Itaconate Shunt (now called INFa-Itaconate shunt) Part 2!

[Ben H]

Hi guys,

I hope everyone is doing well. Here is the latest update on the Itaconate Shunt part 2:

https://twitter.com/i/web/status/1617565789757882390

It’s a brilliant video with Janet and Rob, as usual. If you’re able to watch the video or is well worth it as the biochemistry in this part makes it much easier to visualise!

If not, here is a tweet thread I did to try to explain the basic points:

https://twitter.com/i/web/status/1617566488197578761

I should point out that in my tweet-thread ‘INFa’ should be ‘IFNa’ (interferon alpha). Damn autocorrect. Apologies!

Hope you guys enjoy it. Again-huge thanks to @Janet Dafoe and Rob. Rob has been extremely gracious as always and we are very lucky to have him working on this.

Take care,

B

 

[keepontruckin]

So many many thanks to Robert Phair!

 

[Consul]

The possible drugs are INF-alpha antibody or JAK-STAT inhibitors. For a day or three.

 

[ZeroGravitas]

Thanks for summary and thread. The feel of this video talk was quite interesting. Phair perhaps seemed more confident in what he was saying (than a couple years ago). And quite specific about the source of IFNa serum signal coming from the cells around the site of an initial infection.

Also saying that the (bearly detectable) levels of IFNa found in the blood were not directly problematic. But could be, say, 10'000 times more concentrated at the site of the tissue producing them. Which, I'm thinking, would have to be a part of the central nervous system, for the metabolic changes of the itaconate shunt to cause such strong body-wide symptoms...?

There was no real mention of the IDO1 metabolic trap in this talk. Only a bit about it at the end of the last video. That it also might connect into the IFNa feedback loop..? But not clear to me. And so, no talk here of needing to pull cells out of the IDO/tryptophan trap. When speculating about the couple of (already approved!) drugs that might be investigated to break the IFNa loop.

Has there been any talk of the IDO trap link elsewhere, following the last video? 🙂

Edit: Oh, and Prusty's viral mRNA tie-in. That could be from *transactivation* (of e.g HHV-6), right? Not just full reactivation.

 

[Murph]

There's a transcript too:

https://www.omf.ngo/wp-content/uploads/2023/01/Itaconate-Shunt-Part-2_transcript.pdf

I found that easier than devoting an hour to the video.


We seem to have come a long way from the original theory of a tryptophan problem, and that is fine by me as I thought that initial theory was pretty dubious. The theory now seems to be: interferon alpha signalling is stuck on. The metabolic "trap" part of it doesn't seem, any longer, to explain why this is a positive feedback loop, they are hunting for reasons that might explain why interferon alpha isn't turned off. One theory Phair raises is that viral reactivation causes interferon alpha to keep signalling.

So it's not really metabolic, nor a trap any more. Maybe the metrabolic trap theory is just like sourdough starter, it's something you throw in there that helps the scientist to do some fermenting that leads the correct answer to rise.

 

[serg1942]

This was partly described by Dr. Naviaux previously as part of his cell danger response theory. Actually, he showed how, by inducing CDR in humans cells in vitro, INFa increased as a result, and its levels decreased by giving suramin.

I wonder why the CDR theory is not conceived as part of this theory, given that it is intrinsic to it.

And, why would lowering IFNa would break the cycle if the extracellular ATP is not addressed, which seems to be upstream in the inflammation pathway?

Anyway, I'm glad the theories converge. This is a really good sign!

 

[ZeroGravitas]

Has there been any talk of the IDO trap link elsewhere

OK, so, few months back, Phair explained that the IDO trap might potentially be triggered by the IFNa itaconate shunt (but not vice versa):

[...]genes that respond to interferon alpha (IFNa). We call those genes ISGs, or interferon-sensitive-genes. There is some evidence that IDO1 is also an ISG.

 

[HTester]

When the experimental data do not consistently corroborate a theory like the IDO metabolic trap, I'm naturally disappointed. But if you want to do science, you have to be prepared for that disappointment. You have to get back up, think hard, and imagine another theory to test.

That next theory evolved from weekly talks with Chris Armstrong who was in the SF Bay Area in the fall of 2019, just before COVID. We were trying to explain the data on ME/CFS amino acid catabolism from Chris and his colleagues in Melbourne. Later, we obtained a foundation grant to work harder on this puzzle. My job was computer modeling and it was in building a model of amino acid metabolism that I first encountered the Shen 2017 Cell paper that de-orphaned CLYBL and completed the itaconate shunt. When I built this shunt into a simple model of central carbon metabolism, it not only predicted excess amino acid catabolism, but it was also seriously energy inefficient. What I found even more compelling about the itaconate shunt was that the first enzyme of the shunt (cis-aconitate decarboxylase, CAD) was encoded by a gene (ACOD1) that was originally named (Immune Responsive Gene 1 or IRG1. This direct connection to the innate immune system explains why I changed the name of the theory to the "IFNa-itaconate shunt hypothesis." As you know from my talks on the Janet Show, or from Ben's nice summary, we are now testing for mechanisms that result in "always-on" interferon alpha (IFNa) JAK-STAT signaling, which could make the itaconate shunt chronic in affected cells.

Chris and I recently had a great Zoom meeting with Bob Naviaux and Bhupesh Prusty and agreed on two important points: 1) our two theories are converging on the innate immune system, and 2) ME/CFS is a cell-autonomous or mosaic-dysfunctional disease.

Questions welcome.

 

[ZeroGravitas]

Convergence is great.👍

Bhupesh Prusty

Will this tie in with his recent talk of a non-novel biomarker? 🙂

https://twitter.com/i/web/status/1641403718187753474

ME/CFS is a cell-autonomous or mosaic-dysfunctional disease.

Are you able to clarify what this might involve, yet? 🙂

From what I searched up quickly, "cell-autonomous" might relate to recycling cytoplasmic components, such as defective organelles or protein aggregates [1]..? And "mosaic-dysfunction" to recycling mitochondria, specifically? Leaving them damaged and inefficient in affected cells?

Edit: Oh, sorry, slept on it and realised it's quite likely the other way around! Given Prusty's observation of mitochonridal fission, in response to the serum signal. Excessive mito breakdown?

 

[serg1942]

When the experimental data do not consistently corroborate a theory like the IDO metabolic trap, I'm naturally disappointed. But if you want to do science, you have to be prepared for that disappointment. You have to get back up, think hard, and imagine another theory to test.

That next theory evolved from weekly talks with Chris Armstrong who was in the SF Bay Area in the fall of 2019, just before COVID. We were trying to explain the data on ME/CFS amino acid catabolism from Chris and his colleagues in Melbourne. Later, we obtained a foundation grant to work harder on this puzzle. My job was computer modeling and it was in building a model of amino acid metabolism that I first encountered the Shen 2017 Cell paper that de-orphaned CLYBL and completed the itaconate shunt. When I built this shunt into a simple model of central carbon metabolism, it not only predicted excess amino acid catabolism, but it was also seriously energy inefficient. What I found even more compelling about the itaconate shunt was that the first enzyme of the shunt (cis-aconitate decarboxylase, CAD) was encoded by a gene (ACOD1) that was originally named (Immune Responsive Gene 1 or IRG1. This direct connection to the innate immune system explains why I changed the name of the theory to the "IFNa-itaconate shunt hypothesis." As you know from my talks on the Janet Show, or from Ben's nice summary, we are now testing for mechanisms that result in "always-on" interferon alpha (IFNa) JAK-STAT signaling, which could make the itaconate shunt chronic in affected cells.

Chris and I recently had a great Zoom meeting with Bob Naviaux and Bhupesh Prusty and agreed on two important points: 1) our two theories are converging on the innate immune system, and 2) ME/CFS is a cell-autonomous or mosaic-dysfunctional disease.

Questions welcome.

Thank you for you great work!

After reading the paper where HHV-6 expression leads to mitochondrial fission, it seems clear to me that the purinergic response is upstream the interferon cell response (this is also shown when the P2X7 receptor is stimulated and the IFN response increases).

Then, shouldn't your theory include antipurinergic drugs? Why would lowering the IFN and/or the JAK-STAT signal be effective, if the extracellular ATP is high?

 

[jaybee00]

As per @ZeroGravitas, I would welcome a plain English description of the two disease model options—which is worse and which might have potential druggable targets—thanks.

 

[Deebeewaldo]

When the experimental data do not consistently corroborate a theory like the IDO metabolic trap, I'm naturally disappointed. But if you want to do science, you have to be prepared for that disappointment. You have to get back up, think hard, and imagine another theory to test.

That next theory evolved from weekly talks with Chris Armstrong who was in the SF Bay Area in the fall of 2019, just before COVID. We were trying to explain the data on ME/CFS amino acid catabolism from Chris and his colleagues in Melbourne. Later, we obtained a foundation grant to work harder on this puzzle. My job was computer modeling and it was in building a model of amino acid metabolism that I first encountered the Shen 2017 Cell paper that de-orphaned CLYBL and completed the itaconate shunt. When I built this shunt into a simple model of central carbon metabolism, it not only predicted excess amino acid catabolism, but it was also seriously energy inefficient. What I found even more compelling about the itaconate shunt was that the first enzyme of the shunt (cis-aconitate decarboxylase, CAD) was encoded by a gene (ACOD1) that was originally named (Immune Responsive Gene 1 or IRG1. This direct connection to the innate immune system explains why I changed the name of the theory to the "IFNa-itaconate shunt hypothesis." As you know from my talks on the Janet Show, or from Ben's nice summary, we are now testing for mechanisms that result in "always-on" interferon alpha (IFNa) JAK-STAT signaling, which could make the itaconate shunt chronic in affected cells.

Chris and I recently had a great Zoom meeting with Bob Naviaux and Bhupesh Prusty and agreed on two important points: 1) our two theories are converging on the innate immune system, and 2) ME/CFS is a cell-autonomous or mosaic-dysfunctional disease.

Questions welcome.

Thank you for sharing this recent update and for all your work in general.

Could a similar theory/mechanism be at play in other diseases with a serious energy / PEM component (I’m thinking along the lines of Sjögren’s - especially neuro-Sjögren’s, and lupus)? These diseases seem to have both an autoimmune (antibody) but also a very strong strong inflammatory (innate) component in the pathogenesis. Seeing a lot of research papers coming out talking about upregulation / activation of interferons in Sjögren’s. Could solving this excessive innate immune system response solve/improve many of these diseases, not just ME? This would be huge!

As someone who developed ME after multiple herpes virus infection (EBV, then either BZV or HSV-1), and who has ongoing pain fatigue and other symptoms, I often wonder if the innate immune response actually is appropriate, cos something is going on as per this paper/case study:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618399/
Thank you again for all of your efforts and brain power-I am eternally grateful for your interest in solving these questions.

Best,
Dee

 

[perrier]

All the suffering patient wants to know is if this problem can be reversed and how many more years of agony:
1) with something this complex gone awry it might turn out that only the newly sick may be able to reverse things in the immune system: what do you think?
2) how can a body that has been ill for years/decades hope to get well--doesn't this sickness or shunt then become the new normal and there is no road back?

No science background here, just a desperate parent.
Thanks for your dedication Dr. Phair.

 

[Oliver3]

Yes, thanks for the hard work but goddamn

 

[Deebeewaldo]

One further thought/observation from me-does progesterone dampen the interferon response in some? My ME fatigue/PEM is crushing when I don’t have progesterone in my system (pre ovulation and after it falls again each month). the difference in what I can do in a given day and how fatigued I am is so notable when progesterone is high (obviously not applicable to everyone and not a solution in and of itself). I guess broadly speaking progesterone might dampen the immune system, so it could make sense that progesterone also dampens the interferon response as part of this?

 

[thegodofpleasure]

"ME/CFS is a cell-autonomous or mosaic-dysfunctional disease."

Can you elaborate on what this means please?
Thank you so much for your brilliant work.

 

[HTester]

Can you elaborate on what this means please?
Thank you so much for your brilliant work.

By "cell-autonomous" and "mosaic dysfunctional" we mean that ME/CFS does not affect every cell in the body. In other words, only a fraction of the patient's cells is sick/affected. The cell types of affected cells will determine the symptoms, and the number and criticality of affected cells will determine the severity.

 

[HTester]

All the suffering patient wants to know is if this problem can be reversed and how many more years of agony:
1) with something this complex gone awry it might turn out that only the newly sick may be able to reverse things in the immune system: what do you think?
2) how can a body that has been ill for years/decades hope to get well--doesn't this sickness or shunt then become the new normal and there is no road back?

I do not yet know the answers to the poignant questions asked by the suffering patients or their parents. But I do wake up every morning thinking today might be the day. I do not even know for sure that ME/CFS is a bistability disease. I just know it's a feasible explanation for the symptoms and the data and it's something I know how to pursue.

You ask two good questions. Here is what I think. Bistabilities, such as the IDO1 trap, and the itaconate shunt, are exactly like light switches. One could say that "off" is the "new normal" for a light switch (and the lamp) that has just been turned off, but everyone knows what to do to make "on" the new normal again. I agree with you that in a complex and incompletely understood system like the innate immune system, it may be easier during the early stages of the disease to flip the switch back to normal, but once the switch is identified, the work of delivering a cure for everyone becomes vastly easier. We no longer have to find the switch; we just have to learn, biochemically, how to push.

My mind and my heart are with you and your child, Perrier.

 

[HTester]

One further thought/observation from me-does progesterone dampen the interferon response in some? My ME fatigue/PEM is crushing when I don’t have progesterone in my system (pre ovulation and after it falls again each month). the difference in what I can do in a given day and how fatigued I am is so notable when progesterone is high (obviously not applicable to everyone and not a solution in and of itself). I guess broadly speaking progesterone might dampen the immune system, so it could make sense that progesterone also dampens the interferon response as part of this?

Dee, Before reading your post, the only action of progesterone on the itaconate shunt that I knew about was a 2003 paper showing that in murine uterus progesterone induces ACOD1. If true in other tissues, this would predict exactly the opposite of your experience. But then, in UniProt, I encountered an isoform of the progesterone receptor called M-PR (M for mitochondrial) that I did not know about.
I'm unsure how this works but an October 2022 review tells us that progesterone activation of this alternately spliced PR results in increased mitochondrial membrane potential and ATP production. Depending on how it works, this might overcome the energy inefficiency of the itaconate shunt and account for your keen observation concerning the luteal phase of your cycle.

I often say that much of what I know about ME I've learned from patients. This is a provocative example. Thanks.

 

[HTester]

Could a similar theory/mechanism be at play in other diseases with a serious energy / PEM component (I’m thinking along the lines of Sjögren’s - especially neuro-Sjögren’s, and lupus)? These diseases seem to have both an autoimmune (antibody) but also a very strong strong inflammatory (innate) component in the pathogenesis. Seeing a lot of research papers coming out talking about upregulation / activation of interferons in Sjögren’s. Could solving this excessive innate immune system response solve/improve many of these diseases, not just ME? This would be huge!

I've lost count of how many times Ron and I have said this to one another.