[random023987]

If you're looking for the summary, it's about 1/4 the way in.

> Usually, the viruses that humans care about are successful because they shut down both of these signalling programs. The coronavirus is different. “It seems to block only one of those two arms,” tenOever told me. It inhibits the interferon response but does nothing about the cytokines; it evades the local defenses but allows the cells it infects to call for reinforcements. White blood cells are powerful weapons: they arrive on an inflammatory tide, destroying cells on every side, clogging up passages with the wreckage. They are meant to be used selectively, on invaders that have been contained in a small area. With the coronavirus, they are deployed too widely—a carpet bombing, rather than a surgical strike. As they do their work, inflammation distends the lungs, and debris fills them like a fog.

[nextos]

I've been doing some lab & modeling research on this, and it's more complex. I think it's a non-linear dynamics problem.

In a nutshell, SARS-CoV-2 (COVID-19) does block interferon response by using molecular mimics. Some of the proteins encoded in the virus are really similar to proteins in the interferon pathway, so this is not surprising. Still pretty unexplored and a nice route towards finding treatments.

Now, the interesting part is that the dynamics of interferon is very non-linear. Cells exchange interferon signals with other cells in the same tissue to pass information and coordinate with the immune system. There are fairly sophisticated models (using stochastic message passing!) that confirm lab observations on regular non-infected cells [1].

My hypothesis is that by blocking interferon in a sufficient number of cells on individuals with already disrupted innate immunity (due to ageing, insulin resistance, etc.) the system becomes chaotic. Infection by e.g. pneumococci is tolerated because the signaling is perturbed and then, all of a sudden, you get a massive amount of proinflammatory molecules secreted and cells decide to undergo apoptosis. That's the cytokine storm that everyone talks about.

Sadly, pursuing these ideas within academia is hard as most (but not all) biology labs are really hostile to mathematical models, even if they explain or predict things they can't using hand waving. Perhaps I should seek VC funding.

[1] https://www.nature.com/articles/s41467-017-02640-8

[projektfu]

I’m a bit surprised by that statement about biology labs being hostile to mathematical models. Care to go more in depth?

[tehjoker]

bio people are not frequently math people and vice versa. The undergraduate departments make fun of each other. This is changing slowly. I suspect that a big part of the reason is that biology is complicated while math is good at dealing with distilling the behavior of a few essential elements.

When you start to find essential elements, they get mathified (look at DNA) but look how much experimental work it takes to do that? Scaling up experiments can also take some math, but once you figure out the trick, you just have a lot of experiments to run....

[hanklazard]

And this is why steroids like decadron are helpful in the second phase (now being called the inflammatory phase by many in the ID community) of the infection. Steroids decrease inflammation / immune response.

[AstralStorm]

That's not exactly why it's steroids. If this was the main mechanism we'd use more effective immunosuppressants. As is, stronger immunosuppressants show worse survival rates. You want to keep some immune system activity to not get a secondary infection and fight the virus.

Corticosteroids also kickstart healing process (not really in COVID) and regrowth - you also race against tissue destruction. Most importantly they barely reduce scar formation. And they actually improve breathing via action on alveoli as well as reduce swelling.

The specific two to use are hydrocortisone and dexamethasone based on studies thus far, in critical patients - ones put on respirators. (Prednisolone could also work.)

[rurban]

This would be the proper description for the spanish flu. But with Covid-19 it's different. No cykotine, but BK overreaction. Healthy immune systems are not triggered to kill the body, only weak and old are in danger. Besides the neurological damage in some.