[rolph]

this is something of a bush to beat around.

- when the virus docks with the ACE2 receptor there is a loss of the ACE2 receptor function as it is a destructive process.

- when the virus inhabits the cell there is probably a cytoplasmic down regulation of ACE2 expression as the cell is now "claimed" as a place for replication

so the question would be when would we administer or withdraw such an ACE2 blocker

the loss of ACE2 functionality is devastating to the cell but the presence of functional ACE2 receptor makes a cell vulnerable to entry

-and should we be using a blocker pe se or should we use some sort of hypothetical receptor inhibitor that is not displace by coronavirus spike protien, as in competetive inhibition?

[ptest1]

I wrote a long comment and it got deleted, argh!

Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study!

Chinese paper discusses this as well:

https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m...

They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2.

ACE2-fc being developed- will both stop AT1R activation and neutralize virus:

https://twitter.com/robertlkruse/status/1233986542097567744?...

He is looking for funding if any funders are reading this. Comment here and I can connect.

[rolph]

there would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur.

there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm.

the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis

[ptest1]

I guess what I think could be possible is:

ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point.

Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal?

Check out this paper:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Proportion of reduction of ACE2 correlates with disease severity.

Check out figure 1

“Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.”

Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease.

So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity.

Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen.

Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2?

If damage from increased loss, then I can see the ARB approach helping.

If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.

[rolph]

the physiological cascade that occurs due to disruption of a homeostatic feedback system is the most probable cause of direct lethality. The setpoint and the relative concentrations of the elements in these systems are genetically dictated functions.

There is probably some correlate between predisposition to morbidity/mortality and how far ones setpoints deviate from population setpoints.

there are 2 prongs to this attack, one is the disruption of angiotensin based signalling and effectation

the other is the viral entry to the cell. the virus must do a dance on the head of a pin in a sense to replicate but not hijack somuch of the cells basic metabolism that apoptosis occurs. a virus that allows its host cell to remain viable wins the lottery for natural selection.

the problem is that the virus occupies the expression machinery that creates ACE2, in an indiscriminant fashion many other protiens as well.

so this means the virus has caused damage by entry

the entry damage causes errent feedback which causes further physiological perturberance

a secondary round of disruption occurs when ACE2 expression is inhibited thus interfereing with replenishment of ACE2 that has been damaged as well as disrupting the regular recycling of ACE2 and for that matter disrupts expression of the ATI and ATII receptors

---I am not a founder or funder but simply a concerned professional