Tissue specific signature of HHV-6 infection in ME/CFS, 2022, Prusty et al

Moved from Research News from Prusty

https://www.frontiersin.org/articles/10.3389/fmolb.2022.1044964/abstract

https://twitter.com/user/status/1599736019166691328



First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival.

We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome.

Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls.

Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

 

Great to see an autopsy study done, and that it seems to have clear evidence of HHV-6 involvement in brain and spinal cord.

 

Yes, this seems like it could be an important finding?

 

I have evidence of HHV7 in the blood but not in the CSF, interestingly. But there are no drugs that can effectively eliminate these viruses. So i guess there's nothing to do but wait.

 

OK this may start to get interesting about one particular feature of peptic ulcers: they are caused by the H. Pylori bacteria, but nearly everyone carries those bacteria in our stomachs, they only seem to cause ulcers when they manage to breach the lining, the factors for this being unknown.

There is growing evidence of damage to the myelin sheet in Long Covid, and I am starting to warm up to a model similar where diseases like MS, Parkinson's and Alzheimer's is where the tug-of-war between the immune system is lost, whereas chronic illness is what happens when there is a stalemate that causes continuing illness, just not the level of irreparable damage that is needed for medicine to actually see it.

There have to be factors that allow for the presence of the same pathogens causing illness in some, disease in others, and nothing in most. Factors that combine the presence of certain pathogens with other immune factors, some local, some not.

I'm just not sure medicine is up for this challenge. It's a lot of moving parts and involves complex thinking, in an area polluted by decades of obsessively defaulting to simple-but-wrong answers. The only reason it was accepted for peptic ulcers is because there was a very effective treatment that basically settled all the usual arguments, but general lessons have absolutely not been learned from this.

This may explain why in some a minor illness, barely a cold, can trigger this, it's about opening some doors, a question of timing and complex factors aligning, in a similar sense as so many factors have to align for someone to get hit head-on with a car, vs. missing by a few centimeters, or slipping on a tiny patch of dark ice.

This is a probabilistic model without known initial conditions and where prediction on individual cases is mostly impossible. It's as radical a paradigm shift as going from classical mechanics to quantum field theory, which so far medicine has been unable to even attempt.

Pathogens evolved to survive. It makes perfect evolutionary sense that they would be good at hiding and evading defenses, picking the right opportunities. The idea that they should be perfectly harmless isn't just ridiculous in itself, it's a known feature of many pathogens.

Medicine will really have to let go of the weird obsession with making every pathogen a unique snowflake with fully unique features, mechanism and signs and symptoms. There is a huge number of shared characteristics, this is part of the reason the immune system works at all.

 

The problem with this kind of hypothesis is that ME actually makes you a lot more disabled than illnesses where we see the infection winning. So how come that in the event of a stalemate, without obvious tissue damage, without the pathogen even being detectable in the blood, you end up with much worse symptoms compared to an actual infection? Why don't we ever see people with chronic infections or MS bedridden like certain severe ME patients? Those patients actually die before even reaching such level of disability.

 

Well, there are plenty of diseases where the patient is severely disabled to the point of being bedridden with often no trace of the pathogen in blood or serum or CSF. I can think of at least four from the tick-borne disease category that qualify.

Moreover there is evidence in some circles of a domino effect, e.g., get Lyme and a byproduct is bringing latent infections like HHV back to life in privileged sites.

 

That's true, but it seems unique to certain pathogens and those patients have other signs of pathology. If you are suspected of having Lyme disease they don't even do PCR because they know it will probably be negative, they do antibody testing and look for clinical signs. But the same cannot be said for most pathogens. HHV6-7 can easily be found in the blood by PCR as far as i know.

If it turns out that any (or let's say a large number of) pathogens can form a special kind of chronic tissue infection where they are undetectable in the blood (so undetectable in fact that you don't see a statistical difference even among hundreds of patients) where you would normally be able to find them, without obvious tissue damage/pathology, and this is in fact ME - that's going to be very hard to prove without a large number of autopsies.

 

Case studies with autopsies are not unknown, but yep, autopsies need to become a priority since the brain seems to be a logical hide and seek repository of pick-your-pathogen.

 

If the nervous system is infected at multiple locations, could reactivation in one location without reactivation in other locations explain the fluctuations in symptoms, with appearance and disappearance of symptoms?

 

It's possible to experience fairly profound effects without any lasting pathology, though. It depends what the mechanism is, and some of them would all-nigh impossible to detect directly. For instance, if I eat a heavily sugary meal, my arms and legs stop working; trying to walk involves staggering and falling as if I'm extremely drunk. Once the sugar's out of my system, muscle function returns to normal. As far as I know, my muscles depolarise because after certain triggers, a type of ion channel stops working properly. If that's correct it's genetic, not due to an infection.

But there are all kinds of bodily systems that depend on an incredibly fine balance, and it's unlikely we'd be able to "see" them tipping until technology is very much more advanced. We can look for other types of evidence, but we may not find obvious pathology. Or, we might find some subtle signs, but perhaps we wouldn't have thought them important, or perhaps we'd never have linked them to that particular cause—at least, until we'd worked out that they are linked.

 

Preliminary work was done on the feasibility of a ME/CFS post-mortem brain and tissue bank in the UK

See:
Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS
https://jcp.bmj.com/content/63/11/1032
&
Considerations in establishing a post-mortem brain and tissue bank for the study of myalgic encephalomyelitis/chronic fatigue syndrome: a proposed protocol
https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-7-370

Unfortunately there wasn't enough private funding around.

ETA: Hopefully people can make it happen.

 

Why?

 

Because not that much is raised privately each year for ME/CFS research in the UK, though it is better than most countries in the world in this regard.

 

I'm curious why the abstract focuses mostly on HHV6 when in the Twitter thread Prusty says they found HHV6 in two out of their 3 autopsies conducted and EBV in all 3. For the controls I'm not sure if he means all were negative only for HHV6 or also for EBV.

This is the specific tweet:

https://twitter.com/user/status/1599811192133804045


Really grateful to the people who donated their bodies for the autopsies, and a big thank you to their families, too.

 

Tom, do you know what the price tag was on this? How much needs to be raised?

Christoph Strock is discussing on Twitter.
https://twitter.com/user/status/1600034411126222848


https://twitter.com/user/status/1600061201056079872

 

Unfortunately as there appears to be no sources for ME brain tissue samples this study is unlikely to be replicated in the near future. If the findings in just 3 ME sufferers turn out not to be true (contamination? - remember XMRV?) then this could send us down the wrong path for many years to come.
XMRV was debunked very quickly because they were from easily obtained samples, if it had been brain tissue samples we would still be talking about it and very probably thousands of pwME would still today be taking very dangerous drugs for absolutely no benefit.

Claims that cannot be independently verified have to be treated with extreme caution!

 

there was a proposal by LUis Nacul back in 2014
Considerations in establishing a post-mortem brain and tissue bank for the study of myalgic encephalomyelitis/chronic fatigue syndrome: a proposed protocol
https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-7-370

 

Thread here, Considerations in establishing a post-mortem brain and tissue bank for the study of ME/CFS: a proposed protocol, 2014, Nacul et al