2C%20and%2026.9%25%20respectively.>.
If indeed the vitamin proves effective at reducing the severity of
bradykinin storms, it could be an easy, relatively safe way to reduce the
severity of the virus.

Other compounds could treat symptoms associated with bradykinin storms.
Hymecromone, for example, could reduce hyaluronic acid levels, potentially
stopping deadly hydrogels from forming in the lungs. And timbetasin could
mimic the mechanism that the researchers believe protects women from more
severe Covid-19 infections. All of these potential treatments are
speculative, of course, and would need to be studied in a rigorous,
controlled environment before their effectiveness could be determined and
they could be used more broadly.

Covid-19 stands out for both the scale of its global impact and the
apparent randomness of its many symptoms
<https://elemental.medium.com/every-covid-19-symptom-we-know-about-right-now-from-head-to-toe-bd1d47584096>.
Physicians have struggled to understand the disease
<https://elemental.medium.com/9-things-experts-know-about-covid-19-that-they-didnt-know-then-5f22819807c4>
and come up with a unified theory for how it works. Though as of yet
unproven, the bradykinin hypothesis provides such a theory. And like all
good hypotheses, it also provides specific, testable predictions — in this
case, actual drugs that could provide relief to real patients.

The researchers are quick to point out that “the testing of any of these
pharmaceutical interventions should be done in well-designed clinical
trials.” As to the next step in the process, Jacobson is clear: “We have to
get this message out.” His team’s finding won’t cure Covid-19. But if the
treatments it points to pan out in the clinic, interventions guided by the
bradykinin hypothesis could greatly reduce patients’ suffering — and
potentially save lives.

--

See also
https://spectrum.ieee.org/the-human-os/computing/hardware/has-the-summit-supercomputer-cracked-the-covid-code
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