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How a coronavirus study shed light on Epstein-Barr Virus reactivation in ME/CFS.

Of all the opportunities the SARS-CoV-2 virus has inadvertently opened up for chronic fatigue syndrome (ME/CFS), this one might be the most creative thus far. This study highlights the news ways researchers are using the long-COVID pandemic to better understand ME/CFS.

EBV-infected cells

That Epstein-Barr Virus – it can really do things… Check out an EBV-infected cell (from Wikimedia Commons)

This Swedish study, “Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome“, contrasted the immune response between people with ME/CFS and healthy controls, before and after they came down with mild cases of COVID-19.

The question was whether a pretty darn potent virus would produce a different antibody response in immune-challenged people with ME/CFS. Because this study assessed the antibody response in people with “mild” infections (i.e., people who were not hospitalized), it can tell us how even milder infections can potentially tweak the immune response.

Antibodies – which are produced by B-cells – play a major role in the adaptive immune response that takes several days to kick in but is largely responsible for eradicating pathogens. They also can play a major role in autoimmunity when antibodies – seeking to attack a virus – attack a human tissue instead.

Because pathogens trigger the production of a range of antibodies, assessing which antibodies can tell us the nature of the response. In this case, the researchers were particularly interested in antibodies to herpesviruses and their possible reactivation during the COVID-19 infection. Epstein-Barr virus (EBV) and other herpesvirus reactivation have been found in spades in people with severe coronavirus infections, and EBV reactivation has been associated with long COVID in a couple of studies.

EBV certainly has a long history in ME/CFS. Studies in the mid-1990s, including one from the CDC, suggested ME/CFS was, at least in part, “chronic infectious mononucleosis” or “chronic mononucleosis syndrome“. Even Stephen Straus – not often viewed as friend to ME/CFS – at one point penned a paper on “The chronic mononucleosis syndrome“. In 1998, Peter White concluded that infectious mononucleosis/glandular fever was a particularly strong trigger of ME/CFS and believed it was probably responsible for around 3,000 new cases of ME/CFS a year in the U.K.

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Recent studies suggest EBV may be causing neuroinflammation, turning on pathogenic genes, and triggering the production of autoantibodies in ME/CFS.

The researchers assessed IgG, IgM, and IgA antibody responses to the coronavirus, to six herpesviruses (HHV1-6, HSV1, HSV2, VZV, EBV, CMV, HHV6A), and to a human endogenous retrovirus-K (HERV-K) before and 3-6 months after COVID-19 in 95 people with ME/CFS and 110 healthy controls.

Results

“Our findings demonstrate that SARS-CoV-2 infection, even in its mild/asymptomatic form, is a potent trigger for the reactivation of latent herpesviruses and endogenous retroviruses. This is particularly relevant for individuals suffering from ME/CFS.” The authors

Coronavirus

High rates of an asymptomatic coronavirus infection (42% ME/CFS; 31% healthy controls) puts in stark relief the idea that many people with ME/CFS who had no evidence of an infectious trigger may, in fact, have had one. Symptoms, in other words, are not required.

Interestingly, this study showed that none of the asymptomatic healthy controls who’d been infected with the coronavirus displayed antibodies to the coronavirus in their plasma (blood) – only in their saliva. That suggested that their first line of immune defense – in the nose and mouth – probably knocked out the coronavirus before it got into their bloodstream.

Interestingly, the immune systems of the people with ME/CFS appeared to jump on the virus more quickly as many more people with ME/CFS had antibodies in their saliva, but not their plasma, compared to the healthy controls. This “hyper-inflammatory response” to a pathogen appears to represent an immune system that was on alert and ready to pounce on evidence (such as a pathogen-associated molecular pattern or PAMP) of an invader.

The authors suggested that the immune cells in ME/CFS exist in a state of senescence – something like a state of torpor – when they have problems replicating. We’ve seen something like this before in the suggestions that our cells exist in a hypometabolic, or Dauer, state and/or that NK cells and T-cells exist in a state of exhaustion. Apparently, immune cells in this state start shooting a lot of blanks: they’re firing but not hitting their targets. This could explain the “hyperinflammatory” immune response seen to the coronavirus in ME/CFS, as well as the difficulty ME/CFS patients may have in reining in an EBV infection.

Herpesviruses

EBNA1

Representation of the EBNA1 protein. High levels of antibodies to EBNA1 have shown up in both multiple sclerosis and ME/CFS. (Image by Jawahar_Swaminathan_MSD_staff_European_Bioinformatics_Institute_Wikimedia-Commons)

While the coronavirus infections were “mild”, they were nevertheless able to reactivate EBV, HHV6 and HERV-K in both the people with ME/CFS and healthy controls. As noted above, EBV has been the source of much interest in ME/CFS, and EBV reactivation has been found, but no consensus exists as to whether EBV reactivation is driving the disease, contributing to it in some fashion, or is just a bystander.

The authors pointed out that the same issues have been dogging multiple sclerosis and other diseases for decades. Because virtually everyone gets infected with EBV at some point, it’s been difficult to study. Not everyone, though, gets infected.

The Gist

  • A clever Swedish study compared what happened when people with chronic fatigue syndrome (ME/CFS) or healthy controls were infected with the coronavirus. 
  • They zeroed in on antibodies – the immune factors produced by B-cells that play an important role in the adaptive immune response that takes several days to kick in but which is largely responsible for eradicating pathogens. They focused on antibodies to the coronavirus and to herpesviruses and their possible reactivation. 
  • The first rather startling finding indicated that a surprisingly high percentage of people (42% ME/CFS; 31% healthy controls) had been infected with the coronavirus without knowing it! That means that some people with ME/CFS who thought they did not have a post-infectious onset may very well have. 
  • Ironically, the immune-challenged people with ME/CFS appeared to more rapidly pounce on the coronavirus than the healthy controls. Even more ironically, this “hyper-inflammatory” response is associated with immune cells that are in a state of “senescence” or in their dotage. Apparently, cells in this state fire off a lot of blanks that miss their targets. 
  • Another intriguing finding came when the researchers found that the asymptomatic controls had antibodies to the coronavirus in their saliva but not in their plasma. That indicated that they had been able to knock out the coronavirus before it got in their blood. 
  • The coronavirus was able to reactive herpesviruses and the HERV-K endogenous retrovirus in both the ME/CFS patients and the healthy controls. 
  • Epstein-Barr virus – a herpesvirus – has been the subject of a good deal of study in ME/CFS – and while no consensus exists about its effects, many people came down with ME/CFS after infectious mononucleosis/glandular fever – which is typically caused by EBV. Some studies suggest it could play a major role in some people’s illness.  The same confusing scenario has existed in multiple sclerosis (MS) for many years.
  • EBV is hard to study because it’s almost ubiquitous. A recent Harvard Dept. of Defense study found, however, that virtually no one who’s never been infected with EBV comes down with MS and that people who have been infected with EBV are about 30x’s more likely to come down with MS. EBV is now thought by many to probably be the main driver of MS. 
  • That’s an intriguing finding given the same EBV protein (EBNA1) that’s been implicated in MS popped out in the ME/CFS patients in this Swedish study. Levels of antibodies were EBNA1 were much higher in the ME/CFS patients after they’d been infected with the coronavirus than the healthy controls – suggesting that EBNA1 was more active in ME/CFS. That, of course, suggests that a particular susceptibility to EBV might be present in ME/CFS. Indeed, prior to the coronavirus infection people with ME/CFS were also more likely to experience EBV  reactivation than the healthy controls.  
  • EBNA1 is a pretty potent protein. It’s the only protein being produced during EBV’s latency stage, has been implicated in EBV-associated cancers, and is able to stop T-cells from killing EBV-infected cells.
  • People with ME/CFS were also more likely to experience reactivation of the HERV-K endogenous retrovirus. 
  • Time will tell what will happen with EBV and ME/CFS but the coronavirus, the multiple sclerosis finding, long COVID, and research like this have put an increased emphasis on EBV. 
  • One idea is to develop a “therapeutic vaccine” that could boost the immune response to EBV in people who already are infected with it. Antiviral therapies and therapies that target B-cells that harbor EBV are other options.
  •  The recent discovery of new antibodies the body produces to fight off EBV may help produce more effective drugs. New monoclonal antibodies were able to recently effectively block EBV from infecting cells in the lab. Some drugs can also block some of the transcription factors EBV has inserted into B-cells.
  • A lot of work on EBV appears to be going on – and that’s potentially good news for ME/CFS and long COVID.

 

Earlier this year, a Harvard Department of Defense study found that people who never were infected with EBV “virtually never get multiple sclerosis“. All told, having an EBV infection appears to increase the risk of coming down with MS thirty-fold. Plus, soldiers who came down with MS came down with it about five years after they’d been infected with it. It now appears like that an EBV infection is driving multiple sclerosis. A recent hypothesis proposed that EBV and B-cell dysfunction converge in the gut to drive MS.

The MS saga may be illuminating in more ways than one. A recent Nature study tagged an EBV transcription factor called EBV nuclear antigen 1 (EBNA1) as a possible culprit in MS. Transcription factors turn on and off a wide array of genes. in MS EBNA1 appears to be mimicking a human protein called glial cell adhesion molecule (GlialCAM) that the body is attacking in MS – producing an autoimmune reaction

The EBV autoimmunity connection got a big boost when a 2018 study found that EBV was transmitting a different transcription (EBNA2) into the genome of cells that appeared to be turning on genes associated with autoimmunity in a wide variety of autoimmune diseases.

Rather remarkably, it was EBNA1 IgG antibodies that popped out in the ME/CFS patients in the Swedish study – suggesting that EBNA1 is more active than usual in ME/CFS. That. of course, suggests that a particular susceptibility to EBV reactivation might be present in ME/CFS. We don’t know what EBNA1 is doing in ME/CFS but we do know it’s a powerful protein that plays a crucial role in EBV’s success and its ability to hang around in cells.

EBNA1 is the only viral protein that gets expressed when the virus is in its latent state. It’s also the only viral protein that researchers have found expressed in all EBV-associated cancers. Plus it’s able to shut down the attempts of T-cells to destroy EBV-infected cells. Now the question becomes what EBNA1 may be doing in ME/CFS.

A further twist in the EBV/ME/CFS story came when people with ME/CFS who had not been infected with the coronavirus were still found to have evidence of EBV reactivation (higher EBV VCA antibodies).

Antibody responses to the HERV-K endogenous retrovirus were also increased in the ME/CFS patients whether they’ve been infected with the coronavirus or not. HERV-Ks have shown up from time to time in ME/CFS, and one researcher even received a major NIH grant to assess them in ME/CFS. That project apparently didn’t turn out, but a recent hypothesis proposed that EBV, HERV-W/-K, and HHV-6 are driving the inflammatory cascade found in multiple sclerosis.

The Upshot

The upshot of all this is that people with ME/CFS responded differently immunologically in a most curious way to the coronavirus than did the healthy controls. For one, they exhibited high levels of antibodies to an Epstein-Barr virus-produced transcription factor that’s been implicated in multiple sclerosis (MS). For another, evidence of EBV reactivation was present prior to being infected with the coronavirus. Antibodies to the HERV-K endogenous retrovirus were also increased. Lastly, the authors noted that it was crucial to test for EBV antibodies in the saliva – not the blood.

The infectious mononucleosis/glandular fever connection in ME/CFS, the solidifying autoimmunity/EBV connection, the strong possibility that EBV infections are driving MS, the upregulation of the EBNA1 antibody in MS and ME/CFS connection, the emergence of EBV in long COVID, would seem to put EBV ever more in the crosshairs.

The Future

The authors reported that their studies into ME/CFS and EBV will continue. Eirini Apostolou, principal research engineer and lead author of the study, told Medical Express:

“We now want to continue and carry out more detailed investigations into the immune response in ME/CFS, and in this way understand the differences between the antibody responses against latent viruses,”

Of course, time will tell what will happen with EBV, ME/CFS, and long COVID. It should be noted that other studies have not found the EBNA1 elevation that this one did. What to do, though, if EBV reactivation turns out, in the end, to be a critical factor in ME/CFS and long COVID? Interest in EBV therapeutics appears to have increased dramatically recently with the findings in MS and long COVID.

One idea floating around the MS world is to develop a “therapeutic vaccine” for people who already have MS that could boost the immune response to EBV. Antiviral therapies and therapies that target B-cells that harbor EBV are other options.

Rituximab – an autoimmune drug – of course, failed in ME/CFS, but some think the trial was hampered by a lack of funding, and better autoimmune drugs are now present. The recent discovery of new antibodies the body produces to fight off EBV may help produce more effective drugs. New monoclonal antibodies were able to recently effectively block EBV from infecting cells in the lab. Some drugs can also block some of the transcription factors EBV has inserted into B-cells.

Spirolactonone presents an interesting possibility as its an old drug that could be repurposed to treat EBV.

Old Drug Points To New Way To Knock the Epstein-Barr Virus Down

One option, interestingly, maybe anti-retroviral drugs, as it appears that HIV drugs may reduce risk of getting MS. A recent paper on infectious mononucleosis stated, “There is great interest in developing antiviral regimens for treating infectious mononucleosis.” and noted how poor the current regimes are. One study estimated that it would take at least 11 years of valacyclovir treatment to clear an EBV infection.

In any case, a lot of work on EBV appears to be going on – and that’s potentially good news for ME/CFS and long COVID.

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