thegodofpleasure
Player in a Greek Tragedy
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Thank you.
Itaconate Shunt (now called INFa-Itaconate shunt) Part 2!
- Thread starter Ben H
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bertiedog
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@HTester Thanks for all the hard work you have put in on behalf of ME/CFS patients and I sincerely hope they pan out. I am also impressed that you are more than happy to work with our researchers/scientists which makes so much sense.
One question comes to mind, do your theories explain why some patients never seem to pick up viruses whereas others like myself will pick them up very readily. They don't necessarily make me very unwell but at least I will feel extreme PEM type symptoms for several days provided I take specific herbs several times a day from the first sign of the virus.
Pam
One question comes to mind, do your theories explain why some patients never seem to pick up viruses whereas others like myself will pick them up very readily. They don't necessarily make me very unwell but at least I will feel extreme PEM type symptoms for several days provided I take specific herbs several times a day from the first sign of the virus.
Pam
Violeta
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A common cause for people being less resistant to viruses is oxidative stress.
https://pubmed.ncbi.nlm.nih.gov/11268420/
The role of oxidative stress in viral infections
https://pubmed.ncbi.nlm.nih.gov/11268420/
But why still oxidative stress when you're on shed loads of antioxidants?
I agree tho. In the early days of being ill, antioxidants would rid me of that sympathetic drive
Violeta
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That is the question.
Maybe there are many possibilities.
Problems in the mitochondria can cause oxidative stress.
This is the one I am working with currently. CRFR1 causing oxidative stress, something wrong with CRFR2 not dealing with it the way it should. I don't know if this is a root cause or just somewhere downstream, but using quercetin as a CRFR1 antagonist seems to be helping. L-theanine to reduce cortisol which causes the constant stress is helping, too. Cortisol causes oxidative stress.
Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486520/
I just want to be sure that everyone is agreed on the definition of mitochondrial fission/fragmentation. Neither fission nor fragmentation implies the destruction of the mitochondrial membranes. Fission and fragmentation are used to describe the transition from long tubular mitochondrial networks to short ovoid mitochondria, like the ones in old biology textbooks. These short mitochondria still have completely intact inner and outer mitochondrial membranes. Agreed?
To Serg1942's point:
The purinergic response is upstream of the IFN response in the Naviaux-Prusty model. In the IFNa-itaconate-shunt model, what's upstream is the normal innate immune response to infection or trauma, namely, the cellular pattern recognition receptors (PRRs) detect PAMPs (infections) or DAMPs (damage). PRRs detect many pathogen or damage signals and the sensing of purines in places they shouldn't be is one of them.
When a cell detects any of these signals it initiates two responses: 1) the acute inflammatory response, and 2) the antiviral state. If you have access to a copy of the textbook titled Cellular and Molecular Immunology (Abbas, Lichtman, and Pillai, 10th edition, 2022), there is a nice diagram of this in Figure 4.3. I think this figure is the most interesting one in the book.
Pathway 1 (acute inflammation) paves the way for the adaptive immune system to take over the body's defense. You follow pathway 1 if you are interested in chemokines, T cells, and B cells.
Pathway 2, on the other hand, is a local warning and defense system that begins with the induction of Type I interferon genes, translation of their mRNAs on bound ribosomes, and secretion of Type I interferons into the extracellular space. It's here that the two theories converge. Dr. Naviaux independently conceived the CDR and the healing cycle and they turned out to have much in common with the innate immune system. I'm still working to understand whether/the two theories diverge after this point of convergence.
I am interested in pathway 2 because it leads to the induction of ACOD1 and therefore to the itaconate shunt. This can happen in any cell type because the secreted type I interferons can initiate JAK-STAT signaling by binding to the universally expressed IFNa receptor, consisting of two proteins: IFNAR1 and IFNAR2. This is the warning/defense signal. It says, "Prepare your defenses, there is danger nearby."
IFNa signaling via the JAK-STAT pathway (worked out in the 1980s by a legendary East-coast-West-coast collaboration) induces ~300 genes. Some are antiviral, some antibacterial, some are repair proteins, and one is ACOD1, which drives the itaconate shunt in mitochondria.
This is all part of the innate immune system. There is no mention of T cells or B cells in pathway 2. Normally, the innate immune system is turned off about 4 days after the initial PRR signal. Our hypothesis is that the innate immune system failed to turn off when it was supposed to. We think PWME are sick because a small percentage of body cells are chronically running the itaconate shunt and consequently are not producing sufficient ATP to do their jobs. We're looking for molecular mechanisms that keep ACOD1 up-regulated long after the triggering infection/trauma is gone. One of those mechanisms is chronically elevated IFNa caused by the inherent positive feedback in IFNa signaling.
Today, in this thread, I wrote a plain scientific English description of the IFNa-itaconate shunt model in response to a question from @serg1942. It's on my list to do the same for the Naviaux-Prusty disease model, but I still have some questions for them before I'd feel qualified to speak for them.
As for druggable targets, we are working on three (CAD, the enzyme encoded by ACOD1, blockers of JAK-STAT signaling, also being explored by Kenny DeMerlier, and blockers of the IFNAR.
To choose among them or to identify better ones, I think we have to understand what makes ME/CFS a chronic disease. Here are some candidates: 1) a chronic infection, 2) chronic re-activation of DNA-integrated viruses, 3) chronic nutritional deficiencies, and 4) bistability/positive feedback.
If anyone reading this has something to add to the list, I'd appreciate hearing from you. I'm sure you all understand that I'm working on number 4).
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Thank you for the summary thread! I've been looking to find something that would explain my complete remission overnight from a cold and the INFa feedback makes sense with my experience. I wasn't able to catch any viruses for 6-7 years post-onset, and after I improved with Abilify the first cold I caught completely reset my system. I'm still in remission a year+ later so am very excited for the future of this research!
Pam, The response of ME/CFS patients to (new) viruses remains a puzzle to me. You should probably direct this question to Bhupesh Prusty. He's a seriously smart virologist. Patient responses are all over the map. One patient I know improves while fighting a viral infection. On the IFNa-itaconate shunt hypothesis, almost anything is possible because there are, in theory, "only" a billion, or so, cells that are sick. So the chances are slim that the new virus will interact with sick cells. There are about 1E13 nucleated cells in the human body. That's 10,000 billion.
Parenthetically, I think this ratio (1E-4) explains why it is nearly impossible to identify a blood biomarker for ME/CFS.
I love how counterintuitive this is. I'll probably be thinking about this for weeks. What symptoms did you have before your "reset?" Are you saying you are back to normal after Abilify and a cold? How much time elapsed between the onset of your cold symptoms and your overnight reset? Are you still on Abilify? Did you clear the cold before the reset happened?
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junkcrap50
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Wow. That's awesome and very interesting. Make a dedicated post about this. I'm sure many people would be interested and ask about it, which might take this thread off topic. Gives me another reason to try Abilify, which I've leaned against.
junkcrap50
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@HTester I had severe onset in 2015, which naturally improved to mild by the end of 2017. For the next 4 years I had 0 improvement and was at around 50% function with 6 safe usable hours in a day. Start of November 2021, I started a very restrictive anti-inflammatory diet and by January 2022 I could do 8-9 hours of activity a day with no crash. I started Abilify in January, coming off the diet at the start of February and continuing with Abilify. By late March I could do 11-12 hours of activity in a day with no crash but still required rest in the afternoon to keep going. I would describe my function as around 90% at this time (wasn't doing any exercise.)
Basically, I caught a train in the morning to a university class and felt a slight runny nose, which I thought might be due to the weather getting colder. Put on a mask and the symptoms ramped up throughout the class and it was clear I had some kind of cold! When I got home at 1-2pm I would usually need a rest, but felt my energy levels were fine despite being very congested. This continued throughout the duration of the cold, which isn't an uncommon occurance in some pwme. What is surprising is that the cold cleared and I still had no limitations on my activity/energy levels. In April/May I then tapered off my 0.75mg dose of Abilify completely with no symptom recurrance. I've since had covid and another cold and not had my ME retriggered.
I believe the improvement of my symptoms were really crucial to me being able to catch a virus. I was able to attend school most days for the last few years of highschool, and was exposed to people quite constantly. In 2018 I went to Japan with my brother and he caught a nasty virus, whereas I was completely untouched despite sharing a very small studio apartment for the 2 week trip. I never caught any virus up until March 2022. The only time I fell "normal person ill" was from food poisoning in 2019 and that did not have the same effect.
I now class myself as in complete remission as I have no limits on my energy levels and can exercise for several hours a week.
@junkcrap50 (and for any of those interested as to not derail this thread) I've got a post about my remission which can be found here.
Basically, I caught a train in the morning to a university class and felt a slight runny nose, which I thought might be due to the weather getting colder. Put on a mask and the symptoms ramped up throughout the class and it was clear I had some kind of cold! When I got home at 1-2pm I would usually need a rest, but felt my energy levels were fine despite being very congested. This continued throughout the duration of the cold, which isn't an uncommon occurance in some pwme. What is surprising is that the cold cleared and I still had no limitations on my activity/energy levels. In April/May I then tapered off my 0.75mg dose of Abilify completely with no symptom recurrance. I've since had covid and another cold and not had my ME retriggered.
I believe the improvement of my symptoms were really crucial to me being able to catch a virus. I was able to attend school most days for the last few years of highschool, and was exposed to people quite constantly. In 2018 I went to Japan with my brother and he caught a nasty virus, whereas I was completely untouched despite sharing a very small studio apartment for the 2 week trip. I never caught any virus up until March 2022. The only time I fell "normal person ill" was from food poisoning in 2019 and that did not have the same effect.
I now class myself as in complete remission as I have no limits on my energy levels and can exercise for several hours a week.
@junkcrap50 (and for any of those interested as to not derail this thread) I've got a post about my remission which can be found here.
Murph
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[/QUOTE]
I love this attitude. good one.
My question: what is the balance between experimental evidence and model evidence that makes you suspect interferon-alpha signalling is stuck on?
My other question is whether/how the itaconate shunt operating only in certain immune cells is enough to produce PEM?
Maybe something like this. It reminded me of Ron Davis finding uranium in the hair mineral analysis of 2 severe patients. If i remember correctly that is.
Other than that, maybe some kind of damage, e.g to the ANS. And i think someone has suggested CSF fluid causing pressure against the pituitary or something as well, probably got the details wrong here though, maybe someone else remembers it. But if correct these would be additional mechanisms that could cause chronic disease.
BrightCandle
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I had uranium in my hair sample too.
Thank you so much Dr Phair for your magnificent and detailed response!
I understand that your theory puts the focus on the stimulation of pattern recognition receptors, where the high purines are only one of the many different signals that stimulate these receptors.
Please, let me however highlight a few points that make me conceive the purinergic signal as, at least, a key part. I would really appreciate if you could let us know how you could explain the following facts in the light of your theory.
The studies done by Dr Naviaux showed how a genetic and an acquired murine model of autism could be mostly reversed by just one dose of suramin. Specifically, the acquired model showed a 94% normalization of the metabolites of 18 biochemical pathways, and the genetic model showed significant improvement of the metabolome and the synaptosome. Most importantly, in both models the autistic-like behaviors were normalized.
Among the corrected metabolites by suramin, I think that we can find an indirect sign of normalization of the innate immunity as well as normalization of the itaconate and the Krebs cycle pathway.
For example, most intermediaries of the Krebs cycle increased, including fumaric acid, malic acid, succinil-CoA, 2-oxoglutarate or citramalic acid.
The coenzyme-A and the CoA-containing metabolites also increased, including acetyl-coA and malonyl-CoA. So perhaps this means that the Coenzyme A is not longer sequestered by the itaconate metabolites.
On the contrary, NH3 and glutamate don't increase, in relative terms.
Oxidative stress seems to improve as well. For example, the ratio GSH/GSSG increases . The ratio NADH/NAD+ increased. Coq10 and lipoic acid increased as well.
In addition, and this really amazes me, the microbiome abnormalities showed a generalized normalization.
Finally, the C1q complement decreases significantly, what I understand could mean a concomitant decrease of the complete innate response (given that, for example, LPS stimulate both IFNa and the complement system).
After carefully studying your great lecture on the itaconate pathway, it seems to me that these changes fit with a temporary reversal of the itaconate pathway activation and a restoration of the normal mitochondrial and overall metabolic function.
Would you please let us know how these changes induced by suramin could be explained from the itaconate hypothesis, where the IFNa signal would be central?
Thank you very much for your fantastic work and for your willingness to teach us and to let us discuss with you all these points!
Sergio
PS. the Naviaux's studies I am referring to are:
https://pubmed.ncbi.nlm.nih.gov/25705365/
https://pubmed.ncbi.nlm.nih.gov/24937094/
SlamDancin
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@serg1942 I did a very quick Google search and discovered that’s it’s been documented that Suramin inhibits stimulator of interferon (IFN) genes, STING, and reduces at least ifn-beta in one in vitro study;
Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels
If I’m not mistaken STING also stimulates ifn-alpha production and genetic pathways
Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels
If I’m not mistaken STING also stimulates ifn-alpha production and genetic pathways
Yes, it makes sense after analyzing Dr. Naviaux's study.
I wonder whether an IFNa inhibitor would also lower the extracellular purinergic signal.
Perhaps a combination of drugs including antipurinergic drugs, IFN blockers and JAK inhibitors could be developed and given in very low doses. This is really tough to test in experiments though.
Let's see what Dr. Phair's opinion is about the posible need of suramin. From his answer I guess he thinks it might not be as important as the other targets.
Sergio
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All I can say is thank you kindly (these words seem inadequate really) for your thoughts and these links, and for continuing to work so hard on trying to get to the bottom of this. All pwME appreciate it more than you can imagine. Please don't give up!
Dee