nerd
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Please beware, this theory is highly speculative. However, considering the good risk-benefit ratio from associated solutions, I'd like to discuss it.
One of the many unresolved questions of ME is the role of viral pathology and how it might mediate the ME etiopathogenesis. One of my existing theories is that an overgrown latent/abortive cell reservoir just increases the threshold of reactivation susceptibility so far that these viruses basically remain stuck in their early reactivation phases. This makes them difficult to quantify via IgM antibody and PCR testing.
How exactly this mechanism might work in detail, I haven't elaborated so far. In this post, I'd like to introduce one theory of how this mechanism might play out. The theory is based on the core assumption that one or more viruses have managed to infect the brain or CNS and form a latent/abortive cell reservoir in these regions.
Due to my current work on histone deacetylases (HDACs) and their adverse and therapeutic potential, I identified GABA as a potent HDAC inhibitor (more on this another time) [3, 4]. Given the findings of GABA brain tissue concentrations, I make a reasonable estimate that there is normally a sufficient GABA concentration in most brain regions and cell types for virus reactivations to be triggered (i.e. at high nM to low μM concentrations) [1, 2, 3]. This makes the brain very susceptible to infections if a virus manages to invade it since HDAC inhibition is a cross-cutting viral reactivation trigger.
One prevalent theory of the innate immune system is that it has been shaped via selection pressure from pathogens [7, 8, 9]. What if the selection pressure doesn't only affect the species on an evolutionary/host-macroscopic but also on a microscopic level, and pushes them to minor adaptations within their lifetimes?
Imagine viruses that aren't necessarily lethal (anymore) and hence trigger selection pressure on a cellular level. The immune system will be maternally and paternally inherited to different degrees, thereby coevolve parallel to the genetic sexual reproduction, one might say forming an evolutionary lineage on its own [5, 6, 7]. Generation by generation, viruses and the immune system might be inherited to the offspring and the selection pressure would continue on a cellular level, naturally forcing cells to adapt their gene expressions and gene functions to the parentally endemic pathogens.
The cellular adaptation is not proven and speculative since the subject is still in work in progress, e.g. in the context of the original antigenic sin. But how could it work mechanistically? Pathogens adapt to the species in which they are endemic, thereby integrating their genes in one way or another. This can lead to a cycle of species and pathogen evolution.
The first mechanism I can imagine is this kind of antigen-driven selection pressure, whereby antigens might affect the intracellular innate immune response and gene/enzyme expressions. This would happen on an intracellular level. On a macrocellular level, the cellular selection could be driven by the susceptibility of cells to be damaged by viral infections or by surrounding infected cells and the subsequent destruction of these cells. Lifecycle after lifecycle, the cells would adapt to the existing viral reservoirs.
Let's assume that this cell adaptation theory is applicable to the brain and its immune system. The reproductive cycle in the brain would be driven by GABA-regulated HDAC inhibition. This makes HDAC a target, but also GABA. GABA receptor function is regulated by HDAC3, after all [3]. What if there is a selection pressure that downregulates GABAergic mediators in order to protect the brain from viral reactivations and their toxicity?
This leads to hyperactivity, sleeplessness, unrest, cognitive over-exhaustion, oversensitivity, the incapability to properly rest, and thereby also the whole energy metabolism and excess of oxidative stress by sympathetic overactivation. The excess of oxidative/nitrosative stress subsequently blocks the citric acid cycle (CAC) and causes an oversupply of glutamate, thereby enhancing and enforcing the condition via a secondary pathway, creating a "GABA trap" situation.
The trap would be self-fueling in that the sympathetic overactivation triggers oxidative stressors that can reactivate viruses (e.g. via the CAC blockage). This might trigger PEM. During PEM, more GABA would be released. The GABA triggers reactivations. Also of note is that the oxidative stressors would affect the whole metabolism while the GABA affects the brain predominantly.
How can this translate into solutions? Besides the HDACi antiviral protocol that it is still work in progress and a topic for another time, GABA agonists and positive allosteric modulators could replace the role of GABA. These agonists would need to lack the property that makes GABA an HDAC inhibitor, namely its zinc ionophority and the small size that allows it to fit into the zinc finger binding sites of HDACs. Unfortunately, Taurine seems to be an HDAC inhibitor as well (with mild or moderate effect). At least, this is likely based on the docking simulations. So I'm still looking for more candidates that meet the criteria.
A matching GABA agonist/modulator could be taken in the evening to alleviate sympathetic overactivation without downregulating HDACs, thereby avoiding additional reactivation triggering but alleviating the metabolic consequences that indirectly lead to viral reactivations. At least one side of the GABA trap could be functionally handled this way. It would not remove the viral reservoirs immediately but it might provide a baseline for the immune system to get hold of the virus in the brain, which mediates the other side of the trap.
This theory doesn't exclude alternative theories that can create similar trap situations. For example, viral miRNA and viral proteins could also create reactivation cycles. They can also affect the sympathetic overactivation and indirectly maintain a GABA/HDAC trap. This would be an alternative explanation to the cellular adaptation, though the GABA agonist/modulator therapy would still be applicable. I think GABAergic activation without HDAC inhibition is as important as Melatonin for getting refreshing rest and not exhausting half-sleep, as it is often the case.
One of the many unresolved questions of ME is the role of viral pathology and how it might mediate the ME etiopathogenesis. One of my existing theories is that an overgrown latent/abortive cell reservoir just increases the threshold of reactivation susceptibility so far that these viruses basically remain stuck in their early reactivation phases. This makes them difficult to quantify via IgM antibody and PCR testing.
How exactly this mechanism might work in detail, I haven't elaborated so far. In this post, I'd like to introduce one theory of how this mechanism might play out. The theory is based on the core assumption that one or more viruses have managed to infect the brain or CNS and form a latent/abortive cell reservoir in these regions.
Due to my current work on histone deacetylases (HDACs) and their adverse and therapeutic potential, I identified GABA as a potent HDAC inhibitor (more on this another time) [3, 4]. Given the findings of GABA brain tissue concentrations, I make a reasonable estimate that there is normally a sufficient GABA concentration in most brain regions and cell types for virus reactivations to be triggered (i.e. at high nM to low μM concentrations) [1, 2, 3]. This makes the brain very susceptible to infections if a virus manages to invade it since HDAC inhibition is a cross-cutting viral reactivation trigger.
One prevalent theory of the innate immune system is that it has been shaped via selection pressure from pathogens [7, 8, 9]. What if the selection pressure doesn't only affect the species on an evolutionary/host-macroscopic but also on a microscopic level, and pushes them to minor adaptations within their lifetimes?
Imagine viruses that aren't necessarily lethal (anymore) and hence trigger selection pressure on a cellular level. The immune system will be maternally and paternally inherited to different degrees, thereby coevolve parallel to the genetic sexual reproduction, one might say forming an evolutionary lineage on its own [5, 6, 7]. Generation by generation, viruses and the immune system might be inherited to the offspring and the selection pressure would continue on a cellular level, naturally forcing cells to adapt their gene expressions and gene functions to the parentally endemic pathogens.
The cellular adaptation is not proven and speculative since the subject is still in work in progress, e.g. in the context of the original antigenic sin. But how could it work mechanistically? Pathogens adapt to the species in which they are endemic, thereby integrating their genes in one way or another. This can lead to a cycle of species and pathogen evolution.
The first mechanism I can imagine is this kind of antigen-driven selection pressure, whereby antigens might affect the intracellular innate immune response and gene/enzyme expressions. This would happen on an intracellular level. On a macrocellular level, the cellular selection could be driven by the susceptibility of cells to be damaged by viral infections or by surrounding infected cells and the subsequent destruction of these cells. Lifecycle after lifecycle, the cells would adapt to the existing viral reservoirs.
Let's assume that this cell adaptation theory is applicable to the brain and its immune system. The reproductive cycle in the brain would be driven by GABA-regulated HDAC inhibition. This makes HDAC a target, but also GABA. GABA receptor function is regulated by HDAC3, after all [3]. What if there is a selection pressure that downregulates GABAergic mediators in order to protect the brain from viral reactivations and their toxicity?
This leads to hyperactivity, sleeplessness, unrest, cognitive over-exhaustion, oversensitivity, the incapability to properly rest, and thereby also the whole energy metabolism and excess of oxidative stress by sympathetic overactivation. The excess of oxidative/nitrosative stress subsequently blocks the citric acid cycle (CAC) and causes an oversupply of glutamate, thereby enhancing and enforcing the condition via a secondary pathway, creating a "GABA trap" situation.
The trap would be self-fueling in that the sympathetic overactivation triggers oxidative stressors that can reactivate viruses (e.g. via the CAC blockage). This might trigger PEM. During PEM, more GABA would be released. The GABA triggers reactivations. Also of note is that the oxidative stressors would affect the whole metabolism while the GABA affects the brain predominantly.
How can this translate into solutions? Besides the HDACi antiviral protocol that it is still work in progress and a topic for another time, GABA agonists and positive allosteric modulators could replace the role of GABA. These agonists would need to lack the property that makes GABA an HDAC inhibitor, namely its zinc ionophority and the small size that allows it to fit into the zinc finger binding sites of HDACs. Unfortunately, Taurine seems to be an HDAC inhibitor as well (with mild or moderate effect). At least, this is likely based on the docking simulations. So I'm still looking for more candidates that meet the criteria.
A matching GABA agonist/modulator could be taken in the evening to alleviate sympathetic overactivation without downregulating HDACs, thereby avoiding additional reactivation triggering but alleviating the metabolic consequences that indirectly lead to viral reactivations. At least one side of the GABA trap could be functionally handled this way. It would not remove the viral reservoirs immediately but it might provide a baseline for the immune system to get hold of the virus in the brain, which mediates the other side of the trap.
This theory doesn't exclude alternative theories that can create similar trap situations. For example, viral miRNA and viral proteins could also create reactivation cycles. They can also affect the sympathetic overactivation and indirectly maintain a GABA/HDAC trap. This would be an alternative explanation to the cellular adaptation, though the GABA agonist/modulator therapy would still be applicable. I think GABAergic activation without HDAC inhibition is as important as Melatonin for getting refreshing rest and not exhausting half-sleep, as it is often the case.
- BBB: Permeable Conjugate of Exogenic GABA (2017) [10.1021/acsomega.7b00425]
- Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease (1988) [10.1093/brain/111.4.785]
- As a Histone Deacetylase Inhibitor, γ -Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study (2019) [10.1002/mnfr.201900001]
- Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics (2015) [10.3389/fphar.2015.00260]
- Review: Fetal antigens – Identity, origins, and influences on the maternal immune system (2011) [10.1016/j.placenta.2010.12.014]
- Exposure to non-inherited maternal antigens by breastfeeding affects antibody responsiveness (2019) [10.3324/haematol.2018.199406]
- Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response (2015) [10.1093/molbev/msv051]
- Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes (2016) [10.1016/j.ajhg.2015.11.014]
- Pathogen-Driven Selection in the Human Genome (2013) [10.1155/2013/204240]
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