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

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

 

https://twitter.com/user/status/1253465375217520647

 

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:

 

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.

 

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!

 

Is Prusty agreeing with you on the "antiviral phenotype"?
https://twitter.com/user/status/1253581959323889664

 

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.

 

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.

 

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.

 

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.

 

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)?

 

It was not in relation to the study!

https://twitter.com/user/status/1253606746171588608

 

Hi Grigor. I don't understand your response to my question. Are you saying the test is not used in this piece of research?

 

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.

 

Ok, understood now. No - I saw a different tweet. Someone asked what mito testing was used and someone replied Myhill/McClaren.

 

See the picture attached to my first post.

 

Sorry - my mistake. I've got you now.

 

Something in the serum?