The biology of coronavirus COVID-19 - including research and treatments

lansbergen said:
Also another story talking of ACE2 receptors

https://www.radboudumc.nl/en/nieuws/2020/radboudumc-researchers-publish-new-insights-into-covid-19

which refers to this paper
https://www.preprints.org/manuscript/202004.0023/v1


None of it makes much sense to me as someone who doesn't know much biology.
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This is a very interesting paper, albeit coauthored by a not-so popular Jos van der Meer.

They make some novel hypotheses that I think have been sorely lacking in recent discussion of COVID-19 pathology and it's relationship with ARDS.

But they also state some things I find questionable, such as:
Pulmonary hypertension is not an important clinical component.
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Oh really, why does the epidemiology suggest that it is one of the strongest risk factors?


Pulmonary edema by ACE2 dysfunction was speculated to be due to increased hydrostatic pressure as a result of vasoconstriction of the pulmonary vasculature due to high angiotensin II (a vasoconstrictor) 6 . However, further experiments showed no difference in hydrostatic pressure and made the explanation of high angiotensin II with vasocontriction as a cause of pulmonary edema unlikely 6,7 . Increased bradykinin however could explain this observation without increased hydrostatic pressure. Notably, the RAS system controls vasoconstriction and vasodilatation, and the bradykinin system controls permeability and vasodilatation, whereas ACE2 regulates both.
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But ARDS due to COVID-19 cannot be assumed to be the same as classical pulmonary edema and requires fresh clinical observations of hydrostatic pressure and the like. There is reason to suggest that SARS-COV-2 is uniquely altering ACE2 pathways in ways that don't exist in those cited papers.

it is tempting to speculate that Sars-CoV-2 interaction with ACE2 at the surface also downregulates ACE2 expression and function of ACE2, subsequently leading to a deficiency to inactivate the B1 ligand locally in the lung, and might in this way directly link the virus to local pulmonary angioedema
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An interesting hypothesis, I think they are onto something here. ;)

We speculate that this dysregulated bradykinin pathway is present already early in COVID19 disease. Patients can worsen clinically after days of illness (especially around day 9) which is accompanied by an increase in proinflammatory status often resulting in ICU admission and with necessity of supportive mechanical ventilation. This second hit is reminiscent to observations in SARS-CoV where 80% of patients with SARS-CoV that developed acute respiratory disease coincided with antiviral IgG seroconversion 15. Moreover, patients who developed the anti-S-neutralizing antibody early in disease had a higher chance of dying from the disease.
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The timing is indeed coincidental...

They propose blockage of (Bradykinin) B1 and B2 receptors

In our vision, as long as the virus persists the dysregulated kinin-kallikrein pathway is playing a role in disease via the absence of optimal ACE2 function in the lung. Maybe not everybody needs B1 and B2 receptor blocking since they will recover once the viral load is resolved from the lung and there is no second inflammatory hit or significant production of anti-S-antibodies. However, when disease progresses which is accompanied by increased proinflammatory status which often results in critical illness we would argue that this timepoint has a rationale for aggressive innate anti-inflammatory strategies, however this must be done in the presence of blocking the bradykinin pathway. Several targets in the kallikrein-kinin pathway might be amendable to intervention, namely 1. at the level of blocking tissue kallikrein activity and thus reducing the production of kinins, 2. activating the degradation of kinins by treating with recombinant active enzymes such as ACE2, 3. at the level of B1 and B2 receptors, 4. by inhibiting the common downstream signaling of B1 and B2 receptors, and 5. by suppressing local NO which is largely responsible for the endothelal leakage. By far the most potent and logical would be to block B1
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But one of the comments suggests caution:

Paolo Madeddu said:
The hypothesis suggested by the paper is sound but several other considerations should be made on the use of receptor blockade
1. Many patients manifest severe complication associated with DIC which could be caused by activation of the plasma kallikerin coagulation system. Upstream blockade of tissue and plasma kallikrein could be a more effective way to inhibit angiooedema and DIC than kinin antagonists
2. Our articles in Circulation 2002 -2004 showed that both B1 and B2 receptors are indispensable in tissue healing during ischemia. Blocking them could worsen the recovery during ischemia and vascular damage. Therefore the indiscriminate use of antagonists is not justified until guidelines are put in place
3. Chemokines and cytokines other than kinins could be involved and they could act also after lining blockade
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not everyone may develop that ace2 problems to a "threatening" extend.
it could have a genetic component.

it would be very very very interesting to see, if people with these problems respond super-well to ivermectin.

im wondering... if for quite a few of those "ace" patients other meds, like these ace2 inhibitors or other blockers may bring you to that point "between a hard place or a rock" or whatever this saying goes...

(ivermectin has shown already as something that may help, as so many other odd meds...)

today, in a german newspaper a swiss doctor stated, that ppl "of course" die of "cardiac failure"... they may play as if this is "old news", its not. its definitely not. there was no talk about cardiac failure until mid march minimum.
 
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Mithriel said:
It is very strange if smokers are more immune becasue smokers are more likely to have cardiac problems, hypertension, asthma and COPD which are all risk factors
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nicotine may protect from covid replication (when i understood that right)
slysaint postet https://www.s4me.info/threads/the-b...vaccines-treatments.14022/page-13#post-253515

perhaps, nicotine plasters could be added to that covid-meds-lists as well?

otherwise, smokers may have a more severe disease progress... ?
 
with the ace receptor/angiotensin docking of covid virus, it would be interesting to see, if people with high ace/angiotensinII are

- more likely to die
- while having absoluty not the typical flu-symptoms (sneezing, throat...)

people with (high angiotensin II) shouldnt have any "allergy" issues, for example.
guessing, they are also unlikely to sneeze or react any much on whatsoever...
 
Mithriel said:
It is very strange if smokers are more immune becasue smokers are more likely to have cardiac problems, hypertension, asthma and COPD which are all risk factors
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Is this only true of of Covid 19? Or might it also be true for other similar viruses. Just wondering if the (normally damaging) changes that occur in smokers' lungs may, rather perversely, help to thwart viral attacks on the lungs? Or even if maybe people's lungs adapt in some way to try and offset the effects of smoking, and if so could that then play a part?

For anyone who does not already know: I have no medical expertise whatsoever. Just wondering if anyone who does have such knowledge might have any thoughts.
 
Barry said:
Is this only true of of Covid 19? Or might it also be true for other similar viruses. Just wondering if the (normally damaging) changes that occur in smokers' lungs may, rather perversely, help to thwart viral attacks on the lungs? Or even if maybe people's lungs adapt in some way to try and offset the effects of smoking, and if so could that then play a part?

For anyone who does not already know: I have no medical expertise whatsoever. Just wondering if anyone who does have such knowledge might have any thoughts.
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No knowledge of other viruses but there's something called "cryptogenic organizing pneumonia" (COP), which is an interstitial pneumonia with no known underlying viral or bacterial or fungal cause. "Organizing" means the lung tissue becomes fibrotic and "hardens".

Here, smokers are highly underrepresented, as well, which seems very counter intuitive.

Organizing pneumonia (not kryptogenic because SarsCov2 is identified as the underlying cause) was also found in some Covid cases, accordong this study.
 
Leila said:
No knowledge of other viruses but there's something called "cryptogenic organizing pneumonia" (COP), which is an interstitial pneumonia with no known underlying viral or bacterial or fungal cause. "Organizing" means the lung tissue becomes fibrotic and "hardens".

Here, smokers are highly underrepresented, as well, which seems very counter intuitive.

Organizing pneumonia (not kryptogenic because SarsCov2 is identified as the underlying cause) was also found in some Covid cases, accordong this study.
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Could there just be another reason entirely why smokers are under-represented in hospitalised cases of Covid 19?

Hospitalised cases of Covid 19 are heavily weighted towards the higher age groups, but smokers are going to be dying of smoking related causes younger than average. Is it simply that fewer smokers are getting Covid in the upper age ranges, because less of them are reaching those ages anyway? Have controlled comparisons been made between smokers and non-smokers, where the only real difference is their smoking?
 
Mithriel said:
It is very strange if smokers are more immune becasue smokers are more likely to have cardiac problems, hypertension, asthma and COPD which are all risk factors
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Therefore you can perform a statistical trick - smokers without those risk factors are less likely to be hospitalised.

But these studies are inherently biased as they are sampling hospital care rates, rather than the population as a whole and should be looking at mortality rates, (or requiring intubation), rather than merely hospital admissions - there are other behavioural biases involved.
 
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One of a series of youtube videos
Coronavirus Pandemic Update 37: The ACE-2 Receptor - The Doorway to COVID-19 (ACE Inhibitors & ARBs)
We've produced each COVID-19 video with the best information we could access at the time of recording. Naturally, some videos will contain information that has become outdated or replaced by better information or research. That said, we believe each video contains concepts that have enduring value and reviewing how the response to COVID-19 has progressed over time may be of interest to you as well.

The ACE-2 receptor on our cells is the binding site for SARS-CoV-2, the virus that causes COVID-19. As a result, the ACE-2 receptor is central to many important questions about coronavirus treatment, a COVID-19 vaccine, and should patients continue taking their ACE inhibitor / ARBs (Angiotensin II Receptor Blockers) medications. Dr. Seheult discusses the controversy about some of these questions and illustrates the pathway involved with the ACE-2 receptor.
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18minutes long (I lost the drift after 10 minutes but others might understand better).
 
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