The immunological inconsistency in the IDO trap theory

[nerd]

Is there any means thru which the viruses may be inducing tryptophan to accumulate? Could they be influencing this phenomenon in some way?

Oncolytic HSV could do this (10.1155/2012/815465). So it's theoretically possible that certain viral variants of common viruses exist that contain such a mechanism as wild types. I suspect IDO might just not be an enzyme that is often analyzed by virologists.

Here is also an interesting paper about the effect of IFN-γ and butyrates on STAT1 and IDO (10.1016/j.biocel.2010.07.020).

Spoiler: Abstract

The clinical outcomes of most immunotherapeutic strategies have been less effective than anticipated partially because of the tumor immune tolerance induced by many immune tolerance factors, which originate from the tumor and tumor microenvironment. Indoleamine 2, 3-dioxygenase (IDO) is an interferon-γ (IFN-γ)-inducible enzyme and is one of main immune tolerance factors during tumor development. Sodium butyrate (NaB) has received much attention as a potential chemopreventive agent for cancer treatment due to its protective action against intracellular events including IFN-γ-mediated signaling transduction. Therefore, the question remains whether IDO is a target of the anti-tumor action of NaB. In this study, we demonstrate for the first time that NaB down-regulated IDO via both transcriptional and post-transcriptional mechanisms. NaB repressed the activity of STAT1 to inhibit STAT1-driven transcriptional activity of IDO. These mechanisms included inhibiting STAT1 701 tyrosine phosphorylation, nuclear translocation, and repression of STAT1 binding to γ-activated sites (GAS). Moreover, immunoprecipitation and immunoblotting assays showed that treatment of cells with NaB caused dramatic ubiquitination of total intracellular proteins, including IDO. Blocking 26S proteasome activity by addition of its specific inhibitor, bortezomib, reversed the ubiquitination and down-regulation of IDO. These results suggest that NaB-induced STAT1 activity inhibition and ubiquitin/proteasome-dependent proteolysis are involved in the down-regulation of IDO. The discoveries in this study represent a new mechanism in the anti-tumor action of NaB and may have implications for development of clinical cancer immunotherapy.

It comes down to the same question. If IDO is really downregulated, the ketogenic diet and butyrates would be counterproductive. If it is upregulated, it helps.

 

[Rufous McKinney]

So it's theoretically possible that certain viral variants of common viruses exist that contain such a mechanism as wild types.

or- could the viruses be doing something which triggers the increased nitric oxide that might contribute to the trap?

I got worse- after decades of mild, i got much worse rather quickly- involving gastroenteritis type issues, and in one of my theories, that type of infection can raise Nitrous oxide and could have gotten me significantly more TRAPPED if there is such a thing.

(ed) Here is a paper referring to a high measured build up of nitric oxide in the intestines following gastroentertisis.

https://academic.oup.com/jid/article/180/2/542/883252

 

[nerd]

or- could the viruses be doing something which triggers the increased nitric oxide that might contribute to the trap?

I assume this also happens. But it's more like the natural metabolism of antiviral response because it harms the cells where it is happening. So why don't these cells disappear naturally? And if it's not a virus, what's the origin of all the nitrosative stress? Unstable mast cells?

My first health issues started with a gastritis, followed by MCAS.

(ed) Here is a paper referring to a high measured build up of nitric oxide in the intestines following gastroentertisis.

Considering that a subgroup of the patients had detectable pathogens in the stool, the other ones might have had pathogens as well, but not detectable anymore or unmatched ones.

 

[Rufous McKinney]

what's the origin of all the nitrosative stress? Unstable mast cells?

could there be a relationship between the urea cycle (ammonia gliches) and this Nitrous oxide build up? Both involve some form of nitrogen.

My first health issues started with a gastritis, followed by MCAS.

I keep "gettting something" that shuts off my stomach. In the ER, they called it gastroenteritis, but it had no actual involvement with my intestines. ER did nothing to diagnose.

So then I have a type of gastroperesis for weeks/months after these acute episodes, which involve massive vomiting and nausea. And it seems like a stomach flu yet I could not have caught anything, nor is it food poisoning.

While I "got this" repeatedly over a period of several years- it was two episodes within 2 months of each other- that after that I was NOT MILD any longer: I got MUCH worse ME.

 

[Rufous McKinney]

While I "got this" repeatedly over a period of several years- it was two episodes within 2 months of each other- that after that I was NOT MILD any longer: I got MUCH worse ME

sorry- and here is one more detail I may never know: during these really intense vomiting episodes: what if I made my neck worse? Throwing up can be pretty- vigorous event, when one thinks one may die.

 

[nerd]

I think I found the missing puzzle piece. This all makes sense now.

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice

Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E, Maeda Y, Tawara I, Krijanovski O, Gatza E, Liu C, Malter C, Mascagni P, Dinarello CA, Ferrara JL. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest. 2008 Jul;118(7):2562-73. doi: 10.1172/JCI34712. PMID: 18568076; PMCID: PMC2430497.

Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.

Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors

Fang K, Dong G, Li Y, He S, Wu Y, Wu S, Wang W, Sheng C. Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors. ACS Med Chem Lett. 2018 Mar 26;9(4):312-317. doi: 10.1021/acsmedchemlett.7b00487. PMID: 29670692; PMCID: PMC5900342.

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.

 

[Boba]

@nerd

Can you explain pls.? What makes sense?

 

[nerd]

@nerd

Can you explain pls.? What makes sense?

This post was about the inconsistencies between different CFS/ME etiology and pathogenesis theories so that far-fetched assumptions would be necessary to link these together. HDAC provides an evidence-based link, making the assumptions superfluous. If we assume that pathogens exist, we have to assume HDAC participation and this explains why the IDO trap is triggered and maintained. It might very well be that IDO was just a lucky finding due to the additional genetic predisposing factor in IDO2, causing the functional disease, while HDACs play the real central role in the pathogenesis, not only driving virus latency, pathogen evasion mechanisms, but also metabolic and immunological regulation.

I'm working on a therapy protocol in this post.

 

[Boba]

This post was about the inconsistencies between different CFS/ME etiology and pathogenesis theories so that far-fetched assumptions would be necessary to link these together. HDAC provides an evidence-based link, making the assumptions superfluous. If we assume that pathogens exist, we have to assume HDAC participation and this explains why the IDO trap is triggered and maintained. It might very well be that IDO was just a lucky finding due to the additional genetic predisposing factor in IDO2, causing the functional disease, while HDACs play the real central role in the pathogenesis, not only driving virus latency, pathogen evasion mechanisms, but also metabolic and immunological regulation.

I'm working on a therapy protocol in this post.

Thanks for the reply, but I don’t understand. Is this confirming the inconsistency?

 

[Boba]

Ok I think I get it. HDAC is the missing link between pathogens and the triggered IDO trap. You’re saying influencing the HDACs would untrap us? Assuming that there are pathogens involved, which I’m not sure about.

 

[nerd]

Ok I think I get it. HDAC is the missing link between pathogens and the triggered IDO trap. You’re saying influencing the HDACs would untrap us? Assuming that there are pathogens involved, which I’m not sure about.

Pathogens are involved. HDACs are manipulated by pathogens to evade innate and adaptive immunity. The second paper suggests that a dual inhibition might also be possible that just isn't determined. Overall, this seems to be unlikely though because they artificially attached an IDO inhibitor to an HDAC inhibitor. This manipulation has the side effect of wide-scale systemic metabolic and immunological alteration, including the IDO trap.

We next evaluated whether HDAC inhibitors regulate the transcription of IDO by performing a chromatin immunoprecipitation assay (see Methods). As shown in Supplemental Figure 4A, acetylated H4 was bound to the IDO promoter, demonstrating a direct role for acetylation of histones in promoting transcription of IDO by SAHA.

This is an important finding. SAHA doesn't inhibit HDAC and induce IDO in a dual fashion. It inhibits HDAC and this inhibition upregulates IDO. Pathogens don't have to regulate IDO directly either. They just can regulate HDAC and this causes IDO pathology when the host has a defective IDO2 genotype. The exception are pathogens that can suppress both IDO genes enzymes, but this is probably a rare thing. Overall, there is no need for an IDO-specific drug as Ron Davis tries to find because there are already HDAC inhibitors that could be repurposed.

Ron Davis assumes the IDO trap is a trap because of the tryptophan levels. I would like to see an in vitro study on human cells that actually shows that the tryptophan doesn't leave the cell once it accumulates. HDACs provide an alternative explanation in that the IDO trap is a trap because HDACs suppress IDO and both together maintain the dysfunctional cells' survival.

You’re saying influencing the HDACs would untrap us?

HDAC inhibitors would fix the functional disease, but not completely resolve the causality. It is very likely that HDAC inhibitors contribute to the clearance of latent and abortive infected cells (one pathogen-related causality) just like it is proven that this class of drug can help clear out unhealthy cells by senescent cell regulation. The same is translateable for fungi and probably parasites as well. But I wouldn't trust it to work with every pathogen and also not to be very effective.

I would combine it with low-risk antivirals, antiparasitics, and antifungals. Ivermectin, for instance, combines multiple of these mechanisms. In fact, it's possible that Ivermectin is an HDAC inhibitor. I will have to run simulations to confirm this though. But I suspect it because of the similarity to GABA, which is an HDAC inhibitor. GABA is also the reason why we might not need a highly effective HDAC inhibitor that crosses the BBB. But every one of these mechanisms will be dose-dependent and have to be checked separately. I suspect that high doses will be necessary, making primary HDACi drugs a better option.

 

[Boba]

Thanks for your input. HDAC inhibitors stop mitochondrial fragmentation as well right? I came across it while researching the idea of Prusty, he had the theory that inhibiting mito fragmentation could help cure CFS.

Minute 30+

 

[Martin aka paused||M.E.]

Thanks for your input. HDAC inhibitors stop mitochondrial fragmentation as well right? I came across it while researching the idea of Prusty, he had the theory that inhibiting mito fragmentation could help cure CFS.

Minute 30+

2019. Curious how far this came. He doesn't tweet about it afaik

 

[nerd]

Thanks for your input. HDAC inhibitors stop mitochondrial fragmentation as well right?

Via a macrocellular apoptotic/autophagic mechanism, definitely. This just measures mitochondria based on their overall function. On an intracellular level, I will have to do more research on HDAC's function on mitochondria since mitochondria have a separate genome. I will watch the video later.

 

[SlamDancin]

@nerd Curious, have you ever considered reaching out to Ron Davis directly with this theory? I think I could arrange it.

 

[SlamDancin]

@nerd

https://pubmed.ncbi.nlm.nih.gov/34011981/

HDAC1 was proposed using bioinformatics to be related to altered miR’s in ME/CFS in this recent study

 

[nerd]

Here is my response to the video:

(11:22), they use Trichostatin A, an effective HDAC inhibitor to reactivate HHV-6A in vitro. This is often seen with receivers of donated organs who rely on apoptosis-inducing drugs. They are normally given antivirals for a certain period of time, just for prophylaxis. This is why I would also suggest taking HDAC inhibitors at least with broad virostatics. It has to be combined. In general, this shouldn't be an issue. My concern is just the nerve system and if it's worth taking the risk of an antiviral that crosses the BBB. HHVs seem to reside in the nervous tissue as well. So I'm kind of gauging at the moment. What nerve-specific generic antiviral can be taken long-term and without serious risks and side effects? I will begin co-treatment with Valtrex soon, which is quite safe, but this isn't effective in the nervous system and the brain.

(19:53), they mention miR-30-mediated Caspase and p53 regulation. Their experiment uses TSA again, but I think this is putting bias in this experiment's results in that HDACs are p53 downregulators. p53 and Drp1 might be regulated either by HHV-6 or by TSA after all. Fortunately, they rule this out in the following experiment by using the viral RNA only. Now assume the following. What if you used HDAC inhibitors as p53 upregulators and mutant p53 "cleanup helpers" as explained in this study (10.3390/ijms20102415) while suppressing the released HHV RNA from entering new cells?

(27:18), they explain the finding of Ron Davis of why plasma exchange, or rather serum exchange in particular, as it becomes evident, exhibits pathology in healthy donor cells. It's possibly because of Drp-1. But I assume that this can be translated for other viral proteins as well, from HHV or other viruses. Dr. Prusty mentions this possibility as well in the Q&A.

I wonder what drug they patented, but I assume it's an antibody, so not much use to us until this goes through many years of further research and clinical trials. For HHV, it's mechanistically challenging to develop an antiviral that not only works during the productive phase but also later on. Do I remember correctly that you, @Hip, have looked into HHV and potential antivirals? My focus was always latent-lytic gamma-herpes viruses, so I'd appreciate any suggestions.

@nerd Curious, have you ever considered reaching out to Ron Davis directly with this theory? I think I could arrange it.

Thank you. This is too early though. At the appropriate time, I'd appreciate it. I will keep posting my findings here in the forum because there's always the chance that it gets worse for me and disables me from further work.

https://pubmed.ncbi.nlm.nih.gov/34011981/

HDAC1 was proposed using bioinformatics to be related to altered miR’s in ME/CFS in this recent study

Thank you for referencing this new study! This extends and confirms the findings of Dr. Prusty and his colleagues by other mitochondrial miRNAs. They basically do the same as viral cell cycle-regulating proteins but on a mitochondrial level. Very interesting how many exist. I was only aware of this study (10.1016/j.bbi.2011.04.007), finding HDACs 2 and 3. But now we have confirmation of HDAC1 as well, creating a consistent picture with the miRNA theory and the IDO trap theory. Even the immunology can be explained in a consistent manner by CFS/ME phase-dependency and viral life cycles.

So it's not only about endothelial dysfunction, the main subject of the authors, but also about the mitochondria. Unfortunately, they don't mention the mitochondria in the paper and how consistent this finding is with the theory of Prusty et al. I think it's important for new studies to point out their consistencies because this is one of the main critiques nowadays for why physicians shouldn't take the new research seriously. "Because it's not reproducible", they say. This is the second reproduced confirmation of the plasma exchange model finding of Ron Davis.

If it's really class I HDACs only, there are more treatment options. SIRT1 could be regulated differently or also by a pan-HDAC inhibitor that works on class III as well.

 

[Hip]

Do I remember correctly that you, @Hip, have looked into HHV and potential antivirals? My focus was always latent-lytic gamma-herpes viruses, so I'd appreciate any suggestions.

The main antiviral for HHV-6 and cytomegalovirus used by ME/CFS doctors is Valcyte. Some patients have done well on this. There is also cidofovir and foscarnet, which may be stronger, but these must be given intravenously.

There are some reports of artesunate have some antiviral effects against these viruses, but it is likely only a weak antiviral.

A new drug which target cytomegalovirus only is letermovir, but this is extremely expensive, and I have not heard of it being used in ME/CFS as yet.



When I looked at supplements and drugs which might have possible antiviral effects for ME/CFS viruses, I did not find much. However, my calculations suggest that very high dose genistein might be potently antiviral in vivo against cytomegalovirus. I found a few other supplements have mild antiviral effects against cytomegalovirus (like Terminalia chebula and monolaurin); see this post.

 

[junkcrap50]

What if you used HDAC inhibitors as p53 upregulators and mutant p53 "cleanup helpers" as explained in this study (10.3390/ijms20102415) while suppressing the released HHV RNA from entering new cells?

I know it's a rhetorical question, but why don't you ask Prusty. He is fairly interactive on twitter and will answer questions from patients / the public.

 

[Martin aka paused||M.E.]

@nerd If Valtrex doesn't cross the BBB that might explain why Learner had “only” a success rate of 75% with it. But when it was given 1-6 years and it was effective, patients went into remission. I think HHV-6 will be of great interest in further research.