Thread by @tessfalor

#IIMEC15 Professor Robert Phair

The Itaconate Shunt Hypothesis for ME/CFS

Start with TCA cycle

NAD is reduced to NADH, used to make ATP

Looking at part of pathway not in the textbooks - The itaconate shunt

starts at cis-Aconitate

itaconate is converted to itaconyl-CoA with STK to

Up until 7 years ago, that was the end, then found CLYBL. Lab discovered what it does

If there is a substantial flux through this shunt, the cell is in trouble.

Why do you have the shunt?

consequences and predictions of the shunt

Reduced OCR - Chen, 2022
Reduced substrate-level phosphorylationNemeth, 2016
Poisoning of vitamin B12 - Shen, 2017, Ruetz, 2019
CoA sequestration - Cordes and Metallo, 2021

Innate immunity - phase 1

ACOD1 gene - used to be known as immune responsive gene (active when innate immune system active)

Innate immunity has probably been around 150 million years. In all vertebrates

In all cases, turns on two processes in cell. Inflammatory - NF-κB is signal to turn on. Interferon alpha signal send from infected cell and delivered to other cells (bystander cells)

Explain symptoms by interferon alpha.

JAK-STAT signaling pathway. Turns on IRF1 -> ACOD1 (codes for CAD that starts itaconate shunt) & secretes more interferon alpha into extracellular space.

More IFN alpha makes more IFN alpha

Any cell stuck in a permanent shunt won't have… twitter.com/i/web/status/1…

there's a way to stop it, but I missed it

All nucleated cell types express IFN alpha receptor

Would predict increased plasma IFN alpha in #MECFS, but plasma IFN in humans is around 10 femtograms/mL (hard to measure)

Found company with ultra sensitive assay for interferon alpha. They've measured concentration in #MECFS, median in ME is 4x greater, but there are some healthy controls as high as most serious patients

but in the healthy controls the cells in the plasma are making the high interferon, but in #MECFS think the high values are due to high values in interstitial

If you fix the itaconate shunt, you're good

If you had the shunt running in all your cells, you wouldn't be able to live, so they think it's <10% of cells and severe patients just have the wrong type of cells

Bistability

double negative feedback loops, feedback loops (IFNa, IFNAR1, IFNAR2), mutual inhibition (SOCS3 and JAK1)

feature of nonlinear systems

If you don't move the switch past the midpoint, it will move back to where you started

If we can get you out of the pathogenic state, you will flip back to the normal physiology.

which state you're in depends on external signals

if you've heard of any #MECFS patients who've been cured they will tell you it's been really fast, overnight

How to escape:

block itaconate shunt - is restarting ATP production enough?

Block JAK-STAT - Filgotinib

Block IFNAR receptor

Re-initiate the innate immune response - second chance to turn off positive feedback, Ampligen

@remissionbiome @chydorina @arta_semita

Question: Do you see an integration with all the other research (viral persistence, autoimmunity, etc)?

Answer: "Integration is critical and I think about it every day. There's question about viral reservoir. A hidden virus could be constant stimulus. I hope the virologists are… twitter.com/i/web/status/1…

If you want to hear more info. 2 videos with @JanetDafoe