Why has 'persistent enteroviral infection' been dropped as a research strand in ME/CFS? (Jen Brea asking)

[chrisb]

A nice summary @Trish. My only caveat is that I don't think we have reason to think any of the outbreaks that have been linked in the historical narrative to ME or CFS were enterovirus. In most cases nobody knows what they were.

There was a reported case of an American who caught polio in Iceland in about 1955. His return home was followed by an outbreak of ME in his local community.

It might have been a coincidence.

EDIT Steigman AJ HartRH AdamsonJR Epidemic Neuromyasthenia
N Engl J Med 1969:281: 797-798

 

[Alvin]

I would not be so sure. Arguing back and forth was what got me to understanding enough about rheumatoid arthritis to develop an entirely novel treatment. We eventually realised all the evidence we needed was already available! I find arguing very helpful because at the end of it I tend to have a much clearer idea of the topic than when I started. And these illnesses are hugely complicated so getting ideas clear can make a big difference.

That is a good point

 

[JenB]

Some of those outbreaks which occurred before the days of polio vaccinations may have been similar enough to polio virus to lead to some level of immunity from polio in people affected. This may be of historical interest, but is irrelevant now since polio has been practically eliminated world wide through vaccination.

Yes, but I do think the outbreaks themselves are of interest as they are a unique opportunity to study the disease and have *very* high rates of long-term disability as compared to, say, the flu. It's possible that that strain(s) came and went and we just don't see enteroviral outbreaks like that anymore. Regardless of which infections cause them, we should be aware of and on the hunt for clusters (which do still happen). We may start to "see" clusters again as an organic outgrowth of greater medical education and scientific awareness of the condition.

Some of these outbreaks seem to have triggered enough cases to be noticeable of a long term disabling chronic illness which was probably what we now call ME, defined by PEM and muscle fatiguability among many other symptoms.

The epidemics were also noticeable in the acute stage. Many did not follow patients for more than a few months. Some did do longer-term follow-ups. Regardless, the condition was recognizable in its earliest stages due to the onset, symptoms, course, spread.

And it was definitely what we now call ME. Our definition/idea of ME came from these epidemics.

Many people with ME can pin the start of their ME to an acute viral infection of many different types including mononucleosis, Coxsackie (an enterovirus), influenza, and other viral infections of unknown specific viral origin, the acute symptoms of which resolved quickly but chronic symptoms started immediately following the acute infection.

Right

The chronic symptoms of ME are usually different from the symptoms of the acute infection that triggered it. Viruses have not been found in blood of most ME sufferers. There is not sufficient evidence of sufficient quality or quantity to show whether any virus remains within some tissues of ME sufferers.

Again, in these outbreaks the "chronic" symptoms were observable very quickly. I think it was 4-7 days incubation, 1 week prodromal symptoms, and then as soon as 1-2 weeks after that, the CNS, ANS and muscle involvement. Some noted that second phase came later, but in many cases it was super quick.

Many ME sufferers are likely to have herpes virus in nerve cells because there is a high prevalence of herpes in the population, and once in the system, herpes is there for life, lurking in nerve cells. Antivirals can reduce the symptoms of a flare of herpes symptoms, but don't get rid of the herpes stored in the nerve cells. Most people with herpes don't have ME. There is no evidence that herpes has a higher prevalence in ME than in the rest of the population. (has this been investigated?)

I don't know if it has been. 99% of people with MS have EBV (v. maybe 85% of gen pop), so it's considered a necessary but not sufficient condition. We may come to find that herpesviruses are not the causes but rather the mediators/mechanisms of a wide range of diseases: http://me-pedia.org/wiki/Epstein-Barr_virus#In_human_disease

Flares of herpes simplex are nothing like ME, so reactiviation of herpes virus is not ME. A flare up of varicella zoster (chickenpox) produces shingles - again nothing like ME. So it seems reactivation of these viruses does not lead to ME symptoms. If some other virus, such as an enterovirus, is lurking within cells of some ME sufferers, there is no logical reason to believe it will cause ME symptoms either - it might, but its presence within cells is not evidence that it is causing ME symptoms.

My ME symptoms used to flare *horribly* (go to the ER horrible) every time I had an HSV1 outbreak. Antivirals prevent this and have raised my baseline. Don't know why. Really lucky I don't need a clinical trial to have access to them.

Most people with ME didn't have an enterovirus as the trigger but had some other virus or a bacteria or something else as trigger. Is it plausible that the same symptom pattern resulting from all these different triggers, most of which are not still present in the cells, would result from lurking viruses in tissues in a subset of ME patients?

We have no idea what the trigger is for most people so we have no idea whether most people had an enterovirus or not. I imagine it's a significant subset, just like mono is a significant subset but giardia is probably less common. Some of this will have to do with how common the exposures/infections are. It will also related to which infectious agents can cause these changes (I imagine some will be more likely to than others).

Also, it may be that trigger relates to symptoms. For example, I know people with ME who have cognitive dysfunction and PEM but little or no muscle involvement. I have comparatively little cognitive dysfunction but major muscle PEM. If my trigger was Coxsackie B4, and Coxsackie has a tropism for muscle cells, maybe the trigger does relate to the symptom. It could also relate to site(s) of initial infection (even if no persistence), genetics, a host of other things. But an interesting question to ask. I would be surprised if the nature of the trigger matters nothing and we all arrive at some generic end state. It's a complex interaction of environment, host genes, infectious agent's genes.

Should there be better research to look for viruses in tissues? Is there any point?

Absolutely. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528287/ Understanding what viruses are doing on the epigenetic level is important.

Should there be large clinical trials of different antivirals and antiretrovirals for ME? As I understand it, there is no antiviral treatment that eliminates viruses for chronic viral infections like HIV and herpes. That would suggest that it is not possible, with current drugs, to eliminate enterovirus chronically lodged in tissues, so would not be a cure, but a long term treatment, with all the risks that carries.

I don't think this makes sense until we understand why would we be using antivirals. I think there is a good chance we'd be applying treatments to a heterogenous population and getting murky or null results for interventions that might work for a more clearly-defined subset. For example, if we had a better way to measure a smoldering herpesvirus, we would do a trial of herpesvirus drugs *only* on those patients. I was having recurrent HSV1 outbreaks. I know people who get shingles monthly. Maybe that would be a good place to start. But we'd need to be clear on what subsets we are talking about.

Similarly, I think it would be worth trialling an antienteroviral if we had one, but only, say, on a population with high titers to Coxsackie and confirmed viral RNA via biopsy.

I think we can get specific then yes, absolutely we should trial these drugs.

I was just thinking that both sides have made good arguments but being convincing is not getting us anywhere. We do need to test all likely theories till we figure out the problem. That said we have very limited resources so we need to allocate very strategically but i really do think arguing back and forth won't get us the answer because the evidence is not giving us a clear direction.

I disagree re: limited resources. The world is vast and sits on a sea of trillions of dollars. It's always a mistake to think of what we have as a fixed pie. We can and will attract more interest. And certainly the NIH keeps asking for more applications. As for private donors, some give because they believe in a certain organization. Others because they want to see a certain theory tested. Having more high-quality work being done in new areas will just increase the opportunities for new funders. Some donors are generalists and will support the whole field, but I know of people who could give but sit on the sidelines because they don't see the work that would motivate them to give.

Who knows? Maybe we can get Gates obsessed/intrigued by enteroviruses given his interest in polio.

I would not be so sure. Arguing back and forth was what got me to understanding enough about rheumatoid arthritis to develop an entirely novel treatment. We eventually realised all the evidence we needed was already available! I find arguing very helpful because at the end of it I tend to have a much clearer idea of the topic than when I started. And these illnesses are hugely complicated so getting ideas clear can make a big difference.

Absolutely! I've learned so much from this discussion, including the homework I still need to go do.

 

[JenB]

A nice summary @Trish. My only caveat is that I don't think we have reason to think any of the outbreaks that have been linked in the historical narrative to ME or CFS were enterovirus. In most cases nobody knows what they were.

This puzzles me. We have ample reason to think these outbreaks could have been caused by enteroviruses, namely the first-hand accounts of the physicians who observed them and who almost universally said "I think this is an enterovirus." We also know that the incubation period was 4-8 days, which eliminates a lot of culprits (http://www.virology.ws/wp-content/uploads/2014/10/Screenshot-2014-10-07-13.18.17.png), and that it was spread from person-to-person, so was definitely viral and not, say, vector-born, (solely) water-born or bacterial. The indirect evidence is tantalizing (http://me-pedia.org/wiki/Epidemic_myalgic_encephalomyelitis#Relationship_to_polio) but not enough. Agreed that we can never prove this directly and will never know.

There's a very big difference in statistics between knowing nothing and knowing something (and no such thing as certainty). I disagree with "there is no reason to think" but agree that there is no way to know.

We can certainly restrict the range of virus families. @Hip @Jonathan Edwards do you know what other families of viruses can cause the symptoms we saw in the pre-1984 outbreaks, highly contagious, with that length of incubation period? Also, is there any evidence that can help us distinguish between DNA v. RNA viruses. I know for example, RNA viruses have a higher mutation rate which could perhaps explain sudden appearance and disappearance. (Yes, just conjecture.)

 

[Hutan]

A nice summary @Trish. My only caveat is that I don't think we have reason to think any of the outbreaks that have been linked in the historical narrative to ME or CFS were enterovirus. In most cases nobody knows what they were.

Yes, a nice summary @Trish.

I'd add that another takeaway from the thread, not necessarily related to the enterovirus hypothesis, is the need for better data from both epidemics that look like ME and the sporadic cases. Given that I am a member of a mini-outbreak (three of us in my family getting ME at the same time after a 'gastrointestinal flu' with symptoms that sound a lot like Ramsay's description), I do think past outbreaks could be relevant. I would like to see efforts to get the people involved in outbreaks to donate their bodies for analysis upon their deaths.

There needs to be much better investigation and data recording early on in the illness. I know some members have reported brain lesions that showed up on MRIs early on but disappeared on later imaging. I gave the example of my patellar reflexes that seemed to disappear in the first year of illness and then came back.

If we had specialised centres where people with ME symptoms could be seen early in their illness and properly examined rather than after a year or years of banging their head against the medical system, perhaps interesting things would be found. Maybe we need more prospective studies, following people from the point they first report to the doctor with an infection known to be a trigger for ME, like the Dubbo study but throwing a lot more modern diagnostic tools at the problem to narrow down what hypotheses are worth pursuing.

 

[Guest 102]

. Melvin Ramsay said:


So provided that the accounts of the outbreaks describe both the acute and long-term symptoms, and the long-term symptoms look like ME/CFS, surely that counts as an ME/CFS outbreak?

Behan and Behan (his late wife) studied some of the original Royal Free patients three decades later and found muscle/mitochondrial abnormalities, they detected ‘early’ switching from aerobic to anaerobic pathway.

I have just read through this entire thread. Fascinating. I have Ramsay's book and read with interest the section on epidemic outbreaks.

I am trying to put together for myself some sort of conclusion about what I have learned from this afternoon's reading.

Here's my very simplistic overview:

There have been outbreaks of infections scattered around the world which were probably caused by enteroviruses and were noticed particularly because there were large numbers affected in communities living in close proximity such as nurses or soldiers, but they were also prevalent as sporadic cases in the local community at the same time. (eg Royal Free 1955).

Enteroviruses are more likely to cause such noticeable outbreaks than viruses such as herpes or mononucleosis because of the route of infection (fecal/oral for enteroviruses), and because some enteroviruses occur in epidemics that come and go and don't seem to recur, like the ones in Iceland, Adelaide etc. This may be the result of the fact that enteroviruses have a high mutation rate, so particular strains may arise and then die out particularly in geographically isolated communities - I guess that's a bit like strains of flu that change and mutate rapidly.

Some of those outbreaks which occurred before the days of polio vaccinations may have been similar enough to polio virus to lead to some level of immunity from polio in people affected. This may be of historical interest, but is irrelevant now since polio has been practically eliminated world wide through vaccination.

Some of these outbreaks seem to have triggered enough cases to be noticeable of a long term disabling chronic illness which was probably what we now call ME, defined by PEM and muscle fatiguability among many other symptoms.

Many people with ME can pin the start of their ME to an acute viral infection of many different types including mononucleosis, Coxsackie (an enterovirus), influenza, and other viral infections of unknown specific viral origin, the acute symptoms of which resolved quickly but chronic symptoms started immediately following the acute infection.

The chronic symptoms of ME are usually different from the symptoms of the acute infection that triggered it. Viruses have not been found in blood of most ME sufferers. There is not sufficient evidence of sufficient quality or quantity to show whether any virus remains within some tissues of ME sufferers.

Many ME sufferers are likely to have herpes virus in nerve cells because there is a high prevalence of herpes in the population, and once in the system, herpes is there for life, lurking in nerve cells. Antivirals can reduce the symptoms of a flare of herpes symptoms, but don't get rid of the herpes stored in the nerve cells. Most people with herpes don't have ME. There is no evidence that herpes has a higher prevalence in ME than in the rest of the population. (has this been investigated?)

Flares of herpes simplex are nothing like ME, so reactiviation of herpes virus is not ME. A flare up of varicella zoster (chickenpox) produces shingles - again nothing like ME. So it seems reactivation of these viruses does not lead to ME symptoms. If some other virus, such as an enterovirus, is lurking within cells of some ME sufferers, there is no logical reason to believe it will cause ME symptoms either - it might, but its presence within cells is not evidence that it is causing ME symptoms.

Most people with ME didn't have an enterovirus as the trigger but had some other virus or a bacteria or something else as trigger. Is it plausible that the same symptom pattern resulting from all these different triggers, most of which are not still present in the cells, would result from lurking viruses in tissues in a subset of ME patients?

No large clinical trials have been done to demonstrate whether antivirals are effective in treating ME. Antivirals have serious potential dangers if taken long term, so should not be taken by pwME unless as part of a clinical trial - of if taken, should be done with full understanding of the risks and lack of evidence.

So we are left with the question of what direction research into viruses and ME should go, if any.

Should there be better research to look for viruses in tissues? Is there any point?

Should there be large clinical trials of different antivirals and antiretrovirals for ME? As I understand it, there is no antiviral treatment that eliminates viruses for chronic viral infections like HIV and herpes. That would suggest that it is not possible, with current drugs, to eliminate enterovirus chronically lodged in tissues, so would not be a cure, but a long term treatment, with all the risks that carries.

Agree that while the atypical polio reference certainly has historical significance it is irrelevant now. I could not in any context in 2018 refer to my illness as atypical polio. As an aside, I took part in clinical trial for Imunovir in 1984, it made no difference though turned out I was on placebo.

 

[Alvin]

I disagree re: limited resources. The world is vast and sits on a sea of trillions of dollars.

I agree, we just need to get more redirected to us

 

[chrisb]

Agree that while the atypical polio reference certainly has historical significance it is irrelevant now.

I am not sure that anyone is saying that ME is atypical polio. There may however be a case for arguing that a subset of patients have their illness triggered by a virus related to the polio viruses and which has evaded discovery.

In any event it could be argued that "polio" is atypical polio in that it has been said that for each symptomatic case there were 140 or more asymptomatic cases of people infected by the virus-or, perhaps more correctly, a particular form of a virus within the group of polio viruses. Nature is complex.

 

[adambeyoncelowe]

Re @Trish's nice summary, I'd like to add one thing. While herpesviruses may not, alone, cause or perpetuate ME, I suspect that it's a hole-in-my-bucket scenario. One hole in your metabolic/immune bucket is somewhat easier for your body to plug by itself (or at least the leak of water, or in this case energy, may be relatively slow).

However, if there are lots of holes--even small perforations--then more water/energy will eventually get out, which is harder for your body to cope with.

Alternatively, it might be a straw and your immune system or metabolism is the camel's back. One straw too many (whether herpes or something else) and the back breaks.

What strikes me is that ME is a 'clusterfuck' illness. It's not usually just one thing that goes wrong, but a series of sometimes very little things and sometimes fewer but bigger things. OI or IBS or new sensitivities add veneer upon veneer. Treating one of these layers may mitigate the illness somewhat, but you rarely get lasting benefits unless you address all of them.

So plugging holes, or removing straws, might help. Maybe. Unless, of course, it's a single underlying problem that causes or exacerbates all these other issues that might not be a problem otherwise. But that still might mean it's important to treat, it just might not be a cure, exactly.

 

[Guest 102]

I am not sure that anyone is saying that ME is atypical polio. There may however be a case for arguing that a subset of patients have their illness triggered by a virus related to the polio viruses and which has evaded discovery.

In any event it could be argued that "polio" is atypical polio in that it has been said that for each symptomatic case there were 140 or more asymptomatic cases of people infected by the virus-or, perhaps more correctly, a particular form of a virus within the group of polio viruses. Nature is complex.

Hey, Chris, I was referring to Jen Brea’s MEDIUM narrative, sorry, I should have made that clear. It was late when I commented last night.



Jen starts off saying she has ‘atypical poliomyelitis’. While I think it is very useful and educational to be doing a ‘deep dive’ into the history of ME pre-80s, I could not personally say I had atypical polio in 2018. (I understand Jen also had a Coxsackie B trigger.)

I guess that because young children in areas of Pakistan are still being diagnosed with polio - which is hideous - I’m also hesitant to use polio (atypical) to describe ME currently, as polio has been eradicated in west since all of our respective experiences of ME.

As far as I know, no one on the forum has an ME diagnosis pre-polio vaccine/eradication. As I have said already, my own ME was triggered by a severe enteroviral infection - after an outbreak of Coxsackie - so I fully get/accept the historical perspective of enterovirus/atypical polio, but since polio was eradicated when I got ill, I could not have atypical polio. I hope that makes sense.

Speaking of deep dive, I am very interested in Nath Avindra’s ‘deep-diving’ and his hypothesis that ME is ‘virally-triggered, leading to immune-mediated brain dysfunction’. That is not a million miles from Peter Behan’s hypothesis in 1985 of viral infection and abnormal muscle metabolism. I have linked to an older blog of mine, to save me writing it all out again.

https://velo-gubbed-legs.blogspot.com/2017/05/dr-avindra-naths-research-and-lovely.html

 

[Trish]

I can't get medium to give me access to that article.

 

[chrisb]

Hi @Nasim Marie Jafry Thanks for putting me right on that. For anyone interested in the complexities of the polio epidemics at a personal level this discussion with Shelokov is interesting.
https://history.nih.gov/archives/downloads/ashelokov.pdf

From about p48 he discusses the possibility of patients having more than one form of polio and the discovery of ECHO virus and @p84 he describes his contracting the first recorded case of Coxsackie B2. Hope this is not off topic.

 

[Guest 102]

Hi @Nasim Marie Jafry Thanks for putting me right on that. For anyone interested in the complexities of the polio epidemics at a personal level this discussion with Shelokov is interesting.
https://history.nih.gov/archives/downloads/ashelokov.pdf

From about p48 he discusses the possibility of patients having more than one form of polio and the discovery of ECHO virus and @p84 he describes his contracting the first recorded case of Coxsackie B2. Hope this is not off topic.

Thanks, Chris, I will check out the link.

 

[Snow Leopard]

One thing to note is that enteroviruses are fairly small and simple viruses, contrasted with herpes viruses like CMV and EBV that are large complex viruses with many genes, some of which are there to confuse the immune system.

The fact that both can lead to the same illness is strange.

 

[JenB]

Re What strikes me is that ME is a 'clusterfuck' illness.

Now there's a name that would work!

 

[JenB]

Hey, Chris, I was referring to Jen Brea’s MEDIUM narrative, sorry, I should have made that clear. It was late when I commented last night.

Atypical polio was a misnomer as epidemic ME was not ultimately an atypical presentation of polio. It's the title of a piece of writing, not the name of my disease. I could as easily have called it "I have Iceland Disease." I just think it will be interesting to go back into that time and understand what people thought when they initially observed this and why.

I don't really have the energy or brain to research and structure a massive piece, so am trying to write tidbits when I can and not worry too much about the order/structure. I do wish the "series" feature on Medium was a little more accessible (it's basically for smart phones) but I hope to repackage it later.

 

[Hip]

@Hip @Jonathan Edwards do you know what other families of viruses can cause the symptoms we saw in the pre-1984 outbreaks, highly contagious, with that length of incubation period? Also, is there any evidence that can help us distinguish between DNA v. RNA viruses. I know for example, RNA viruses have a higher mutation rate which could perhaps explain sudden appearance and disappearance. (Yes, just conjecture.)

Certainly out of the list of pathogens that we know through studies are associated with ME/CFS, it's only enterovirus that fits in the incubation period of 4 to 8 days observed in the outbreaks.

The incubation period of coxsackievirus B is usually stated to be 3 to 5 days, and the for echovirus its 2 to 14 days. So both would fit.

The other pathogens linked to ME/CFS have longer incubation periods:

EBV: 4 - 7 weeks
CMV: 3 - 12 weeks
HHV-6: 9 days (but virtually all adults are already infected with HHV-6, it's usually acquired in infancy)
Parvovirus B19: 4 - 14 days
Chlamydia pneumoniae: 3 - 4 weeks
Coxiella burnetii: 2 - 3 weeks typically

Parvovirus B19 might approximately fit the observed 4 to 8 day incubation period of the outbreaks, but acute parvovirus in adults often causes joint soreness that lasts weeks, and causes a distinctive "slapped cheek" rash in children, so I think any parvovirus outbreak would be recognized as such.

But of course there is the possibility that some of these ME/CFS outbreaks may have involved some unknown virus, rather than a known virus like CVB and echovirus. Even in the world of enteroviruses, new enteroviruses are often discovered, and Dr John Chia suspects that some cases of ME/CFS might be caused by enteroviruses other than the CVB and echovirus serotypes that we can currently test for using antibody tests.



I've also wondered whether the high mutation rate of enteroviruses might explain the sudden appearance and disappearance of outbreaks. When you get infected with coxsackievirus B, the mutation rate in your body is high, and the virus starts genetically diverging into multiple sub-species of itself, which are called quasispecies of CVB. So you catch one Coxsackie B virus, but end up being infected with multiple sub-species of that virus.


I don't know offhand if there is any way to distinguish between RNA and DNA virus infections.

 

[Hip]

I've just realized that the response of ME/CFS patients to corticosteroids might be more evidence for a chronic viral infection underlying ME/CFS:

It's quite common for ME/CFS patients to feel rapidly and dramatically improved on corticosteroids; in fact one severe bedbound ME/CFS patient on the PR forum uses prednisolone once a week, and a few hours after taking this drug, he is fit and well enough to go for a major workout at the gym, without feeling any PEM repercussions! Which is quite remarkable for a normally bedbound patient.

He's been using prednisolone once a week to facilitate a gym workout for over a year (see the corticosteroids section of this post for more info about this patient's gym exploits). And although his once weekly exercise regimen did not help his ME/CFS, it cured his POTS, he said (exercise is known to be good for POTS, but is normally bad for ME/CFS).

And there are other stories of corticosteroids providing temporary relief from ME/CFS symptoms. (And incidentally, since corticosteroids suppress the Th1 immune response, suppress T-cell function, but boost the Th2 response, that suggests that ME/CFS symptoms may involve Th1 and/or T-cell responses.)

But in the long term, when taking corticosteroids for weeks or months, patients usually report their ME/CFS becoming worse. So why would they initially feel a lot better on corticosteroids, but in the longer term become more ill? If ME/CFS was cause purely by an immunological dysfunction which the corticosteroids addressed, then you would expect corticosteroids to keep working even in the long term. But what actually happens is patients on steroids get worse in the long term.

So one obvious explanation for this long-term worsening is that the Th1 and T-cell immunosuppression of corticosteroids is allowing underlying viral infections to proliferate, and thereby worsen ME/CFS.

So the pattern of response to corticosteroids does suggest a viral infection playing a causal role.

 

[Trish]

Some fascinating information to add to the discussion on this thread. I've just been reading the latest SMCI research update and read this about one of the projects they funded:

Team 5: Molecular Mechanism Behind Mitochondrial Dysfunction Indicated, for Further Study

Dr. Bhupesh Prusty, a molecular virologist in the Department of Microbiology at University of Würzburg, designed his 2016 Ramsay project to explore the hypothesis that mitochondrial dysfunction in ME/CFS has a pathogenic connection. He focused on HHV-6 (a herpesvirus that has been implicated in chronic conditions) based on his previous findings of HHV-6 activation and changes to mitochondria.

The preliminary results indicate that HHV-6 activation can lead to changes to mitochondrial structure and function, potentially even in healthy cells via a mechanism of remote activation.

The article is here, and our thread about it is here.

Looks like I might have to eat my words about lack of evidence that herpes could have anything to do with ME. I love it when science proves me wrong!
Though it's not clear whether he's applied his research to ME yet???

 

[Hip]

I was just reading that article on Dr Bhupesh Prusty's HHV-6 research the other day. This preliminary finding of HHV-6 being able to remotely affect the mitochondria in healthy uninfected cells sounds a promising line of investigation.