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

Kalliope

Kalliope

Senior Member (Voting Rights)
by Philipp Schreiner, Thomas Harrer, Carmen Scheibenbogen, Stephanie Lamer, Andreas Schlosser, Robert K. Naviaux and Bhupesh K. Prusty

Published in ImmunoHorizons

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing.

To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis.

Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. 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.

Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.



https://www.immunohorizons.org/content/4/4/201
 
In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism. [my bolding]
Click to expand...

I wonder if this lends credence to the reports of some patients who have reported resistance or "immunity" to the flu after the onset of ME/CSF.

ETA:
However, using an in vitro reporter cell assay, 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.
Click to expand...
 
Last edited:
I am afraid that I think this paper is meaningless. the literature review is completely unbalanced and scattershot. It is unclear to me how any of the experiments lead to the conclusion reached. It is a pity yet again to see such poorly crafted research in the ME field.
 
Jonathan Edwards said:
I am afraid that I think this paper is meaningless. the literature review is completely unbalanced and scattershot. It is unclear to me how any of the experiments lead to the conclusion reached. It is a pity yet again to see such poorly crafted research in the ME field.
Click to expand...

Could you expand a bit on what makes you say that? Less for me personally (any explanation will go over my head anyway) but more to make your stance easily communicable to people who will inevitably say 'well Prof Harrer says one thing, Prof Edwards says another, I will go with the guy actively doing research right now'.

This paper has the names of the primary group of people trying to give ME legitimacy in Germany on it so it could be really useful to have a more detailed explanation I can simply point to. If those people get basics wrong that could obviously have negative implications for advocacy/research funding and so on and we're already not in a good situation. I imagine this would be one of the papers a journalist who is trying to talk about recent ME research would quote without hesitation!
 
Putting the HHV-6 issue aside for a moment,
There's the application of serum from ME/CFS patients and from healthy controls to cells - with measurements of mitochondrial surface area. If this is true, this is surely a useful clue?

We thus asked if serum from ME/CFS patients can alter mitochondrial morphology in healthy cells in a similar way, as observed with HHV-6 infection. We thus grew U2-OS cells having soluble mitoGFP but no HHV-6 in the presence of serum from ME/CFS patients as well as control cases (Fig. 4A).
Click to expand...

Screen Shot 2020-04-24 at 10.08.03 PM.png
(soluble mito GFP is the marker for mitochondria, GFP = Green fluorescent protein)

Mitochondrial dynamics was analyzed using SIM (Fig. 4B) as well as confocal imaging. Our results showed increased mitochondrial fragmentation as quantified by average mitochondrial surface area in healthy cultured cells upon incubation with serum from ME/CFS patients but not with healthy donor serum (Fig. 4C).
Click to expand...



Screen Shot 2020-04-24 at 10.12.30 PM.png

Screen Shot 2020-04-24 at 10.01.51 PM.png

There does look to be a difference between the average surface area of mitochondria in the cells with healthy control serum vs those with CFS serum. Mitochondria in cells with CFS serum tend to be smaller. Yes, the sample size is small, especially of the controls and there is quite a bit of variability.

It looks like a finding that is worth doing more work on though. ?


I haven't really read the rest of the paper yet.
 
Jonathan Edwards said:
I am afraid that I think this paper is meaningless. the literature review is completely unbalanced and scattershot. It is unclear to me how any of the experiments lead to the conclusion reached. It is a pity yet again to see such poorly crafted research in the ME field.
Click to expand...

Prusty appears to have confirmed the "transmissable factor" in ME blood - no small addition to ME research. If abnormal mitochondrial fragmentation is indeed the basic pathological mechanism in the illness - even if it's not caused by the specific lncRNA Prusty has worked on - then he would still have potentially cracked the illness. As ever....needs replication. I find the concept of abnormal mitochondrial fission a very attractive one to explain ME. Worthless without data, of course. But a welcome new hypothesis.
 
Last edited by a moderator:
Philipp said:
Could you expand a bit on what makes you say that?
Click to expand...

That is hard to do because it is a bit like explaining to an someone with no knowledge of engines why the parts in a new lawnmower delivered cannot possibly fit together - as if there was a petrol tank but no cylinder and instead an electric flex and brushes.

The first problem is that the paper tarts off stating that there is growing evidence for HHV6 reactivation being involved in ME. However, there is a strong body of evidence that this is not the case. Nobody has found more HHV6 in ME in a properly done study as far as I know. The paper then does a lot of very technical things to cells in culture and shows things relating to viral infect ability and mitochondria. A few ME sera happen to produce a change in mitochondria similar to one of the changes seen in the cultured cells under other conditions. But there is no coherent story of how this is relevant.

If ME symptoms were due to a major defect in mitochondrial function then the metabolic shifts occurring would have been measured long ago either with MR spectroscopy or on exercise testing (e.g. muscle contraction on electrical stimulation or CPET). So far nothing consistent has been found.

As far as I can see this is a group with an interest in HHV6 who have seen ME as a field that might produce grant funding to continue work on HHV6 without any cogent story as to why HHV6 should have any relevance to ME.

I am afraid I could go on for pages but basically I learnt to discount papers where the abstract shows no logical relation between results and conclusion - and includes no data. I was in biomedical science for thirty years and in the early days an abstract had to be easily intelligible and contain hard facts. Sadly in recent years anything seems to be publishable. But good science stays the same - an intelligible abstract with hard data.

This is not the way to give ME legitimacy. It is the way to make people even more sceptical than they are now.
 
Hutan said:
It looks like a finding that is worth doing more work on though. ?
Click to expand...

I am sorry to say that any data presented as in this paper for me is not worth trying to replicate. The appropriate response from the scientific community is to tell the authors to go away and write a paper that makes sense and to replicate it themselves with an adequate number of blinded samples from an external source.
 
Jonathan Edwards said:
That is hard to do because it is a bit like explaining to an someone with no knowledge of engines why the parts in a new lawnmower delivered cannot possibly fit together - as if there was a petrol tank but no cylinder and instead an electric flex and brushes.

The first problem is that the paper tarts off stating that there is growing evidence for HHV6 reactivation being involved in ME. However, there is a strong body of evidence that this is not the case. Nobody has found more HHV6 in ME in a properly done study as far as I know. The paper then does a lot of very technical things to cells in culture and shows things relating to viral infect ability and mitochondria. A few ME sera happen to produce a change in mitochondria similar to one of the changes seen in the cultured cells under other conditions. But there is no coherent story of how this is relevant.

If ME symptoms were due to a major defect in mitochondrial function then the metabolic shifts occurring would have been measured long ago either with MR spectroscopy or on exercise testing (e.g. muscle contraction on electrical stimulation or CPET). So far nothing consistent has been found.

As far as I can see this is a group with an interest in HHV6 who have seen ME as a field that might produce grant funding to continue work on HHV6 without any cogent story as to why HHV6 should have any relevance to ME.

I am afraid I could go on for pages but basically I learnt to discount papers where the abstract shows no logical relation between results and conclusion - and includes no data. I was in biomedical science for thirty years and in the early days an abstract had to be easily intelligible and contain hard facts. Sadly in recent years anything seems to be publishable. But good science stays the same - an intelligible abstract with hard data.

This is not the way to give ME legitimacy. It is the way to make people even more sceptical than they are now.
Click to expand...

I am a skeptic by nature and having worked in academia I feel the quality of science being published is slowly being reduced by ever increasing funding and publication pressures. I have no biomedical or clinical science background but I am sort of shocked by some of the stuff that gets published in this field. It's good to read your thoughts. It would be great if some of the authors could respond to these points.
 
Last edited:
Yikes

I was withholding any excitement for this study until Jonathan reviewed it, seems like it was an good idea..

If we look away from herpesvirus for a second

They state that ME is due to a "multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism."

On the surface id say that looks like an intuitive explanation when we consider that viral infections are the main trigger for ME

But i have some questions

(1) What happens under a cell danger response and have we found any of its metabolic features in ME? In another paper, Naviaux, one of the authors here, writes that "The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling." (https://www.ncbi.nlm.nih.gov/pubmed/23981537). Has any of this been found to be elevated in research on ME?

(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 ?

Ps: I havent gotten through the whole paper yet
 
I have not read the paper, or even looked at it. Have they really used the Myhill/McLaren mitochondria tests (as I just read on twitter)?
 
InitialConditions said:
Hi Grigor. I don't understand your response to my question. Are you saying the test is not used in this piece of research?
Click to expand...
I have not read the study so I can't comment if they didn't use it. But if this is the tweet you were referring to then that tweet is not about the study itself.
 
Grigor said:
I have not read the study so I can't comment if they didn't use it. But if this is the tweet you were referring to then that tweet is not about the study itself.
Click to expand...

Ok, understood now. No - I saw a different tweet. Someone asked what mito testing was used and someone replied Myhill/McClaren.
 
Hutan said:
Putting the HHV-6 issue aside for a moment,
There's the application of serum from ME/CFS patients and from healthy controls to cells - with measurements of mitochondrial surface area. If this is true, this is surely a useful clue?



View attachment 10731
(soluble mito GFP is the marker for mitochondria, GFP = Green fluorescent protein)





View attachment 10733

View attachment 10730

There does look to be a difference between the average surface area of mitochondria in the cells with healthy control serum vs those with CFS serum. Mitochondria in cells with CFS serum tend to be smaller. Yes, the sample size is small, especially of the controls and there is quite a bit of variability.

It looks like a finding that is worth doing more work on though. ?


I haven't really read the rest of the paper yet.
Click to expand...
Something in the serum?
 
You must log in or register to reply here.
Back
Top Bottom