[conspire] SARS-CoV-2's Turning T Helper Cells into Death Metal Factories

[Deirdre Saoirse Moen]

This is a reorganizing of a reddit comment I made earlier today about a research paper.

We're only covering a small bit of the adaptive immune system here, specifically CD4+ cells.

https://en.wikipedia.org/wiki/CD4

The most famous of these are the T helper cells that are listeners for messages:

https://en.wikipedia.org/wiki/T_helper_cell

The purpose of T helper cells is to essentially marshal the entire rest of the adaptive immune system into what it's supposed to be doing. Are we fighting a virus? Fungus? T helper cell will referee that call. They also help activate T killer cells, among others.

Notably, they are the kind of cell that HIV infects, though it does not *initially* infect T helper cells. But because suddenly the ability to handle like *anything* thrown at the immune system is nerfed, the symptoms of AIDS are wildly varied.

Charmingly, in severe/critical/fatal cases, it turns out that SARS-CoV-2 *also* infects CD4+ cells, and specifically also T helper cells, turning them into little virus factories. But, like HIV, it needs co-receptors, and this paper (coming up on the guitar in a moment) shows the research they did on what exactly those receptors were. (ACE2 and TMPRSS, which have already been known to be problem co-receptors for SARS-CoV-2, but not fully how they figured into the generation of the cytokine storm.)

From a Unix perspective, it might be helpful to visualize a receptor as an open port on a cell, and each cell is a server, and the cytokines (cyto- cell and kine- movement, proteins that move between cells) an are the network traffic. Interleukin (iner- between and leukin- leukocyte aka white blood cell) is also a messenger/network traffic. Cytokine can be between different kinds of cells where Interleukin tends to be only between white blood cells (except immunology is complicated).

https://en.wikipedia.org/wiki/Cytokine
https://en.wikipedia.org/wiki/Interleukin

Two big issues in the worst cases of COVID-19 are: lymphopenia (severe lack of certain classes of white blood cells) and the cytokine storm. 

It might be helpful to think of the cytokine storm as where the load average of not just one server (cell), but the entire freakin' cloud (meaning the entire person who's got COVID) goes up to 1000 and you get one of those Cloudflare oops pages and, if they're lucky, they're still alive enough to be in the ICU.

But what hasn't really happened is having a hypothesis about a) what happened to those white blood cells (which are sometimes significantly suppressed even weeks after people get out of the hospital, sometimes leading to re-admission), and b) how the cytokine storm happens.

Until now.

SARS-CoV-2 Uses CD4 to Infect T Helper Lymphocytes (preprint)
https://www.medrxiv.org/content/10.1101/2020.09.25.20200329v1

So the bastard virus infects the T Helper cells and uses them to crank up the volume on interleukin 10. This has been known to figure highly in critical and fatal cases, but it's more like: oh well, that's unfortunate. :P (There are some things they've tried with limited success.)

From the paper:

> These results show that SARS-CoV-2 infection induces IL10 expression in CD4+ T cells.

Ahh, so the virus frobs the switch and then the cell starts to resemble something out of Colin's death metal guitar video demos.

https://youtu.be/WdEQv6I_n_c?t=448

Lots of very loud messaging. (I tease, Colin's got a great channel if you want to know neepery about guitar parts and how the innards of them work. Just…his taste in music isn't mine.)

So the paper is saying that the virus is altering these immune system cells to basically add this signaling protein that has been part of the cause of severe and critical disease.

On the lymphopenia part, when the immune system recognizes that a cell's been compromised by a virus, it generally destroys it via T killer cells. Unfortunately, those need signaling from T helper cells (which, if available, could then get infected). The innate immune system has other methods, which have been seen in COVID-19 patients. That's out of the scope of this paper, though. (And it's been a while since I read it, but some of the methods the immune system's using to kill cells are genuinely weird. Like it's using techniques usually used on bacteria, seriously, and not well adapted for viruses, but that may be why they're working.)

While not covered in this paper, the good news is that if SARS-CoV-2's using some techniques similar to HIV and part of the problem of severe COVID-19 is how CD4+ cells are being affected, we have a world full of world-class HIV researchers and a body of research on how those cells work that we can now aim at that. It's just a pity we haven't funded it better all these years. :P

Deirdre