All posts in Pathogens

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

A recent study suggested that Epstein-Barr reactivation might be present in substantial number of people with ME/CFS.  Anti-herpesvirus drug protocols in ME/CFS, however, tend to last very long and aren’t always successful.  The same drugs have been used for decades. That, however, could be changing, though.

Some studies remind us to always be ready for surprises – to not think that we know so much. The body is always throwing us curveballs and it turns out that sometimes drug companies can as well. The spironolactone saga in EBV reminds us that important answers to ME/CFS and other diseases might not need to come from some sophisticated R&D drug program but might literally, right now, be found down the aisles of a pharmacy.

EBV Reactivation

The goal – find a new drug that could stop EBV from reactivating.

Sankar Swaminathan MD, Chief of the Division of Infectious Diseases at the University of Utah, has been publishing on Epstein-Barr virus  for almost 20 years. Besides infectious mononucleosis – a common trigger for ME/CFS – EBV has been associated with autoimmune diseases and a host of cancers.

Four years ago, Swaminathan and colleagues went on a search to find a drug not to kill EBV – the bug is too firmly embedded in our cells to hope for that – but to stop it from reactivating. It’s when EBV awakens from its latent state and begins reactivating that it becomes the most dangerous. If Swaminathan could stop EBV from doing that he would have achieved a momentous goal.

He had an important clue. He knew that EBV (and other herpesviruses) produced a protein called SM that played a critical role in the early stages of EBV reactivation. He also knew that current slate of herpesvirus drugs left SM untouched – suggesting the protein presented a new possibility for a new herpesvirus drug.

The Study

Verma D, Thompson J, Swaminathan S. Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proc Natl Acad Sci U S A. 2016;113(13):3609-3614. doi:10.1073/pnas.1523686113

“It’s remarkable that a drug we have used safely in the clinic for over 50 years is also an effective EBV inhibitor. It goes to show how basic research can reveal things we would never have found otherwise”  Swaminathan

His team found a way to target the protein, and then created an assay that allowed them to screen compounds for antiviral activity.

Then came the surprise – spironolactone – a 50 year old drug knocked EBV down. The drug not only stopped EBV from forming the capsid or top layer of EBV that it needs to replicate, but it also blocked the expression of genes the virus used to replicate as well.

aldactone - spironolactone

No one suspected that a kidney drug of all things might hold the key to beating EBV. (Aldactone – brand name for spironolactone)

Spironolactone, though, has never been known as a antiviral. Far from it – it’s a mineralocorticoid receptor antagonist used to treat kidney disease, heart failure and edema.

The researchers found that its mineralocorticoid antagonist properties weren’t suppressing EBV – something else was.  Although, the researchers were unsure just how it was doing it, it was clear the drug doing something to EBV that no other drug had done. It had the potential to open a new era of more effective herpesvirus treatments.

Spironolactone, itself wasn’t the answer. While it’s been used for decades it can have significant side-effects. Besides some potentially toxic effects, it also increases the secretion of salts – something that salt craving ME/CFS patients might not find so beneficial.

The authors suggested that spirolactone’s most important role lay not in the drug itself, but in its ability to pointing to how produce more effective herpesvirus drugs. Noting that the current basket of anti-herpesvirus drugs suffers from problems with side effects and increasing rates of drug resistance, they suggested spirolactone be used “as the template for development of antiherpesvirus drugs”.

“We think there is great potential to modify this molecule so that it can work as an antiviral without having undesired side effects,” Swaminathan.

First, though, they would have to find out how Spironolactone was doing what it was doing.

Mystery Solved –  and the Hunt for a Better Anti-Herpesvirus Drug Begins 

Dinesh Verma 1Trenton Mel Church 1Sankar Swaminathan 2 3Epstein-Barr Virus Co-Opts TFIIH Component XPB to Specifically Activate Essential Viral Lytic Promoters Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):13044-13055. doi: 10.1073/pnas.2000625117. Epub 2020 May 20.

“These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action” Verma et. Al.

Four years later – and at about the same time that an ME/CFS study found direct evidence of EBV reactivation in about a quarter of patients –  the mystery of how a kidney drug came to beat back EBV was solved.

Active Epstein-Barr Infections Found in Large ME/CFS Study

Spironolactone, it turns out, stops or inhibits the transcriptions of 15 genes the virus needs to replicate. The researchers knew that SM – the protein which had lead to the discovery of spironolactone – enhances the activation of those genes. What they didn’t know is that the SM protein does that by ferrying another protein called XPB to EBV’s DNA, at which point XPB turns on the genes that begin EBV’s replication process.

EBV virions

EBV virions (circles). An XPB directed drug might be able to keep EBV under wraps.

XPB, then, provided a new, earlier, possibly more effective target for shutting down EBV. The University of Utah researchers are now trying to find new drugs that target XPB with the goal of keeping EBV and other herpesviruses in their latent states.

Spironolactone, then, didn’t turn out to be the EBV inhibitor the medical world is looking for. The 50 year old kidney drug did, however, provided the clue they needed to start developing a new generation of more effective anti-herpesvirus drug.

The Spironolactone saga shows that  answers to medical issues can come from unexpected places – including old, old drugs – that no one would think to explore.

Novel assays – like the one developed by the University of Utah team – and new data mining techniques will undoubtedly provide surprising new insights in the years to come. Some answers to ME/CFS and other diseases could be in plain sight – if only we can see them.

Active Epstein-Barr Infections Found in Large ME/CFS Study

“EBV is an important factor for the development of the disease” in at least a subset of patients.  The authors

A new study is revitalizing a long simmering question about the role of Epstein Barr Virus and other herpesviruses in ME/CFS.

herpesviruses ME/CFS

Herpesviruses have been studied in ME/CFS for decades. Few studies, though, have looked for direct evidence of active infection.

Herpesviruses just never seem to go away, in the ME/CFS field. They’ve been studied on and off for decades in chronic fatigue syndrome (ME/CFS) and yet the research keeps coming.

Why? For one reason, reactivated latent viruses are too juicy a possibility for an illness that often starts with an infection. ME/CFS also produces symptoms similar to those  produced by “sickness behavior”: a process initiated by the brain that’s designed to keep us in bed to stop spreading an infection. Plus enough positive study results have kept the herpesvirus theme alive in ME/CFS.  While negative studies can be found, too many positive studies have kept this inquiry from fading.

The Study

And now we have another positive result. A Bulgarian team (on behalf of the European Network on ME/CFS (EUROMENE)) assessed the prevalence of latent and active Epstein-Barr, cytomegalovirus and human herpes virus 6 in 108 ME/CFS patients and healthy controls (58 ME/CFS; 50 healthy controls).

Besides being larger than many past studies, this study went a step further than most past studies. Most studies have relied on more indirect measures such as antibody tests that assess whether an immune response has been raised to determine whether active herpesvirus infections are present. This study, though, assessed antibodies and used a process called PCR to directly look for signs of herpesviruses (herpesvirus DNA) in the plasma.

While several EBV antibody studies have had conflicting results, I was able to find only published two studies that have assessed active EBV infections using PCR. Neither found evidence of active herpesvirus infections in ME/CFS. One, however, was very small (n=20) and the other was 20 years old.  In 2013, though, Ian Lipkin reported in a CDC talk that he failed to find direct evidence of herpesvirus infection in almost 300 people with ME/CFS.

Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

If pathogens are in a latent state they should remain in the cells and not be present in the blood. Almost all of us carry latent or inactive herpesvirus infections in our cells. They are not a cause for alarm. Active herpesvirus infections, in which the pathogen is actively replicating and spreading from cell to cell through the blood, are another matter.

Results

The study did not find evidence of increased active cytomegalovirus or HHV-6 infections in the ME/CFS group.  Two findings, however, suggested that active EBV infections – perhaps similar to those found in infectious mononucleosis/glandular – were significantly more prevalent in the ME/CFS group.

Cell infected with herpesviruses

A cell infected with herpesviruses (green dots) (from National Cancer Institute)

Almost 25% of the plasma samples from ME/CFS patients were positive for EBV DNA.  Almost 2/3rds of those patients also had high levels of antibodies (EBV‐CA IgG class antibodies) that have been linked with active infections.  (This type of antibody latches onto an antigen on the capsid or shell of the virus. These particular antibodies fade quickly after the virus is vanquished from the blood.)

The study didn’t find evidence of active HHV-6 or CMV infections. (Some researchers, however, believe that a smoldering infection that this type of research wouldn’t detect may present in a subset of ME/CFS patients. Also low level HHV-6 infections in the organs may not  show up in the blood.  Nor did the study assess the early EBV proteins that Williams at Ohio State University has been finding in ME/CFS.)

Using both serological tests and PCR, this study provided a robust finding of an active EBV infection in about 20% of the ME/CFS patients tested. The authors asserted that this finding indicated “EBV is an important factor for the development of the disease” in at least a subset of patients.

The EBV ME/CFS Saga Continues

There’s plenty of reason to be concerned about an active EBV infection. Researchers are continuing to explore the role EBV plays in many serious illnesses including multiple sclerosis (MS), systemic lupus erythematosus (SLE), Guillain-Barre Syndrome, several cancers,  rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, schizophrenia, and others.

 

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

The EBV saga in ME/CFS is littered with interesting and sometimes conflicting findings. We know that EBV – the main pathogen associated with infectious mononucleosis/glandular fever – is a common trigger for ME/CFS. Several studies also suggest that immune response to EBV may be lacking in some patients; i.e. some people with ME/CFS appear to have trouble fighting it off.  Some studies have found a paltry antibody response to the virus. Other studies, however, have found no evidence of an immune hole.

Over the past decade Ariza and Williams at Ohio State University have methodically been making the case that a smoldering EBV infection is producing fatigue and other symptoms in a subset of people with ME/CFS. A recent study suggested that smoldering infection could be producing neuroinflammation.

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

The Autoimmune Virus?

On a broader front, a 2018 study which the lead researcher called “a capstone to a career in medical research” suggested that EBV is a kind of autoimmune accelerator that is turning on genes associated with autoimmune disease – an interesting finding given the possibility of an autoimmune subset in ME/CFS.   Two gene expression studies done ten years ago suggested that EBV was turning on/off multiple genes in ME/CFS patients cells.

Epstein-Barr Virus May Be Turning On Pathogenic Genes in ME/CFS

 

This Euromene study was too small (n=108) to be definitive, but the dual testing approach (PCR and serology) provided confidence in its results. Clearly, the EBV story in ME/CFS – like the EBV story in so many diseases – is not over.  If an active EBV infection is present in a significant subset of patients the next question is what to do about it.

With regards to that question, a recent study has produced some potentially very good news on the treatment front. That blog is coming up next.

From the Tahoe Outbreak to COVID-19 Dr. Peterson and Simmaron Take on the Coronavirus – and ME/CFS

“Testing is so important to everyone in our community, especially front-line workers and people who are at higher risk of severe disease. Simmaron is excited to serve our neighbors and lead the way to broader testing, so we help keep Nevada safe and learn more about this outbreak.” Courtney Miller, President of Simmaron’s Board.

Peterson COVID-19

COVID-19 brought Dr. Peterson’s mind back to the first infectious disease outbreak he’d encountered – the 1984 Incline outbreak – which helped introduce ME/CFS to the U.S.

As Dr. Daniel Peterson watched an infectious disease outbreak bear down on his community like a freight train, his mind flashed back to a time, almost over 35 years ago, when a mysterious infectious event had sent scores of sick people to his office.

The pathogen in what became the infamous 1984 Incline Village outbreak, which helped to put chronic fatigue syndrome (ME/CFS) on the map, has never been definitively identified. The inability to identify it has had significant ramifications: the patients weren’t believed and the paltry CDC investigation chalked their symptoms up to hysteria.

Being able to identify the original pathogen could have changed much for those involved and for how the disease was portrayed. Decades later, some of those afflicted still remain ill with chronic fatigue syndrome (ME/CFS). Theirs and Dr. Peterson’s lives took a course change that no one could have anticipated.

Since then Dr. Peterson focused specifically on the post-infectious cohort of ME/CFS patients. He was one of the few doctors to use Ampligen – an immune modulator – and introduced the use of the powerful antiviral Vistide to the field. He brought decades of experience dealing with post-infectious illnesses to the formation of the Simmaron Research Foundation ten years ago.

Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients

In the decade since, at the core of Dr. Peterson and Simmaron’s research has been a unique collaboration with Columbia University’s Center for Infection and Immunity (CII), led by Dr. Ian Lipkin. CII’s Dr. Mady Hornig is also a member of Simmaron’s Scientific Advisory Board.

Together, they have published 8 peer-reviewed manuscripts assessing the immune response across blood, spinal fluid and microbiota, identifying multiple subsets of ME/CFS and characterizing post-infectious immune patterns. The NIH’s current intramural study of ME/CFS focused on post-infectious patients is an overdue but pivotal, and it turns out timely, acknowledgment of the role of infection in triggering this chronic disease.

Dr Nath Talks on the ME/CFS NIH Intramural Study

Thirty-five years after Tahoe’s CFS outbreak much has changed. We have technologies that can identify a pathogen almost in the blink of an eye. The identity of the SARS-CoV-2 virus hasn’t been in doubt since early January.

Some issues remain however. The low coronavirus testing capability in the North Tahoe region meant that even today many, probably most people infected with the virus, were not going to get tested – leaving them in anxious limbo, tying Dr. Peterson’s hands to some extent, and leaving a key question unanswered.

Catching it in the Act

This time the coronavirus offered the opportunity to catch ME/CFS in the act.

This time the coronavirus offered the opportunity to catch ME/CFS in the act.

That question involved ME/CFS. Peterson knew that COVID-19 – the illness associated with the SARS-CoV-2 virus – was likely to birth an immense ME/CFS cohort. This time the outbreak presented a unique opportunity to catch the process of coming down with ME/CFS in the act. It also presented an opportunity to educate a whole generation of doctors about post-infectious illnesses and ME/CFS.

That could only really happen, though, if Dr. Peterson and other doctors and researchers knew their patients had been infected with the coronavirus. COVID-19, after all, will be taken seriously. The common cold will not. It was critical, therefore, to get people tested.

Just as inadequate testing tied Peterson’s hands almost 40 years ago, shortages in vital test kit components were tying his hands today.

Solving the Testing Snafu

What to do? Dr. Peterson and the Simmaron Research Foundation had formed a strong connection with Coppe Labs – an FDA CLIA certified pathogen testing lab with high-complexity clinical testing status.  The founder of the lab, Dr. Konstance Knox, actually sits on the Simmaron Research Foundation’s Scientific Advisory Board. Dr. Knox has been testing ME/CFS patients for viral infection, reactivation and antibodies for decades.

Coppe labs

Dr. Peterson, the Simmaron Research Foundation and Coppe labs collaborated to bring a new coronavirus test to the North Tahoe region.

Peterson, Simmaron staff, and Knox brainstormed. The nasopharyngeal swabs currently being used to identify the virus were available but the viral media they needed to be placed in was not.  But what about the urogenital swabs being used for some rapid polymerase chain reaction test (PCR) testing? They could be shipped frozen in saline to labs for testing.

An application for an Emergency Use Authorization (EUA) from the Food and Drug Administration to collect and test samples using that technique was granted. So was an application to provide an IgG antibody test.

Gunnar Gottschalk, PhD, Simmaron’s Clinical Research Director and emerging scientist trained by Dr. Peterson, Simmaron and Rush University, led the effort.

“The supply chain crisis has severely hindered the nation’s COVID-19 testing capability. We repurposed materials and sought a creative solution which helped our collaborative team achieve FDA authorization rather quickly for both the PCR and the IgG antibody test. This ingenuity, along with the hard work of our research staff, places us in a position to be the leader for COVID-19 testing in Northern Nevada.”

Over the past several weeks, over 500 people have been tested in the Tahoe area for the virus. Since getting approval, the Simmaron Research Foundation has been seeking local funding to allow it to test economically disadvantaged residents.

This Time It’s Different

This time it’s different.  Many of those sickened by the virus will not have to live in limbo. Doctors will be able to follow COVID-19 treatment guidelines knowing that their patients actually have COVID-19. Doctors will be able to treat patients and track their stages of recovery without being ostracized or looked down up. Simmaron can help elucidate the long term impacts of this virus and use that to inform our understanding of chronic ME/CFS.

This time, if pandemic patients develop ME/CFS, doctors will know they did so not because of an unidentified, usually benign cold virus but because of COVID-19 – a fearsome pathogen we know can wreak havoc on many systems of the body. They won’t be able to sweep ME/CFS under the rug with claims of hysteria, depression or somatization like they did 35 years ago.

Knowing COVID-19 is involved is a potential game changer not just for the patients who have trouble recovering, and the doctors treating them, but for the field of ME/CFS itself. The opportunity exists for this disease to finally be taken seriously.

Finally, it shouldn’t pass notice that simply by taking center stage in the Northern Tahoe COVID-19 testing effort, the Simmaron Research Foundation – which is devoted to understanding and treating ME/CFS – is spreading the word on ME/CFS and publicly rooting it in the science of post-viral disease – something the world is likely soon to become all too familiar with.

To learn more about Simmaron Research’s COVID-19 testing effort:

Email: covid19@simmaron.com
Visit: simmaronresearch.com

To donate to Simmaron Research, visit: https://donatenow.networkforgood.org/SimmaronResearch

A Never-Ending Immune Battle in ME/CFS? The Regulatory T-cell / Herpesvirus Hypothesis

The failed Rituximab trial might seem like the death knell for autoimmunity in chronic fatigue syndrome (ME/CFS) but it’s not – not by a long shot. While the B-cells that Rituximab targeted are at the heart of much autoimmunity, T-cells can also cause autoimmune diseases. They also play a very important role in stopping infections.

Nuno Sepulveda

Once Sepúlveda, a theoretical immunologist, learned about ME/CFS he knew he had to be involved.

This interesting paper, conceived and led by a Portuguese researcher named Nuno Sepúlveda, PhD suggests that both options are on the table in ME/CFS. He proposes that a battle between a subset of T-cells called regulatory T cells (Tregs) and herpesviruses may be causing ME/CFS.

Nuno Sepúlveda’s PhD is in theoretical immunology, and he’s on the faculty of the London School of Hygiene and Tropical Medical.

The study, the third Sepúlveda has co-authored on ME/CFS, is the tale of both a new hypothesis and a new researcher entering the field.

I asked Sepúlveda how he got involved.

My interest in ME/CFS and the conception of this research came a bit by chance as most things in life. I am a statistician by training but I did a PhD project on theoretical immunology in Gulbenkian Institute for Science in the outskirts of Lisbon. In my PhD theory (supervised by Dr Jorge Carneiro, second author of the paper), I developed mathematical theories on how regulatory T cells regulate autoimmunity throughout life; these cells are thought to be master regulators of the adaptive immune system.

In my post-doctoral research, I was a statistical geneticist and a biostatistician doing research in genetics, immunology and epidemiology of tropical and infectious diseases.

Along the way I met Luis Nacul and Eliana Lacerda (we are all from the same faculty/institution) who asked me to help them with the statistical analysis of UK biobank data.

One day I came across a review paper about autoimmunity and ME/CFS, and I got amazed that no one had done a comprehensive assessment of the role of regulatory T cells on ME/CFS.  So I thought to resuscitate my old work on regulatory T cells and give it a go. Then I got hooked up in the field.

We can see how this field widens. Luis Nacul PhD, the senior author of the study, has spent much of his career deeply embedded in ME/CFS. The former leader of the CureME team at the London School of Hygiene and Tropical Medicine, as well as the UK ME/CFS biobank, Nacul is now the Medical and Research Director of the Complex Chronic Diseases Program at BC Women’s Hospital in Vancouver, Canada. He enrolled Sepulveda in taking on ME/CFS.

The Model

“Given this observation, one can hypothesize that these (ME/CFS) patients might be healthy individuals who, by chance, were infected with a microorganism with a strong molecular mimicry to a human protein.” Sepúlveda et. al.

Nuno Sepúlveda 1 2Jorge Carneiro 3Eliana Lacerda 4Luis Nacul 4 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections. Frontiers in Immunology.   eCollection 

The story begins with the infectious onset that many people with ME/CFS experience. The ferocious immune response that pathogens evoke puts a strain on the immune system’s regulatory processes. The “policeman” of the immune system  – the regulatory T or Treg cells – are tasked with ensuring that the immune system in its frenzy doesn’t run amok and start attacking the human body.
Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

Regulatory T-cell (Treg) (red) cosying up to an antigen (blue)

It’s an inexact science. As with any complex system, the immune system walks a fine line between too much and too little regulation. Too much suppression by the Tregs will impair the immune system’s ability to fight off invaders, while too little suppression could result in autoimmunity. Each of us is genetically predisposed one way or the other.

People genetically predisposed to more Treg activity would be better at suppressing autoimmunity, but they might also be more prone to letting infections flourish when their Treg cells mistake the pathogenic antigens as self –  and call off the immune response.

Other individuals predisposed to less Treg activity might be more effective at wiping our pathogens, but more prone to developing autoimmunity. (Since infections, evolutionarily speaking, are more destructive, the authors believe this subset might be more prevalent.)

The big question is where do people with ME/CFS fit in?  On the one hand, many of their symptoms mimic those found in autoimmune diseases – suggesting they may be immunologically predisposed to have an overly strong immune response to pathogens but are poor regulators of that response.

On the other, many people come down with ME/CFS in response to an infection – which suggests they weren’t all that good at fighting off pathogens.

The Third Way – the ME/CFS Way?

There is a third way, though – a kind of a worst of both worlds way –  and that’s what this group’s mathematical modeling, the first of its kind done in ME/CFS, uncovered. If the authors are right it could explain why people with ME/CFS are in such a fix.

The Herpesviruses

The authors demonstrated how such a situation could happen by modeling the effect of herpesviruses on the T regulatory cells in ME/CFS in different immunological contexts.

HHV-6

Using HHV-6, the authors proposed that an ME/CFS state could occur when a smoldering infection is responded to by a T-cell clone with a high potential for producing an autoimmune state.

T-cell clones are populations of T-cells which contain both T regulatory cells and T effector (helper) cells.  Because their composition reflects the immune milieu around them, a T-cell clone with a high autoimmune potential reflects a T-cell clone existing in an environment loaded with self-antigens; i.e. antigens from a pathogen which look like they come from humans. In this example, an HHV-6 infection producing many self-like antigens is present.

Because the infection is smoldering and the viral load is low, though, the full T-helper immune response which would serve to stop the infection is not initiated.  Nor do the T regulatory cells fully step in to ward off an autoimmune response.

Instead, the virus, replicating slowly, triggers both responses. As the Treg cells tamp down the chronic immune response, they also shut down the the cytotoxic NK cells. With the immune system not geared up in either direction, the smoldering infection continues in perpetuity causing high energy costs as well as inflammation and fatigue, and there you have it – a metabolically exhausting state of inflammation and fatigue; i.e. ME/CFS.

Epstein-Barr Virus

A similar situation may occur with EBV when a Treg clone with a high autoimmune potential co-occurs with a low T-cell killing rate.  Instead of a blatant autoimmune response that racks the body, or an effective response to the pathogen, you get partial amounts of both: you get both a sucky immune response to a pathogen AND an autoreactive reaction.  If the authors are right it’s no wonder ME/CFS is such a puzzle and so difficult to treat.

How do the authors believe this shows up biologically? In a high density of and increased percentage of Treg cells in ME/CFS patients compared to healthy controls and people with autoimmune diseases. That’s actually what they see in their ME/CFS patients in their lab.

Different Roads Taken

Interestingly, the authors believe both autoimmune diseases and ME/CFS start off the same path – both are triggered by the cumulative effects of an autoreactive response to a common viral infection – but then both flit off on different paths.

Treg cells immune response

The ways Treg cells tamp down the immune response

Herpesviruses may be setting off autoimmune reactions in both autoimmune diseases and ME/CFS, but in ME/CFS the Treg cells kick in to dampen down the autoimmune response.

Unfortunately, as they’re doing that they’re also bollixing up the immune response to the pathogen – leaving ME/CFS patients in the strange state of both defending against a pathogen and trying to dampen down an autoimmune response at the same time – a metabolically exhausting situation.

The authors believe that a genetic predisposition affecting T-cells would probably be present in ME/CFS, and pointed to genetic polymorphisms that have been found.  Defective T-cell responses to Epstein-Barr Virus have also been found in ME/CFS. Further study of the T-cell repertoires in ME/CFS are needed, though, as well as studies to validate whether Treg density and percentages are increased in ME/CFS.

T-cells – perhaps the single most impactful immune cell in the body – have become the focus of interest of a number of other ME/CFS researchers including Derya Unutmaz at the Jackson Labs, and Mark Davis at Stanford.

Smoldering viral infections have also become a hot topic in ME/CFS. Bob Naviaux and Bhupesh Prusty propose a smoldering HHV-6 infection, and Marshall Williams proposes a smoldering Epstein-Barr infection may be present in ME/CFS, as well.

A Further Widening Field

The “widening” of the ME/CFS field is continuing with Sepúlveda. When I asked him what he’s working on next he reported he was bringing new researchers (and new funders) into the field as well. His research into this possible aspect of ME/CFS is continuing full-bore.

Currently I have a PhD student working full time on a project extending some ideas about the role of regulatory T cells on ME/CFS. This project is funded by the Portuguese Foundation for Science and Technology and my student is doing his research in the Molecular Medicine Institute in Lisbon. I am also trying to find/identify candidate molecular mimicries between viruses and human proteins that could explain ME/CFS.

Will COVID-19 Leave An Explosion of ME/CFS Cases in its Wake?

SARS CoV

The first SARS (SARS CoV) virus was more lethal but killed less people.

The first SARS epidemic in 2003 featuring SARS-CoV now seems like a poor dress rehearsal for today’s SARS CoV-2 outbreak. With just 8,000 cases in total and 774 deaths, (compared to almost 1,000,000 cases and 4,000 plus deaths and rising rapidly) it seems hardly worth including in the same sentence.

Yet it was a “pandemic” (infecting people in 29 countries) that landed many in the hospital and it had a chillingly high death rate – almost ten percent. The first SARS virus was far more lethal than the second one we’re dealing with now.

A few studies that tracked the survivors suggested that 2003, like 2020 surely will be, was probably a banner year for new cases of chronic fatigue syndrome (ME/CFS) and/or fibromyalgia. That’s no surprise. We’ve known since the 2006 Dubbo study that a severe infection will leave a percentage of those infected with an ME/CFS-like condition.

The Toronto Outbreak

Like the present SARS-CoV-2 epidemic in the U.S. and other countries, the first SARS virus began its spread into Canada long before the authorities realized it was there or moved to stop it.

One woman returning from Hong Kong, who came down with a fever two days later sparked the pandemic in Toronto. She was dead in two weeks. Only after her son died a week later and several other family members became ill was a link made to a new infection spreading in Hong Kong.

A couple of weeks later, Toronto health authorities instituted emergency measures allowing them to track and detain anyone possibly infected. By the time the outbreak was over 345 people had been confirmed infected and 44  had died.

The Survivors

Several studies tracked the survivors. The first one – a year after the pandemic had passed – assessed lung functioning, provided a chest x-ray, had them do a 6-minute walk test, and assessed their quality of life. Most of the participants were health care workers.

All but two had been admitted to a hospital, 16% had ended up in intensive care and 9% had been put on a respirator.

While the lung functioning and chest x-rays were normal, fatigue (60%), difficulty sleeping (44%), and shortness of breath (45%) were common 12 months later. Only 13% said they’d fully recovered.  Eighteen percent demonstrated a reduced walking distance during the 6-minute walk test.

Thirty-seven percent reported significant reductions in their physical health, and 33% reported a significant reduction in their mental health.

After one year, 17% of patients had still not returned to work, and 9% more had not returned to their pre-SARS work levels.

The conclusion of the study was confounding, dismissing the physical deficits and focusing on mental health. After noting the high degree of fatigue, the problems with sleep, the reduced walking distance, the difficulty returning to work in a significant subset in the results, the authors concluded:

“Most SARS survivors had good physical recovery from their illness, but some patients and their caregivers reported a significant reduction in mental health 1 year later.”

A 110-person 2005 UK study, on the other hand, found significantly reduced exercise capacity and health status six months after the infection. Still another post-SARS study seemed strangely eager to put a gloss on the aftermath of the epidemic as well.

Despite reporting in the results that people aged over 40 experienced significantly reduced “health-related quality of life” over “multiple domains”, and that reduced lung functioning was associated with reduced SF-36 (functional scores) and a lower score on the walk test, the authors concluded that:

“Patients had good recovery of pulmonary function and HRQoL.”

Eight Years Later – Moldofsky’s Fibromyalgia Post-SARS Study

University of Toronto professor Harvey Moldofsky was under no such illusions. A kind of an unsung hero in the ME/CFS and FM world, Moldofsky has been exploring the sleep, pain and fatigue connection in FM, in particular, over the past 30 plus years.

In 2011 – 8 years after the SARS outbreak in Toronto – Moldofsky published a study “Chronic Widespread Musculoskeletal Pain, Fatigue, Depression and Disordered Sleep in Chronic post-SARS Syndrome; A Case-Controlled Study” comparing 22  post-SARS patients with fibromyalgia patients and healthy controls.

The Forgotten

The SARS threat long over, the medical world had moved on to focus whatever the next emergency was – cancer, heart disease, diabetes, Alzheimer’s, etc. leaving behind the SARS survivors to manage as best they could.

SARS patients unable to work

Eight years after the outbreak in Toronto a group of 50 former healthcare workers remained unable to work

Eight years later, noting that a group of 50 health care workers were still unable to work and were experiencing “musculoskeletal pain, profound weakness, easy fatigability, (and) shortness of breath that accompanied psychological distress” Moldofsky, a sleep researcher, dug deeper.

After assessing their physical and mood symptoms, Moldofsky put post-SARS survivors through a sleep study.

Results 

Moldofsky found, as he suspected, that the post-SARS patients looked very much like ME/CFS and FM patients. Along with the disabling fatigue and pain came non-refreshing sleep, more arousals at night and the mysterious alpha-wave intrusions that often disrupted sleep in the two diseases. Moldofsky also found a delayed entry into REM sleep and increased stage 2 NREM sleep.

One difference did stand out – the post-SARS patients experienced more fatigue and less pain than the FM patients did; i.e. they looked a bit more like chronic fatigue syndrome patients than FM patients.

Moldofsky came up with two possible explanations for the long term disability he saw: psychological trauma from the illness and the direct effects of the virus itself.

Noting that studies indicated the virus is able to spread throughout the brain including the hypothalamus, Moldofsky proposed the virus had produced a chronic neuroinflammatory state affecting sleep, pain sensitivity and energy levels. That hypothesis, of course, is identical to similar ones proposed for ME/CFS and fibromyalgia.

Ending the paper Moldofsky asserted that:

“A longer term, large scale study is needed to establish the contribution of epidemic and pandemic viral disease to the disordered sleep, chronic fatigue and somatic symptoms of chronic fatigue/fibromyalgia syndrome.”

While the 1918 flu pandemic involved the flu – not SARS-CoV-2 –  recovery was so often contracted that it spawned a syndrome known at the time as “encephalitis lethargica”.

The Present SARS Pandemic

That study has never been done, and now here we are with another potential nervous system infecting coronavirus.

SARS-CoV-2 virions

COVID-19 presents a unique opportunity to catch the emergence of post-infectious illness in its tracks.

Avindra Nath at the NIH reported that the virus can cause multiple central nervous system problems (dizziness, headache, impaired consciousness, epilepsy, meningitis, encephalitis as well as delirium, hallucinations, mood disorders, hypomania, anxiety, depression). (It can also hit the peripheral nervous system causing loss of smell, taste problems, neuralgia and muscle injury.)

According to one report, Nath stated that patients with multiple sclerosis, myasthenia gravis, dermatomyositis who are on immunotherapy are at higher risk of developing corona infection.

Severe Infections Found in Younger People

The virus’s lethality for older people is well-known but less well-known are the devastating effects it can have on the young and healthy. While they’re not dying at the rate of the elderly, younger people appear to be being hospitalized at a torrid clip.

Governor Cuomo recently reported that over 50% of coronavirus hospitalizations in New York City are between 18 and 49 years of age.

With models predicting millions may fall ill in the U.S. alone, the emerging SARS-CoV-2 cohort presents an immense opportunity to understand chronic post-infectious illnesses that will (hopefully) not come again.

Since studies indicate that the severity of illness greatly increases the risk of coming down with a post-infectious illness, the high numbers of younger people being hospitalized for COVID-19 suggests considerable numbers of people in the prime of their lives may have an ME/CFS-like illness in their future.

Opportunity Knocks

It’s possible that post-SARS illness cohort will be so large, affect so many younger people, and cause such losses in economic productivity that the NIH and other research institutions will, this time, focus considerable resources on the post-infectious consequences of having a severe infection.

The Dubbo studies and others have invariably found that the type of infection (bacterial or viral), the type of tissue it primarily infects (respiratory system, gut, brain) doesn’t matter. For the most part, after a period of time, the post-infectious illness patients look like each other: they look like ME/CFS/FM patients.

Using post-infectious ME/CFS patients to help understand what post-SARS patients will be going through seems to make perfect sense as well. Avindra Nath’s small, but comprehensively studied, ME/CFS group in the NIH’s intramural study, could provide clues for post-SARS studies.  Expanding Nath’s ME/CFS cohort and using the study to help understand the massive hit SARS-CoV-2 is likely to produce, not today, not tomorrow, not in three months, but in the years to follow would make perfect sense.

Even more impactful would be rigorously following and studying the mass post-COVID-19 cohort that will emerge in order to understand how post-infectious diseases emerge and how to treat them.

Avindra Nath reported that “a lot of people have been asking about post-viral syndromes”, that it would be good to follow the many “postviral immune mediated diseases” (including ME/CFS), and that attempts are being made “to develop nationwide databases”.

Vicky Whittemore reported that the NIH has recognized a huge problem may be brewing, and that an opportunity exists to learn about post-infectious illnesses. She started talking about post-COVID-19 infection illnesses (e.g. sequelae) with Joe Breen and others at NIAID a couple of weeks ago, and have heard from several researchers who are interested.

Whittemore suggested that everyone who tests positive for COVID-19 get on a COVID-19 registry and she mentioned this one. (There may be others.)

It’s possible that ME/CFS holds clues to what hundreds of thousands of people may be experiencing over the next year and onwards. It’s clear that those having difficulty recovering from COVID-19 will hold clues to what has been happening with us as well. A vigorous research effort to understand their plight should provide a boon for us all.

The dark cloud that is the coronavirus could produce a silver lining after all.

Lipkin Brings Disease Busting Technology to ME/CFS

Our biggest weapon in the battle against chronic fatigue syndrome (ME/CFS) has to be the almost dizzying emergence of new technologies being developed. ME/CFS may not have much money, but somehow it’s attracted several pioneers in the medical technology field.

Dr. Ian Lipkin specializes in creating new technologies, one of which he will soon bring to bear on ME/CFS

Ian Lipkin (Columbia), Ron Davis (Stanford), Gordon Broderick (Rochester), and Travis Craddock (Nova Southeastern) aren’t just using the latest technologies – they’re actually creating them. Lipkin, the Director of the Center for Infection and Immunity at Columbia University, and a longtime Simmaron Research Foundation collaborator, is internationally known for his ability to create new molecular diagnostic techniques.

Lipkin developed MassTag-PCR, the GreeneChip system, and was the first to use next generation sequencing technology to identify pathogens. The 1,500 or so pathogens Lipkin identified include the West Nile Virus, numerous tick-borne agents, Lujo virus, MERS-CoV, and Tilapia Lake Virus to name a few. He also played a critical role in battling the SARS epidemic in China.

Lipkin, who has worked with Dr. Dan Peterson for many years, has a long collaborative research history with ME/CFS. Since September 2017, Lipkin has been the Director for the Center for Solutions for ME/CFS (CfS for ME/CFS) at Columbia University funded by the NIH.

Mystery Disease Strikes Children

Lipkin made news recently with his discovery of the apparent cause of a puzzling and devastating disease mostly affecting children called acute flaccid myelitis (AFM). The way the disease develops bears some interesting similarities with ME/CFS.

Several striking bits of evidence suggest a pathogen might be involved. The bug is not new – it first showed up in 1962 – and usually causes nothing more than a respiratory infection  – but in rare cases (600 cases in the U.S. since 2014) it can be devastating.

A spike in AFM incidence in the U.S. in 2014 suggested a virus might have become more prominent.  The fact that most infections appear during late summer and fall as pathogens start to sweep the U.S., plus a CDC report which indicated that the disease almost always followed a respiratory infection, turned a big spotlight on pathogens.

Lastly, symptom onset was abrupt and the disease produced polio-like symptoms such as difficulty moving the eyes, drooping eyelids, facial droop, facial weakness, difficulty swallowing, slurred speech, sudden arm or leg weakness (paralysis). The difficulty breathing that caused some children to be placed on ventilators brought back memories of the iron lung which kept people with polio alive in the early 20th century.

With that the hunt was on for an enterovirus – the cause of polio and a sometimes conjectured cause of ME/CFS. Although attempts to snag the intruder in the cerebral spinal fluid proved fruitless, it wasn’t for lack of trying. The CDC created a task force (which included Avindra Nath, the lead investigator of the NIH intramural study on ME/CFS) and embarked on a cerebral spinal fluid (CSF) study that included over 500 people.

Lipkin Tries New Tack

Lipkin proposed a low viral load, a hit and run virus, and technical issues might be bollixing up the PCR search in AFM, and turned to a much more powerful new technology developed by his team called VirCapSeq-VERT, as well as the use of peptide arrays that looked for immunological responses to pathogens. (VirCapSeq-VERT with its ability to detect novel and mutated viruses is like PCR on steroids.)

The peptide arrays proved the trick. Lipkin found antibodies to EV peptides present in almost 80% of the study participants’ CSF, and zeroed in on a specific enterovirus called EV-D68.  Since then a separate study has confirmed his finding. Now some researchers are calling acute flaccid myelitis “the new polio“.

Lipkin on Acute Flaccid Myelitis

ME/CFS Next

Lipkin will begin testing people with ME/CFS shortly

Lipkin will soon begin testing ME/CFS samples

The question now is whether Lipkin can do the same thing for ME/CFS. A VirScan analysis funded by Solve ME failed to produce results; however, that method may not have had the specificity needed to find the footprints of an infectious agent. Lipkin and his colleague Dr. Nischay Mishra are using the same Serochip method they used to solve AFM, to begin an intensive search for an immunological response to a pathogen (viruses, bacteria, endogenous retroviruses, fungi) in ME/CFS.

The Serochip will scan through up to 6 million peptides (small amino acid chains) in an attempt to uncover a hidden pathogen that has been, or still is, tweaking ME/CFS patients’ immune systems. The work could also uncover an autoimmune reaction.

ME/CFS with its multiple subsets is likely far more complex than AFM, but if Lipkin can find a distinct immune signature or more likely distinct immune signatures in ME/CFS, he might be able to break another mysterious, pathogen triggered disease wide open.

Lipkin and his team will begin testing the blood or spinal fluid of ME/CFS patients in early 2020.

Click on the stories below for a look back at Simmaron’s collaborative work with Dr. Lipkin.

Ian Lipkin & Simmaron to Collaborate in New NIH ME/CFS Research Center

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

Researchers Closing in on Definitive Lyme Tests As NIH Amps Up Lyme Efforts

It wasn’t until 1983 that Borrelia burgdorfii, a bacteria carried by the black-legged or deer ticks, was identified as the cause of Lyme disease. That didn’t mean a good diagnostic test has been available – far from it.

None of the currently available tests (PCR, antibodies) are anything near definitive. PCR tests often fail when they simply miss the low numbers of bacteria present. The most commonly used tests, antibody tests, on the other hand, don’t begin to be accurate until a month or more into the disease.

That’s not a good scenario for a person bitten by a tick who needs a quick regimen of antibiotics to ward off the potential joint, connective tissue, heart and nervous system complications that can occur, 20-30% of whom never get the infamous Lyme rash. Public health authorities estimate that as many 300,000 people are exposed to Lyme disease every year – but only 30,000 cases are reported.

Lyme disease

Lyme disease has been a scourge for decades, but doctors still use tests developed in the 1990’s.

The current tests are so problematic that health officials in areas with high rates of Lyme disease often simply provide prophylactic doses of antibiotics to anyone exposed to a tick who comes down with a fever, headache, etc.

Plus people who remain ill after treatment, or who are diagnosed using controversial tests, can be given long term courses of antibiotics long term which carry their own risks. The number one thing that’s wanted and needed in the Lyme world is an effective diagnostic test. The good news is that one may be on the horizon.

The current slate of antibody tests were agreed upon back in 1993 at the Dearborn Conference when our understanding of Lyme disease was in its infancy. Twenty three years later, experts experienced in the clinical and laboratory aspects of Lyme and other infectious diseases met at the Cold Spring Harbor to discuss better Lyme diagnostic tests.

That meeting and discussions afterward laid the basis for a 2019 Viewpoint article in the Journal of Clinical Infectious Diseases with the provocative title, “Direct Diagnostic Tests for Lyme Disease“.

Direct Diagnostic Tests for Lyme Disease

Direct Diagnostic Tests for Lyme Disease Steven E Schutzer Barbara A Body Jeff Boyle Bernard M Branson Raymond J Dattwyler Erol Fikrig Noel J Gerald Maria Gomes-SoleckiMartin Kintrup Michel Ledizet … Show more Clinical Infectious Diseases, Volume 68, Issue 6, 15 March 2019, Pages 1052–1057, https://doi.org/10.1093/cid/ciy614

The Viewpoint effort was lead by Stephen Schutzer – an immunologist and sometime ME/CFS researcher – who in 2011 used an analysis of proteins in the cerebral spinal fluid to distinguish post-treatment Lyme disease from chronic fatigue syndrome (ME/CFS).

The authors got right to the point: the serologic tests presently used, they wrote, “cannot distinguish active infection, past infection, or reinfection”. “Reliable direct-detection methods, on the other hand, now appear achievable”.

It should be noted that the scientific advances allowing such statements to be made provide hope not just for Lyme disease patients but for those with other difficult-to-detect infections. Reliable diagnostic tests have recently been developed quickly for a number of newly emerging diseases such as Middle East respiratory syndrome – coronavirus, Zika infection, and even 2 newly recognized tick-borne borrelia infections (Borrelia mayonii, Borrelia miyamotoi).

B. burgdorfii is a different case, however. Three factors in its makeup (low bacterial load, high antigenic diversity and a wacky genome) have made it particularly difficult to capture.

Antigen Capture

Instead of directly looking for the bacteria itself, it’s possible to look for the antigens (proteins) the bacteria sloughs off into the blood, urine, etc. Past antigen capture efforts have been thrown off by the high antigenic variability found in the Lyme bacteria but new developments in mass spectrometry, and antigen enrichment and stabilization are making antigen capture a real possibility for capturing B. burgdorfii. 

A Better PCR

B burgdorfii

Three aspects of B. burgdorfii make it difficult to find.

B. burgdorfii’s second trick for evading capture – low bacterial loads in the blood – have made it difficult to capture by PCR.  Enter high-throughput sequencing techniques that have been developed to scan larger blood samples. Frequently used to detect exotic infections, the authors asserted these techniques can “be applied successfully to Lyme disease diagnostics”.

They know – because they’ve done them. These tests, which are 200 times more sensitive than normal PCR, may just be the tip of the iceberg, though. Adding other measures to their Lyme test kit allowed the authors to increase the sensitivity of their PCR a jaw-dropping 16,000 fold – enabling them to catch many more cases of Lyme disease than had been previously detected.

Instead of the .5 ml of plasma usually taken, the authors took 1.25 ml of whole blood, used a technique to amplify the bacteria present, and then used multiple primers.

Next Generation Sequencing

B. burgdorfii’s third evasive maneuver – its complex and unusual genome consisting of high levels of circular plasmids – has enabled it to evade capture in the past, but the development of a new technique (“long-read sequencing”) has allowed Pacific Bioscience to uncover hallmark sequences of the bug’s genome that can conceivably be targeted in diagnostic tests.

Serology Not Dead Yet

Serological testing, which relies on assessing the immune response to the bug, has a couple of problems, but doctors are familiar with serological testing and it may be cheaper and easier to use than other techniques. Improved serological testing could clearly provide a boon as well.

Just a week ago, a biomedical engineering group from Columbia published a study using a new serological test which purportedly can diagnose a Lyme infection in just 15 minutes. This test which uses “microfluidics” was much more effective than the standard tests at diagnosing early infections. The test needs to be further refined and tested, but the early results were good.

Effective Lyme Test Now Technically Possible

The advances enabled the authors to assert that “the goal of an active-infection diagnostic test is now technically achievable”. Note the word “technically”. We’re not there yet.

Understanding the full breadth of B. burgdorfii’s genetic diversity, creating better genomic databases, optimizing sample collection procedures and other issues need to be resolved for that to happen. That’s all a matter of funding; i.e. the political will to get the Lyme (and other tick-borne illnesses) under control.

New NIH Emphasis on Lyme Disease 

Finally, in a last bit of good news – the NIH will be ploughing more resources into Lyme research over the next five years.

Lyme disease has differed little from ME/CFS, fibromyalgia and others in its neglect at the NIH, and new NIH emphasis on Lyme was the result of years of advocacy work. In some ways, ME/CFS advocacy is on a parallel track – it’s just a few years behind. A Congressional Lyme Disease Caucus,led by two Lyme champions, and that was officially formed in 2013, paved the way.

Lyme strategic plan

Years of advocacy paid off when the NIH published a strategic plan for Lyme. The NIH is now working on a strategic plan for ME/CFS.

The 2016 21st Century Cures Act mandated the establishment of the Tick-Borne Diseases Working Group the NIH. In 2018, that group produced a report outlining recommendations for research which included increasing funding, improving diagnostics and, more importantly, developing a strategic plan.

That plan was recently published, and when it was, Rep. Chris Smith, one of the leaders of the Lyme Caucus, and a long time advocate for more Lyme research, reported advocacy efforts had paid off:

“After lagging for decades, NIH is all in for researching Lyme and other tick-borne diseases to better diagnose and treat those suffering from this horrific disease. This is great news for patients and Lyme-literate doctors who will now have serious, federal partners working aggressively to improve strategies for the detection, treatment, and one day, prevention of Lyme.”

That plan includes a number of intriguing focii, including determining the cause of an ME/CFS-like disease (post-treatment Lyme disease syndrome), better understanding the only known food allergy that can be induced by an insect bite (alpha gal syndrome), and developing rapid and direct detection diagnostic tests as well as vaccines and immune-based treatments.

Lyme isn’t the only neglected disease benefiting from effective advocacy. The money the HEAL project is pumping into efforts at the NIH to fight the opioid epidemic and create better pain drugs resulted from a public outcry. ME/CFS, with its ramp-up of advocacy efforts, and the NIH’s work on a strategic plan, is hopefully following a similar path as Lyme disease.

See- Did a Pivotal Moment for ME/CFS Just Happen?

Smith is not nearly done with Lyme advocacy. His next trick is a bill (TICK Act (HR 3073) that would create a national strategy to prevent and treat Lyme and similar diseases.

Conclusion

Rapidly decreasing technological costs are helping the search for better diagnostic tests. More work needs to be done, though, to validate a test and bring it to market.

The takeaway message from the Direct Diagnosis paper is that we now have the technology needed to develop a reliable, effective test for Lyme disease. Such a test would identify many people who don’t know they have the disease and stop unneeded treatment in those who don’t have it. It should also help us understand what’s going on in those who have been treated and remain ill (post-treatment Lyme Disease).

The missing element has been the political will to comprehensively tackle the disease and provide the necessary research funding.

That appears to be changing as well. Years of advocacy paid off with the recent production of a strategic plan to comprehensively fight Lyme disease. The NIH’s new emphasis should further advance the development of better diagnostic tests and, hopefully create new treatment possibilities. With ME/CFS on a similar path with it’s own strategic plan being developed, it’ll be illuminating to see how much Lyme disease funding shoots up over the next couple of years.

More on Lyme Disease From Simmaron

Post Treatment Lyme Disease Unmasked? Immune Hole in the Illness Identified

The Epstein-Barr Virus – Could it be Causing Neuroinflammation in ME/CFS?

EBV has been a virus of interest since almost day one in chronic fatigue syndrome (ME/CFS). In fact, at one point, EBV was such a hot topic that ME/CFS was called for a time “chronic Epstein-Barr virus” disease.

Virion EBV

Epstein-Barr virus virions (circular centers). Virions are the form of the virus which infects other cells. EBV dUTPase is released when the process of creating virions is aborted…

While studies have generally failed to find evidence of EBV reactivation, EBV has never fallen out of the picture with ME/CFS and for good reason. For one, it’s entirely possible that researchers were looking in the wrong place to determine if EBV is an issue in this disease.  For another, EBV infection in adolescence or later and the infectious mononucleosis (glandular fever) it produces, is a common trigger in ME/CFS, and is a proven risk factor for multiple sclerosis.

Besides ME/CFS, researchers are continuing to assess the role EBV may play in many serious illnesses including multiple sclerosis (MS), systemic lupus erythematosus (SLE), Guillain-Barre Syndrome, several cancers,  rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, schizophrenia, and others.

Neuroinflammation, of course, is a hot, hot (pun intended) topic in both ME/CFS and fibromyalgia. Recent studies suggest neuroinflammation is present in both diseases and major studies are underway to validate that finding.

Nobody until now, though has attempted to complete the circle, and bring that “original gangster” in ME/CFS – Epstein Barr Virus – and the new guy in town – neuroinflammation – together.  Could EBV be causing or contributing to the neuroinflammation present in the disease?

Some History

Over 10 years of work by an Ohio State University team lead by Maria Ariza and Marshall Williams has been turning the EBV question in ME/CFS on its head. High levels of EBV, they believe, are not the problem in ME/CFS at all. In fact, their studies suggest that EBV may be at its most dangerous in ME/CFS not when it reactivates – but when it fails to reactivate properly.

dTUPase model

The Ohio State University dUTPase continuing NIH grant is in its 9th year.

By the time the impaired immune systems of people with ME/CFS have started knocking down EBV’s attempt at reactivation, the bug has already produced a potentially pathogenic protein called dUTPase. The Ohio State University researchers believe this protein may be wreaking havoc in a large subset of people with ME/CFS.

With the NIH supporting them every step of the way – their continuing grant on dUTPase is now in its 9th year – the evidence that this protein is contributing to ME/CFS (and other diseases) has continued to build.

In 2012, the group found evidence that the immune systems of people in a large subset of ME/CFS patients were indeed battling this protein. Just a year later they showed that even when viral loads of EBV were low, dUTPase could still be triggering a significant pro-inflammatory response. That finding suggested that failed prior attempts to link EBV reactivation to ME/CFS were barking up the wrong tree.

Two years later, they demonstrated that dUTPase was able to make its way into exosomes (now a major topic of interest in ME/CFS), cross the blood-brain barrier, produce major immune effects, and perhaps even promote further EBV infections.

Then a 2017 study added another herpesvirus long suspected in ME/CFS – HHV-6 – to the mix. That study found antibodies to dUTPases produced by both EBV and HHV-6 in almost fifty percent of the ME/CFS patients.  That suggested that the two herpesviruses might even be reactivating each other – a feature found in some very immune suppressed states including organ transplant patients and drug induced hypersensitivity syndrome.

Then again, really significant immune suppression in ME/CFS may not be a surprise. Up to 75% of ME/CFS patients were found to have low numbers of the B-cells designed to keep EBV in check in a recent study.

If the immune system wasn’t having enough trouble, in 2017 the first evidence of an autoimmune process involving EBV dUTPase was found in ME/CFS. Autoantibodies to the human dUTPases (humans produce a dUTPase as well) were found in ME/CFS – at much higher levels than in healthy controls (39% vs. 5%). That suggested that the immune response to EBV and HHV-6 dUTPase may have gone awry in some people with ME/CFS. Their bodies were now attacking their own human dUTPase.

The 2019 Study

In the present study we provide further evidence…. (that) dUTPase protein…could contribute to the development of a neuroinflammatory microenvironment in the brain(s) (of a subset of ME/CFS patients.)  The authors

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Marshall V. Williams PhD; Brandon Cox ; William P. Lafuse PhD; and Maria Eugenia Ariza, PhD. Clinical Therapeutics March 2019

In 2019, the team took another step. In an earlier study they’d demonstrated that the EBV dUTPase protein could be causing or contributing to the symptoms present in ME/CFS. Since many of these symptoms can be produced by the brain, they next asked if the enzyme could be affecting the integrity of the blood-brain barrier (BBB) and other aspects of neuroinflammation.

There’s a pretty good reason to believe this might be the case. EBV, after all, has been associated with some pretty nasty neurological diseases. The virus loves to hang out in nerve cells and astrocytes, is a risk factor for M.S. and has, in fact, been found scattered throughout the astrocytes and microglial cells in MS patients’ brains.

The Ohio State University researchers plopped the dUTPase protein into a variety of cells and then determined how it affected the expression of genes that play an important role in maintaining the blood brain barrier (BBB) and the functioning of various brain cells (cerebral microvascular endothelial cells, astrocytes, microglia cells).

The big bug’s dUTPase protein turned out to be quite adept at tweaking genes and proteins associated with the BBB and neuroinflammation. It turned on 12 of 15 genes and 32 of the 100 proteins examined in vitro (in the lab) and 34 of the 84 genes examined in mice.

The fact that these genes play a role in BBB integrity/function, fatigue, pain synapses and their functioning as well as tryptophan, dopamine, and serotonin metabolism suggested that this enzyme, in or out of the brain, could conceivably cause widespread problems.

How the Blood-Brain Barrier Works

 

 

All in all, the protein appeared to be doing its best to find a way to get EBV into the brain. That’s perhaps not a surprise given how much EBV loves to hang out in neurons. As EBV dUTPase was down regulating the expression of genes dedicated to producing a tight BBB it was “strongly” inducing the expression of two cytokines (IL-6 and IL-1β) known to disrupt The BBB.

If EBV dUTPase gets inside the brain, it seems almost guaranteed to cause neuroinflammation.  Studies indicate it can trigger microglial cells and astrocytes (star-shaped immune cells in the brain) to produce potent pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). It also prompts astrocytes to produce a substance (PTGS2/COX-2) associated with neuroninflammatory toxicity. Plus it’s able to alter the expression of genes associated with pain (GPR8451 and GCH152) and fatigue (TBC1D153) to boot.

In mice, it altered the expression of genes associated with cognition (synaptic plasticity, learning and memory).  One of the more intriguing findings, given the possible disruption of the kynurenine pathway in ME/CFS, was the protein’s potential to increase synthesis of a potent neurotoxin called quinolinic acid. Genes associated with the metabolism of two of the major neurotransmitters in the brain, dopamine, and serotonin, were also affected.

EBV dUTPase neuroinflammation

If EBV dUTPase has indeed been able to get into ME/CFS patient’s brains it seems almost guaranteed to cause neuroinflammation

All in all, EBV dUTPase is not a protein anyone wants hanging out in their head. It is, however, a protein that could potentially produce a lot of the problems found in ME/CFS.  This study demonstrated that the protein appears to have the capability to make its way to ME/CFS patient’s brains. Determining if it has will take further investigations, however.

It should be noted that the protein and its antibodies (or the autoantibodies to the human dUTPase) are not found in everyone with ME/CFS but the potential subset – ranging from 30% to 60% of those tested so far, is pretty darn large.

Plus, the virus is heavily implicated in the stress response. If you feel like your nervous system is over-reacting to, well, anything (or everything), EBV and this protein could be a factor. Of all the viruses, EBV and the herpesviruses love most to come out and play when one’s system is stressed.

In fact, Ron Glaser, one of the initiators of the EBV dUTPase research effort, demonstrated back in 1991 that EBV thrives in situations of psychological stress. Given the enormous stress people with ME/CFS are under, and the affects the illness has on both axes of the stress response, it makes sense that the virus might be continually trying to reactivate – and spilling it’s toxic protein into the bloodstreams of some people with this disease.

A Good-bye to a Pioneer

Ron Glaser

Glaser was shocked he couldn’t get his ME/CFS grant applications funded at the NIH

Ron Glaser was something of a legend in his own time. With his doctorate in pathology, his EBV citations alone total over 100. All told he published over 300 papers. Glaser co-founded Institute for Behavioral Medicine Research, which under his leadership brought in over 140 million in grant money over 20 years. At one point he was one of the world’s most cited authors.

His memorials mention his impact on the psychoneuroimmunological (PNI) field, his enthusiasm, (and the red and white Corvette he loved). What they don’t mention is that this leader also devoted time to a much neglected field called chronic fatigue syndrome. Glaser, in fact, took the time out of his busy schedule to sit on the now disbanded federal advisory committee for ME/CFS (CFSAC).

I vividly remember talking to him. He was not a man to mince words. An accomplished researcher with a long history of grant success, Glaser was first shocked, and then very angry at the rejections piling up for his ME/CFS grant applications. He just couldn’t understand it. Never in his decades of work had he experienced such a thing.

Stating, ironically, he couldn’t stand the stress (he did look like he was about to burst a blood vessel), he eventually moved on, but not before making his experiences perfectly clear to the federal advisory committee and everyone around him.

Glaser was not happy at not being able to work more in ME/CFS, but the work he did did not go for naught. Glaser first published on EBV dUTPase in 1985 and on EBV and ME/CFS in 1988 and his work lives on in Ariza and William’s studies on ME/CFS today. Check out a memorium to Ron here. 

Marshall Williams – On the Continuing Hunt for EBV dUTPase in ME/CFS

What about the connection between this protein and the presence of infectious mononucleosis/glandular fever in ME/CFS? Do we have any idea if the enzyme is more likely to be found in people who’s disease was triggered by IM or who had an acute, flu-like onset?

That is an excellent question. We are in the process of trying to obtain longitudinal serum samples from an IM cohort who developed CFS as well as age matched patients who had IM but never developed CFS. Hopefully, that may address this question.

EBV dUTPase exosomes

When EBV (lytic) replication is aborted it tosses EBV dUTPase into exosomes (circles with red marks) which, after binding to TLR receptors on immune cells, tells those cells to turn on proinflammatory and other genes (from Ariza, Williams and Glazer -https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069827)

This study demonstrated that this enzyme has the potential to disrupt the BBB and enter the brain – and as added bonus – perhaps helps get EBV into the brain. Is there any way to tell if this has actually happened in ME/CFS?

Not really at this point but maybe in the future. Screening CSF from ME/CFS patients for antibodies to the EBV-dUTPase or HHV-6 dUTPase might suggest potentially the presence of these viruses in the brain.

Exosome research is heating up in ME/CFS. Some anecdotal reports show that exosomes in the blood may be affecting energy metabolism and other functions. Could herpesvirus dUTPases be involved? Is there any more information on exosomes and EBV dUTPases?

We have not looked at energy metabolism but there are some reports in the literature that some herpesviruses including EBV and HHV-6 alter mitochondrial function. There is information concerning EBV products in exosomes but most of these have focused on proteins/microRNAs involved with latency.

What is next for your team? 

We are in the process of submitting a manuscript detailing a mechanism(s) by which the EBV-dUTPase and to a lesser extent the HHV-6 dUTPase alter germinal center function, which could contribute to autoimmunity in CFS patients. We will be continuing these studies as well as those regarding neuroinflammation. (B-cells manufacture autoantibodies in the germinal centers found in the lymph nodes and spleen)

Epstein-Barr Virus May Be Turning On Pathogenic Genes in ME/CFS

If there was ever a “prodigal virus” in ME/CFS it would surely be the Epstein-barr virus (EBV). Since the first EBV ME/CFS study 1984 no less than 51 ME/CFS or post-infectious viral studies have featured either Epstein-Barr virus or infectious mononucleosis in their titles. (That leaves out a considerable number of viral and immunological studies which didn’t put EBV in their titles.) While hypotheses of chronic viral reactivation in ME/CFS have lost favor the virus is too complex, too fascinating, and simply too problematic for it not to continue to be studied.

EBV budding out of B-cell

A B-cell with EBV budding out of it

A PubMed search brings up over 500 EBV citations associated with multiple sclerosis and over 30,000 citations associated with the virus.  To get an indication of how broad EBV research continues to be – one of the latest  EBV studies determined if the stress of space flights results in increased levels of EBV reactivation in astronauts. (It did and they advised astronauts to stay away from immunocompromised individuals upon return home…)

The research community clearly continues to find EBV – one of the few viruses our bodies are unable to kick out – a fascinating and important topic. Check out the first in  a series of two blogs on EBV’s possible contributions to ME/CFS.

The Review

In his EBV and ME/CFS review longtime ME/CFS researcher Jonathan Kerr digs down into some past ME/CFS EBV findings which recent understanding of EBV is shedding some new light.

Kerr notes that psychological stress is associated with EBV reactivation and maintaining that state of psychological stress can result in prolonged states of EBV reactivation and diseases such as ME/CFS, nasopharyngeal cancer and post-transplant lymphoproliferative disorder (PTLD).

Many studies have found that stress triggers the release of glucocorticoids which tell the pathogen that the coast is clear and it’s time to start growing the family and producing more virions.

Whether or not the original ME/CFS trigger is associated with increased levels of  psychological stress, the dysfunctions found in both stress response axes (HPA axis, autonomic nervous system) post-ME/CFS suggests that psychological stress could  possibly give a bug like EBV a leg up in diseases like ME/CFS. Plus, other studies have found evidence of an immune hole which could give EBV an extra foothold in ME/CFS.

In the U.S., Ariza and Williams have shown that attempts at EBV replication in ME/CFS can trigger the production of an enzyme called EBV dUTPase which, among other things, results in the production of pro-inflammatory cytokines which may produce fatigue, pain, flu-like symptoms, etc.

Kerr’s group in the U.K., though, has taken a different tack.

The 2008 Study

Assessing the expression of 88 genes Kerr suspected were playing a role in ME/CFS, his group was able to separate healthy controls from ME/CFS patients, and then break those ME/CFS patients into 7 subsets in 2008. No less than 12 of the genes his group assessed were known to be associated with EBV.

Finding such a huge split in gene expression between ME/CFS patients and healthy controls, and then being able to split up the ME/CFS group into gene expression subsets with unique symptom profiles, was striking.

One of the genes which stuck out back then is called Epstein-Barr Virus (EBV) induced gene 2 (EBI2). While EBI2 sounds like it comes from EBV, it’s a human gene. As EBV begins to reactivate it induces the expression of this gene, which regulates B-cell functioning, T-cell mediated antibody responses, and inflammation.

Kerr’s 2008 study suggested the gene was working overtime in 55% of ME/CFS patients. In another analysis, EBI2 was upregulated in 38% of 31 patients vs zero of 40 healthy controls.

The 2010 Study

A larger (n=117 ME/CFS patients) 2010 study analyzed antibodies associated with EBV in eight gene expression subsets. As before, twelve of these genes were known to be associated with Epstein-barr virus (EBV)

EBV Gene 2 expression

Greatly increased expression of the EBV Induced Gene 2 was found in the ME/CFS group

One subset – subset D – stood out in its severity. This group of patients, all females, demonstrated a consistency of the worst kind, posting the lowest functional scores  in no less than five of SF-36 functional domains (physical role, vitality, general health, bodily pain, and total score) and experiencing high rates of muscle pain and sleep issues.

They also led the pack in the expression of  EBV associated genes. Their EB12 genes were turned on and pumping away at higher levels of activity than in any of the other groups. So were all the other 11 associated EBV genes.

In other words, this appeared to be a highly afflicted EBV ME/CFS subset.  EBV may be involved in other subsets, but it appeared to be wreaking special havoc in this one.

Interestingly, the abnormal antibody (EBNA IgG) result found indicated the antibody was not elevated but was reduced. Since antibodies play a key role in immune clearance, the low levels suggested an immune deficit could be present.  For one, they suggested EBV was probably more often found in its latent state in this group.

EBV is found in two forms: its lytic form occurs mostly in epithelial cells, and its latent form in B-cells.  The low levels of EBNA IgG appear to suggest, if I have it right, that EBV is able to survive in B-cells longer, giving it more time, one would think, to possibly tweak those B-cells more. That’s an interesting finding given the role B-cells play in autoimmunity.

Nine Years Later – Science Marches On

Nine years ago, not much was known about EB12 but science has been moving on. EB12 is now recognized as a “critical regulator of the immune response”. It ordinarily plays a valuable role in the interaction between B and T-cell and the antibody response.

Gene expression

Jonathan Kerr believes EBV may be causing a gene to over express itself in ME/CFS

As one might suspect, though, EBV activation of this gene is not associated with good outcomes.  Increased EBI2 expression appears to dysregulate the delicate immune response – increasing B-cell activity (and therefore the risk of autoimmunity)  – while inhibiting T-cell activity – and potentially suppressing the immune system’s ability to deter pathogens and knock out cancerous cells. Kerr pointed out that EBI2 could also be contributing to the reduced cerebral perfusion, gray matter reduction and white matter hyper intensities found in both multiple sclerosis and ME/CFS.

Given the findings of the past 11 years, Kerr suggested that the EB12 gene deserves a deeper look in this disease.  The possibility that a severely ill EBV subset – characterized by a hyperactivation of the EBI2 gene – is present, is, of course enticing. Given that ME/CFS often has an infectious trigger, a special EBV subset makes perfect sense, and if it is present, it may offer some unforseen opportunities.

One of the advantages of having an upregulated gene that’s been implicated in a bunch of nasty diseases is possible increased interest from big pharma. If the EBI2 gene is wreaking havoc in some of the more severely ill ME/CFS patients, help may be at hand in the future.  Kerr pointed to two EBI2 modulators  (GSK682753A, NIBR189) currently under development.

Kerr acknowledged several caveats to his hypothesis. His findings need to be validated by other laboratories using other sets of ME/CFS patients. He noted that finding EBV antibodies in ME/CFS does not in any way indicate that the bug is causing ME/CFS – that is still in doubt. His hypothesis – that EBI2 upregulation is playing an important role in a subset of ME/CFS patients –  is unproven at this point.

It’s a hypothesis though, which is consistent with the data presented thus far and could account for “many of the immune and neurological abnormalities” found in a group of patients.

East African Disease Informs Nath’s Search for the Cause of ME/CFS

Could a disease found in the remote villages of East Africa end up being a model for chronic fatigue syndrome (ME/CFS)?

Ugandan Village

Ugandan Village (from the NIH)

Dr. Avindra Nath – the leader of the NIH Intramural study on ME/CFS –  thinks perhaps so. He’s not daunted by mysterious diseases and nor should he be. Just a couple of years ago his NIH team was able – by bringing new technology to bear – to unravel a mysterious disease plaguing children in Africa. Using a much larger array of tests he’s hoping to do the same in ME/CFS.

Nath became acquainted with “nodding syndrome” at a meeting in Uganda in 2012. This strange and often devastating disease, found in the remote regions of Uganda, Tanzania and South Sudan, causes children’s heads to periodically nod  and can produce seizures, mild to severe cognitive impairment, muteness, gait problems, paralysis and often death. Brain scans have shown significant brain atrophy.

Studies suggested that the disease was linked to a parasite, Onchocerca volvulus, carried by the black fly, but numerous efforts to find the parasite in the brain or cerebral spinal fluid failed.  Attempts to tie it to immune factors including autoantibodies, as well as genetics, toxins, nutritional factors, and others came to naught as well.

Like ME/CFS the speculation regarding the cause of nodding syndrome has been rife with possible connections to autism spectrum disorder, Alzheimer’s, poor nutrition, PTSD and others being put forth. Ugandan psychiatrists have even proposed that the disease is a form of “Developmental Trauma Disorder” brought on by the war.

Enter Nath, Tory Johnson, a former postdoc fellow of his, and Thomas Nutman, a National Institute of Allergy and Infectious Disease (NIAID) researcher.  Suspecting the problem was autoimmunity, they brought out one of their big guns – a kind of protein chip technology that allowed them to screen for thousands of antibodies at once.

The results were tantalizing. The levels of four antibodies were 100 fold higher in the sick children compared to the healthy children.  Further testing revealed that two of these antibodies were more reactive or active in the sick children. They ended up focusing on one antibody found in both the blood and cerebral spinal fluid.

This antibody – which was linked to the leiomodin-1 protein  – reacted 33,000 times more strongly in the children with nodding syndrome.  Interestingly, both groups – the sick and the healthy children – carried the antibodies, but they were elevated in the sick children.

Leiomodin-1 staining neurons

Staining reveals Leiomodin-1 antibody (green) interacts with human neurons

After finding this link, they deepened their search. The leiomodin-1 protein had been found primarily in smooth muscle tissue and the thyroid, but if it was causing the neurodegenerative symptoms it had to be in the brain as well. Further testing, including immunostaining human neurons, indicated that protein was indeed found in parts of the brain imaging studies had indicated were associated with nodding syndrome.

Having established a putative link between the antibody and the disease (that it was found in and could potentially affect the brain) the next step was to demonstrate that the antibody could indeed be causing the disease. Subjecting cultured human neurons to the antibody showed that the antibodies could indeed be damaging the childrens’ neurons.

Getting at the source of the antibody was next. The authors hypothesized that an immune attack against the parasitic worm had gone awry and was attacking the ill childrens’ neurons. This could only happen, though, if the parasitic worm and human neurons shared genetic sequences that could cause the immune system to mistakenly attack human neurons. Studies confirmed that a very short sequence of the parasite’s tropomyosin gene was quite similar to a sequence expressed in human neurons.

autoimmune responses ME/CFS

Nath believes the infections may have triggered a variety of autoimmune responses targeting the brain in ME/CFS

With that, the circle was closed. They had identified an antibody, shown it was in the brains of the sick children, showed that it could do damage to the neurons that were damaged in the children, and demonstrated similar genetic sequences were present in the parasite and humans.

There was still the nagging issue of antibody prevalence, though.  Only slightly over 50% of the sick children had antibodies to leiomodin-1. If the antibody to leiomodin-1 was causing the disease in these children, what was causing the disease in the others?

Nath et al proposed that the parasite triggers a different immune response in different children.  Some of the children developed autoantibodies that damaged neurons in their CNS  – and produced nodding syndrome (which is now understood to be a form of autoimmune epilepsy).

This syndrome is likely not a disease mediated by a single immune specificity. We speculate that nodding syndrome may not be a single antibody syndrome.  Nath et al.

Citing test results which showed a range of elevated autoantibodies in the sick children, they suggested that some children with nodding syndrome have developed antibodies to  neuronal proteins other than leiomodin-1.

A Model for Chronic Fatigue Syndrome (ME/CFS)?

Nath reported that his approach to ME/CFS has been shaped by his experiences with nodding syndrome. He suspects the infectious onset that so many people with this disease experienced triggered their immune system to accidentally produce autoantibodies that are attacking their central nervous system or other parts of the body.

If suspect antibodies show up, future research efforts will presumably proceed down the same pathway as they did in Nodding Disease: first they will identify the proteins the antibodies are attacking, and then they will determine where those proteins are found, and demonstrate experimentally that the antibodies are likely doing damage.

Nath and his compatriots uncovered the antibody connection to nodding disease seven years ago – a long time in this age of fast moving medical technology. Nath reported he’ll be using a newer approach involving mass spectrometry, or phage display, in ME/CFS which will allow him to “probe almost infinite numbers of proteins/peptides”.

Seven years ago, extensive testing had failed to find a culprit leaving the cause of nodding syndrome a complete mystery. In 2017 Nath et. al. produced a clear pathway that explains about 50% of nodding syndrome victims.

Technology Paves the Way

Note that the breakthrough didn’t come from the slow accumulation of results over decades; –  it occurred very quickly and simply required the right technology being applied to the disease. When that happened, a cause of the disease became clear, and researchers simply proceeded down established pathways to prove  it.

Nath and the NIH are looking at much more than antibodies in their intramural study, and ME/CFS, with its multiplicity of triggers, is likely to be more complex than nodding syndrome. The same principle, though, – a variety of autoimmune processes produced by an infectious trigger – may apply.

Dr. Nath appears to have gotten at a cause of one mysterious disease. May he be as successful with this one.

Check out an interview with Dr. Nath

Dr Nath Talks on the ME/CFS NIH Intramural Study

The NIH’s Accelerating Research on ME/CFS Conference

Because of a death in the family, Brian Wallitt will be presenting in Dr. Nath’s place at the NIH conference. Dr. Nath reported that Wallit will present on the high rate of rare diseases found during the first half of the study and some other data but will not present statistical analyses. With just half of the projected participants having finished the first part of a two-part study, the lack of statistical analyses is not really a surprise.

Brian Wallitt will be presenting at 10:00 AM EST on April 5th (day two) of the Accelerating Research on ME/CFS conference – the first NIH sponsored research conference on the disease since 2011. Check out the agenda here.

Learn more about the NIH Conference below.

NIH Brings in New Faces and Looks to the Future in Accelerating ME/CFS Research Conference