Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS - 2020 - Schreiner

[butter.]

If there is something in serum that causes me, why is plasma exchange not working?

 

[Jonathan Edwards]

(2) Why would it last forever? The immune system usually eliminates the foreign object, and if something viral around the cell is initiating its cell danger response, u wud expect the immune system to eventually clear it? Naviaux says in the paper above that "The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem.". Is this the scientific consensus? And if so, how does that fit with ur signalling theory @Jonathan Edwards ?

Yes why would it last forever. There might be a reason b ut is is all very obscure.
I think the idea about a purinergic cell danger response is very much a Naviaux idea. Purinergic signalling sounds like an interesting pathway that might explain why nobody has pinned down the central problem in ME but I have yet to see any real evidence to hang it on.

 

[Marky]

If there is something in serum that causes me, why is plasma exchange not working?

I think u have to know what to filter, if ur referring to the plasmapheresis-study by Scheibenbogen et.al

 

[Jonathan Edwards]

It is possible that I am missing something in this paper but a don't have the energy to go through it all. If someone can explain to me how the findings support the conclusions - the way Simon M does for HLA things - I am happy to read.

 

[Mij]

My baseline in 2001 was up at 80-90% after 'recovering' from PVFS, but HHV6 and EBV were both reactivated from taking Immunovir that triggered a terrible relapse and reduced my baseline (energy level/stamina) down to 40%.

I've never returned to my baseline (energy wise) since then.

 

[spinoza577]

The abstract looks a bit like the Meas papers, almost full of wishful thinking.

Nevertheless I would be interested especially in this:

Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited.

dUTPase would be a common with Ebstein-Barr virus, whatever this further might say.

Then SOD2 = MnSOD, why is it inhibited? I personally have progredient effects from a low manganese diet, so maybe an inhibited SOD2 indicates high intracellular Mn. This may be conceivable, as EBV has been shown to block the Vitamin D receptors, which is necessary for an Mn exporter (ZnT10). And then I remember that Mn would induce enlarged but separated mitochondria (sadly I cannot remember where I have read it).

So, very interesting, I think.

 

[ME/CFS Skeptic]

Don't know enough about biology to determine if this hypothesis makes sense or not, but here are my attempts to understand what's in the paper.

It seems like Prusy's team was doing research into HHV-6. Their experiments suggested that HHV-6 reactivation not only induces changes in the immune function but also some changes in mitochondrial function.

Old (but unconfirmed) ME/CFS research suggested a connection with HHV-6 (the person who co-discovered HHV-6, Dharam Ablashi, also became co-founder of what is now the IACFS/ME) and some of the key HHV-6 abnormalities found in mitochondrial metabolism such as pyruvate dehydrogenase were also mentioned in ME/CFS research. I think that sparked the interest of the group to look at ME/CFS and how HHV-6 might be relevant there. They write: "our in vitro HHV-6A reactivation studies pointed toward potential similarities between viral reactivation and ME/CFS pathophysiology."

So they looked at HHV-6 in the blood, isolated cells, serum, and hair follicles of 25 ME/CFS patients and 10 controls. Unfortunately, they couldn't find much. The paper writes that "low copies of virus DNA and RNA in blood of ME/CFS patients created a confusing scenario."

But there was one other option the researchers were thinking of. Their experiments suggested that fluid from HHV-6A–reactivated cells cause similar changes in the mitochondrial architecture of nearby non-infected cells. That suggested a transferrable factor coming from HHV-6A– reactivated cells that can induce those abnormalities in other cells.

They thought that maybe something like this was happening in ME/CFS. Maybe some difficult to trace part of the body is infected and sending this factor to the rest of the body. The authors write:

"A plausible explanation can be localized viral infection/activation in distant parts of the body, thereby releasing a few infected cells carrying activated virus or releasing some of the activation-mediated cellular factors into the blood stream." ​

That's when they started to test whether serum from ME/CFS patients also causes the changes induced by HHV-6A– reactivated cells. And this seemed to be the case. The paper reports:

"we showed that serum from ME/ CFS patients contained an activity that produced mitochondrial fragmentation, decreased mitochondrial ATP production, and induced a powerful antiviral state." ​

Those were the results Prusty mentioned at the NIH conference. Unfortunately, this paper provides little data to support this. It mostly seems to describe their way of thinking and some preliminary experiments. I suspect that's why Jonathan wasn't very excited. What we would like to see is a proper test of whether ME/CFS serum really induces those abnormalities.

I see this as a hypothesis paper - hopefully a proper test with more data will follow.

 

[Hutan]

Thanks Michiel.

What we would like to see is a proper test of whether ME/CFS serum really induces those abnormalities.

Exactly. The results the ME/CFS serum on mitochondrial fragmentation suggest replication is warranted I think - rapid and robust replication.

If mitochondrial fragmentation is really caused by exposure to ME/CFS serum, then hypotheses about that become more interesting to think about. It's a shame the ME/CFS serum experiment wasn't presented on its own, without all of the HHV6 hypothesising to muddle things.

 

[Penelope McMillan]

I agree with those who describe the paper as incoherent and appearing to have been written to support a pre-existing theory.
(Maybe I just agree that it was not clearly written because I found it hard to follow, but I do suspect that my failure to follow the line of argument wasn't entirely due to my own weaknesses.)

However, on the plus side, it feels intuitively right to me when dodgy mitochondria and ATP production are directly linked to the fact that I rarely get sick with a cold or flu. When people around me have a cold/flu, I can feel myself being drained by fighting the virus off for a day or two, before not getting sick.

For me, it is always intriguing to find a study that fits with my lived experience of ME. So I would definitely be interested in further research exploring the mitochondria-antiviral angle for those of us who fit into the "never get a cold or flu" subgroup.
Long stretch from that to relevant therapies, of course.

 

[Hutan]

There's a pdf: MDPI Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A review and update, 2019, Zorov et al.
It looks to give some nice background and suggests that lots of teams have been looking at, and quantifying, mitochondrial fragmentation in a range of diseases and circumstances. So there is plenty of expertise out there on the subject.

I was interested to see something that suggests that incorporation of a green fluorescent dye can itself cause fragmentation when the cells are repeatedly exposed to light. I wonder if that might be a cause of bias that would have to be guarded against.

 

[butter.]

I think u have to know what to filter, if ur referring to the plasmapheresis-study by Scheibenbogen et.al

maybe I am mistaken here, but plex takes out most of your plasma in the body if you are doing a full cycle of treatments,...

 

[butter.]

There's a pdf: MDPI Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A review and update, 2019, Zorov et al.
It looks to give some nice background and suggests that lots of teams have been looking at, and quantifying, mitochondrial fragmentation in a range of diseases and circumstances. So there is plenty of expertise out there on the subject.

I was interested to see something that suggests that incorporation of a green fluorescent dye can itself cause fragmentation when the cells are repeatedly exposed to light. I wonder if that might be a cause of bias that would have to be guarded against.

but there were controls, no?

 

[Jonathan Edwards]

Their experiments suggested that fluid from HHV-6A–reactivated cells cause similar changes in the mitochondrial architecture of nearby non-infected cells. That suggested a transferrable factor coming from HHV-6A– reactivated cells that can induce those abnormalities in other cells.

I think that is a fair summary of what the experiments were about @Michiel Tack.
But this looks like some sort of interferon-type response, which is about the most non-specific defensive cellular response around. My objection is to then conclude that a similar non-specific response in ME has anything to do with HHV-6, when all other evidence is against that.

I see this as a hypothesis paper - hopefully a proper test with more data will follow.

Except that it isn't. It purports to be an experimental paper drawing a conclusion from data.

It's a shame the ME/CFS serum experiment wasn't presented on its own, without all of the HHV6 hypothesising to muddle things.

Exactly, but done properly, with an adequate number of controls.

 

[Andy]

Exactly, but done properly, with an adequate number of controls.

To my mind it would have been good to include patients with other fatiguing conditions as well, to see whether similar things are seen with them.

 

[Hutan]

but there were controls, no?

Yes, there were. And I'm not saying that the ME/CFS samples were more exposed to light (and therefore had more mitochondrial fragmentation due to the fluorescent marker) in this case.

Just that it wasn't something that I had thought of as a source of bias. You'd want the protocol to address it.

 

[Forbin]

FWIW...

I've mentioned this before but, maybe a month into ME/CFS, I woke up with a rash of scattered, flat, pinkish spots on my neck, torso, abdomen and arms. The spots averaged about the diameter of a pencil's eraser and the rash only lasted a day or two, but I'd never had any other kind of rash like that as an adult.

Decades later, the closest visual match I could find for the rash on the Internet was linked to a viral illness that very young children get called roseola (aka "sixth disease"), which is caused by HHV-6 (and less frequently by HHV-7).

Since it was so transient and unaccompanied by fever (though I was having night sweats), I kind of wonder if this was an old, early childhood HHV-6 infection briefly re-emerging in the wake of ME onset. The virus can re-emerge in adults who become immunocompromised, but I never saw the rash again.

Even if it was HHV-6, there's no way to tell if it was a factor in my developing ME/CFS, or if it was just some strange, brief consequence of onset (if it was even that). It does make me wonder, though...

 

[InitialConditions]

I see this as a hypothesis paper - hopefully a proper test with more data will follow.

Yes - this is what I thought, and perhaps what the paper should have been.

 

[jaded]

@Forbin the patchy red rash all over my torso also happened to me twice. Once during my first ME onset aged 11 into mild ME then again preceding the decline of my ME to severe levels aged 28. The paediatricians at the time when I was young said it was roseola. I’ve got no idea how this links to my ME.

 

[cassava7]

But this looks like some sort of interferon-type response, which is about the most non-specific defensive cellular response around. My objection is to then conclude that a similar non-specific response in ME has anything to do with HHV-6, when all other evidence is against that.

They address the interferon-type response in the last paragraph. Hopefully that is enough to rule it out.

Ruling out TNF-α and IFN response
One of the most prominent candidate molecules that can provide strong antiviral defense is IFN. Hence, we tested IFN response in A549 cells upon treatment with ME/CFS or HC serum. We observed a strong decrease in mRNA levels of IFN-β, IFIT-1, and ICAM-1 within the A549 cells in presence of ME/CFS serum in comparison with HC serum (Fig. 5D–F). Then we asked whether the secretory IFN response in isolated PBMCs is higher in ME/CFS patients. For this we used a different cohort of 22 CFS patients and 22 HC. Upon challenge with LPS, we found lower levels of secreted TNF-α (p < 0.01) and IFN-γ (p < 0.05) from CFS patient PBMCs compared with HC (Supplemental Fig. 2B). No significant differences were seen for IL-1 and IL-5. These results ruled out a potential role of IFN response in the mitochondrial fragmentation and antiviral response in ME/CFS patients.

 

[cassava7]

What we would like to see is a proper test of whether ME/CFS serum really induces those abnormalities.

Seems to be underway. I believe the recently completed fundraiser for Prusty is meant to help him with developing and assessing that test, as it kicked off in February while the paper was submitted in late January. It will be a while until this test is finalized, reviewed and published though, if it is even viable enough to reach those stages.