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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS - 2020 - Schreiner
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Jonathan Edwards
Senior Member (Voting Rights)
I don't think it in any way rules it out. The experiments are tangential and difficult to interpret.
wigglethemouse
Senior Member (Voting Rights)
There is more data on the interferon-type response here in the supplemental section.
https://www.immunohorizons.org/cont...ental/IH_2000006_Supplemental_Materials_1.pdf
https://www.immunohorizons.org/cont...ental/IH_2000006_Supplemental_Materials_1.pdf
wigglethemouse
Senior Member (Voting Rights)
And this seems pretty clear to me and my untrained eye. Take cells, put them in CFS or HEALTHY serum, add HSV-1, observe clear difference (- is control sample, + is experimental sample). CFS treated samples clearly have lower HSV-1 RNA compared to HEALTHY, showing the antiviral effect.
rvallee
Senior Member (Voting Rights)
I think there is far more to this than the one paper here. It seems to point to the central mechanism of mitochondrial defense against pathogens. We know that some viruses attack mitochondria and that they must have evolved defenses against such attacks because the viruses don't always win.
So one of the defense mechanisms, at least against HHV-6 and HHV-7, is what we are seeing in action. The 99% reduction in both HHV-6 and Influenza infection rates is, I think, the clincher. And this defense comes at a distinct cost, which makes sense, and possibly explains the fundamental process of what fatigue is, the medical definition of fatigue, not the mix-and-match-of-various-things-to-fit-a-conclusion.
If I understand it correctly (and I probably don't), mitochondrial fission would be one part of that mechanism. It lowers the virus' ability to infect them and that process involves messenger molecules that have localized effects, both intracellular and intraorganelle as it's explained in the paper, but likely some of those do make it into the bloodstream to activate the immune system into springing into action in case localized defense fails. Which could explain the delayed response of PEM, depending on how taxed the mitochondria are and how difficult it is for them to fight off the infection, with time more make it into the bloodstream leading to a general increase in symptoms as mitochondria elsewhere adopt their own shelter-in-place-with-physical-distancing equivalent.
One interesting thing is how 8/20 patients had partial viral activation. I would be very curious to know if that test were done at different times if the same people would show the same, or if we would see variation. Would the same test at other times have the same 8/20 or would we see seemingly random fluctuations that correlate with current symptomatology. This could explain the fluctuating nature of the illness, with viral activation periodically trying to mount an attack, repelled by mitochondrial defenses. Locality of each new attack could explain what symptoms arise as a consequence, especially in the immune system, with the virus randomly building back up and attacking at various places in the body. It could also potentially explain digestive issues for viruses in the GI tract, as this place is basically under constant warfare by various germ populations, possibly creating regular opportunities for the viruses to try a few sucker punches and see if they land.
This could also explain PEM, in that any demand on the system essentially requires mitochondria to get into gear to produce more energy, only to make themselves more vulnerable to the viruses, which sense this mitochondrial activation and use it as a signal to try a sneak attack and depending on where they are in the replication cycle, basically building up local resources over and over again, not always in a position to be opportunistic.
In that light I see the CDR as a partial explanation that more of less is this mitochondrial defense system. There are probably many pathogens that try to hijack or attack the mitochondria and the consequences of defending against each would explain the difference in illness presentation. They are so juicy sitting right there producing energy, what more could a pathogen want?
But the mitochondria fight back, at the expense of the host's ability to function, but all in order to keep us alive longer. It only buys time, though, which would explain how rest is critical, as any demand on the energy system effectively acts to reset the fight like people not respecting social distancing.
So one of the defense mechanisms, at least against HHV-6 and HHV-7, is what we are seeing in action. The 99% reduction in both HHV-6 and Influenza infection rates is, I think, the clincher. And this defense comes at a distinct cost, which makes sense, and possibly explains the fundamental process of what fatigue is, the medical definition of fatigue, not the mix-and-match-of-various-things-to-fit-a-conclusion.
If I understand it correctly (and I probably don't), mitochondrial fission would be one part of that mechanism. It lowers the virus' ability to infect them and that process involves messenger molecules that have localized effects, both intracellular and intraorganelle as it's explained in the paper, but likely some of those do make it into the bloodstream to activate the immune system into springing into action in case localized defense fails. Which could explain the delayed response of PEM, depending on how taxed the mitochondria are and how difficult it is for them to fight off the infection, with time more make it into the bloodstream leading to a general increase in symptoms as mitochondria elsewhere adopt their own shelter-in-place-with-physical-distancing equivalent.
One interesting thing is how 8/20 patients had partial viral activation. I would be very curious to know if that test were done at different times if the same people would show the same, or if we would see variation. Would the same test at other times have the same 8/20 or would we see seemingly random fluctuations that correlate with current symptomatology. This could explain the fluctuating nature of the illness, with viral activation periodically trying to mount an attack, repelled by mitochondrial defenses. Locality of each new attack could explain what symptoms arise as a consequence, especially in the immune system, with the virus randomly building back up and attacking at various places in the body. It could also potentially explain digestive issues for viruses in the GI tract, as this place is basically under constant warfare by various germ populations, possibly creating regular opportunities for the viruses to try a few sucker punches and see if they land.
This could also explain PEM, in that any demand on the system essentially requires mitochondria to get into gear to produce more energy, only to make themselves more vulnerable to the viruses, which sense this mitochondrial activation and use it as a signal to try a sneak attack and depending on where they are in the replication cycle, basically building up local resources over and over again, not always in a position to be opportunistic.
In that light I see the CDR as a partial explanation that more of less is this mitochondrial defense system. There are probably many pathogens that try to hijack or attack the mitochondria and the consequences of defending against each would explain the difference in illness presentation. They are so juicy sitting right there producing energy, what more could a pathogen want?
But the mitochondria fight back, at the expense of the host's ability to function, but all in order to keep us alive longer. It only buys time, though, which would explain how rest is critical, as any demand on the energy system effectively acts to reset the fight like people not respecting social distancing.
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Hoopoe
Senior Member (Voting Rights)
Referring to the image above, most ME/CFS papers don't report such clear differences. That is encouraging.
However it could be that the resistance to viruses is not specific to ME/CFS or indicative of viruses being the problem. It could be part of an unspecific response to illness.
However it could be that the resistance to viruses is not specific to ME/CFS or indicative of viruses being the problem. It could be part of an unspecific response to illness.
wigglethemouse
Senior Member (Voting Rights)
Yep. The answer to that doesn't really matter at this stage. The question is, can you identify the factor(s) in ME/CFS serum that cause it, could those factors lead to the next clue, and could those factor(s) be unique to ME/CFS. This work leads to more questions and that is what is truly exciting. Will it lead to the next clue?
Bhupesh Prusty has said on twitter to have a reasonable numerically powered study he needs Eur 400K for 3 years to fund the work and Phd's.
So in the meantime the sample sizes are small, experiments limited, can't be choosy on choice of publisher, peers and other scientists may poo poo the work as it goes against conventional wisdom, but the money is spent wisely to follow up on interesting leads. With limited funding you can follow up on a small number of patients to see if you can find those clues that can make future more expensive studies better focused.
And I am grateful he has published so that he can share what he has found. Spark more ideas and conversations. It's promising that Robert Naviaux has joined in a collaborative way. He is an experienced and respected mitochondrial scientist who's lab solved the molecular basis of Alpers Syndrome so he has some disease solving success. Here's hoping together they can submit to NIH to fund continuation of this work.
Hoopoe
Senior Member (Voting Rights)
Shows how broken research is I think, but maybe I'm just underestimating the amount of work this takes. How hard is it to repeat the most important experiment in this study say 40 times or whatever passes as reasonably well powered?
With the coronavirus, they can get studies done in a few weeks.
wigglethemouse
Senior Member (Voting Rights)
For anyone wanting to learn more, Dr Bhupesh Prusty covered a lot of whats in the paper at the recent CMRC 2020 conference. He talks rather fast, but it does help understanding of the paper.
Ravn
Senior Member (Voting Rights)
Phew! That was one epic read.
Maybe Prusty could only get this published as a single paper but it would have made more sense to split it into at least two, and probably more, separate papers. That would also have made it easier to write more informative abstracts. It would definitely have made it easier to follow.
One possible division could have been this:
One paper on HHV6 reactivation, including incomplete reactivation in just a few cells, and how that can cause mitochondria in other, uninfected cells to fragment.
One paper on ME serum, but not HC serum, causing mitochondria to fragment.
One paper on ME serum, but not HC serum, reducing in-vitro cell infection by influenza and HSV1 (except for the 1 case out of 10 where the patient serum increased influenza infection - weird).
And a separate hypothesis paper about the proposed link between HHV6 and ME.
I find the individual experimental parts of the paper intriguing enough to want to see them replicated. Preferably with larger numbers and also some disease controls. Preferably asap so we know if they're worth spending time and energy on or if it would be better to move on. Which is probably wishful thinking since we're talking ME research here...
I don't really understand the proposed link between HHV6 and ME, apart from there being some similarities in how mitochondria behave after exposure to ME serum and supernatant from HHV6-infected cells. I suspect there's more to it than that but I can't untangle it from this paper.
Maybe Prusty could only get this published as a single paper but it would have made more sense to split it into at least two, and probably more, separate papers. That would also have made it easier to write more informative abstracts. It would definitely have made it easier to follow.
One possible division could have been this:
One paper on HHV6 reactivation, including incomplete reactivation in just a few cells, and how that can cause mitochondria in other, uninfected cells to fragment.
One paper on ME serum, but not HC serum, causing mitochondria to fragment.
One paper on ME serum, but not HC serum, reducing in-vitro cell infection by influenza and HSV1 (except for the 1 case out of 10 where the patient serum increased influenza infection - weird).
And a separate hypothesis paper about the proposed link between HHV6 and ME.
I find the individual experimental parts of the paper intriguing enough to want to see them replicated. Preferably with larger numbers and also some disease controls. Preferably asap so we know if they're worth spending time and energy on or if it would be better to move on. Which is probably wishful thinking since we're talking ME research here...
I don't really understand the proposed link between HHV6 and ME, apart from there being some similarities in how mitochondria behave after exposure to ME serum and supernatant from HHV6-infected cells. I suspect there's more to it than that but I can't untangle it from this paper.
cassava7
Senior Member (Voting Rights)
I understand the link/their hypothesis as: "Secretions from cells infected with HHV-6A and ME/CFS serum have the same effect(s) in our experiments, so they share the compounds that cause these effects". Per the abstract (spacing mine):
I couldn't find where they start justifying this link between HHV-6 and ME/CFS. For other readers, it starts at the beginning of the discussion (bolding mine):
The rest of the discussion says "we found this data in our HHV-6 reactivation experiments, here are papers showing that this happens in ME/CFS too". I haven't looked at these citations, but I'm afraid the data haven't been replicated. So their hypothesis is not backed up by experimental data yet. To prove it, they would need to isolate and identify the compound(s) both in ME/CFS serum and in the supernatant. Only then can they know if they're the same compounds.
I don't understand figure 6 clearly:
So they didn't transfer the supernatant and ME/CFS serum to the HSV-1 or H1N1 infected cells at the same time? Instead, they did a first experiment where they transferred the supernatant of iHHV-6 cells, and in a second experiment (with a new batch of HSV-1/H1N1 infected cells) they transferred ME/CFS serum? The red arrows confuse me.
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I think Bupesh is looking for something which is a biomarker for mitochondrial fragmentation (anyone know if he's found it?) ---- measuring mitochondrial length is expensive (specialist equipment).
Ron Davis has been looking for something in the blood -- finding that might move things on --- Bupesh is basically looking for something similar/the same component?
Might not be filtering out the same thing --- or the signal is constantly produced.
Yes I'm in favour of funding research. However, as @strategist has said could the key elements be extracted and worked up rapidly --- how common is mitochondrial fragmentation in ME (measure mitochondria in a bunch of samples) -- if there are identified biomarkers for mitochondrial fragmentation then validate these and test how common mitochondrial fragmentation is in ME
@Jonathan Edwards @wigglethemouse any parts of this which could be scaled up i.e. rather than doing a 4 year (1.2 million euro?) project
makes no sense at all ...
wigglethemouse
Senior Member (Voting Rights)
I believe this section is where a link between HHV6 and a subset of ME patients comes from - presence of sncRNA-U14
From methods section
Sure would be nice if someone could replicate the FISH analysis, say from the UK ME biobank samples. No idea what FISH entails, or if it requires fresh blood.
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wigglethemouse
Senior Member (Voting Rights)
That diagram is a bit confusing. It is so easy to miss the "or" which shows they are separate experiments.