Thread by @fitterhappierAJ

1/Friends, I have written up the thoughts I have on the immunopathology of COVID and how to prevent the exubeerant immune activation that causes pulmonary infiltration by lymphocytes. Especially pertinent were the papers of Israelow and Mathew that both osf.io/2egsm/

2/characterized the immune programs and suggested mechanism. I filed a patent application only to not get scooped- I have seen work taken from Nobel Prize winners so for someone less than Zizek's nothing it was important. I don't foresee patent award in the future.

Best drug is made by @Merck so I wish them godspeed if they choose to do this. AKT inhibitors are well characterized- there were trials @theNCI and certain immunotherapy companies like kite pharma and bluebird etc have used or explore their use.

In my opinion, AKT inhibition is far better than PI3K inhibition due to this mechanism, and B cell germination centers will thank you for it. A few papers show the terminal levels of differentiation and the function that causes are not helpful in tumor and viral clearance.

So far, many therapies seek to cut viral load but there is an interesting decouple between viral load and organ/lung damage in this disease. In fact, it looks like pathology is more associated with increased T cell differentiation/ cytokine secretion, as Israelow showed. AKT

6/ inhibition is the BEST way to target this- I have done it in 100s of bags of human t cells. Other pathways are not worth the effort (like mTOR) because they seem to arrest T cell proliferation altogether. In my opinion, we have yet to use a precise T cell immunomodulator as of

7/ yet, and this is a very good one that has proven itself in utility. There are many high impact papers on T cell function modulation that, in practice, are garbage, and had phenotypes that needed to be eeked out with optimization on a disingenuous level. AKT inhibition is no

8/ such anemic modulator; the phenotype is massive and reproducible unlike others.

9/ Especially reassuring, is the fact that in murine xenograft models of T cell immunotherapy of human malignancies, is that you can continually attenuate the FAS signal and STILL get excellent T cell function and Tumor clearance. FAS carries a differentiation signal through AKT

10/ that terminally differentiates the T cells and harms their proliferation, function, and increases the IFN they spew. In my opinion, the class I downregulation that SARSCOV2 makes, induces a pathological compensatory effect from the T cells, but t cells cant go back in time

11/ all they can do is die from that point on- perhaps that is why we see such extensive CD8+ T cell aging and death. It doesn't help that (still, I think) some immunologists believe in a non-linear pathway of T cell differentiation, but for them, the effect still holds- AKT

12/ inhibition comes with greater memory and less Interferon release, but the How/why are lost.