Genetics, Chronic Fatigue Syndrome, and Long Covid

We often think of viruses as a quick, couple-of-days being sick, type of deal. “It’s just a virus“. Perhaps the flu will get you down for a week or so, once in a blue moon. But sometimes a virus can linger, reactivate, or seemingly permanently alter your immune response…

This article digs into the science of the lingering effects that viruses can trigger. I’ll touch on chronic fatigue syndrome (myalgic encephalomyelitis) as well as other persistent, viral-initiated illnesses. Genetic variants, of course, come into play here, and I’ll cover which variants increase susceptibility. Finally, I’ll wrap up with a few possible treatment pathways to investigate, based on genetic susceptibility.

The Long Haul: Continuing effects after a viral infection

While this topic is timely in relation to ‘long-haul’ COVID, let me state up-front that not a lot of definitive answers exist yet on post-COVID symptoms.

Although making headlines today, the aftereffects of a virus triggering chronic tiredness or pain is not a new phenomenon. My focus here is on the mechanisms that have been proven for other fatigue or pain-related conditions. Hopefully, the information will be relevant both for long-haul COVID and for individuals with previous fatigue-related conditions.

There’s more to this story: I want to say up front that I’m not an expert. I’m merely gathering some of the research, but this is just the tip of the information iceberg. So please take this article as a starting point rather than a definitive treatise on the topic.

Why do viral infections make us fatigued?

You know that feeling of being unable to get out of bed when you’re sick…too tired to sleep, too tired even to read, and you just want to lay there? That is the type of fatigue we are talking about here.

But why does fatigue (and muscle ache) happen when fighting off certain pathogens?

Doctors used to say a fever caused the fatigue, but more recent research shows that is likely incorrect. Instead, it is neuroinflammation – inflammation in the central nervous system – causing fatigue when you have a virus. This doesn’t mean the virus is in your brain, but rather the inflammatory cytokines, such as IL-1β and interferon, are acting on the central nervous system. The brain then suppresses activity throughout the body.[ref]

An interesting animal study showed that ‘sickness behavior’ and cognitive disfunction go together with viral illnesses. One key to the behavioral changes is the blood-brain barrier interferon receptor, which when activated by interferon releases a cytokine into the brain.[ref]

Chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS):

CFS/ME is a multi-systemic disease affecting somewhere between 0.1% and 2.5% of the population (depending on the source of the data).[ref] In some parts of the world it is commonly referred to as myalgic encephalomyelitis (ME), while in other areas it is called chronic fatigue syndrome (CFS).

The symptoms include chronic exhaustion, pain and flu-like symptoms, cognitive dysfunction, and a general reduction in their overall quality of life. The majority of people with ME/CFS are unable to work, and about 25% are homebound or bedridden.[ref]

History side-note: You would think that there would be a lot more research and better answers for something that has been defined and talked about since at least the 1930s. At least we’ve moved beyond calling it a psychiatric issue just all in the patient’s head…like it was in the ’80s and ’90s.

Interestingly, ME/CFS was known as ‘chronic Epstein-Barr virus syndrome’ in the ’80s, pointing towards one of many possible viral causes.[ref] ME/CFS was also called the ‘yuppie flu’ at one point, which is ironic since it disproportionately affects certain minority groups and lower socioeconomic groups.[ref] Dr. Anthony Fauci, as the head of the NIAIH, has been strongly criticized for the lack of research focus and funding for ME/CFS for over two decades.[ref]

Links between ME/CFS and viral infections:

For some patients, ME/CFS seems to be triggered by an acute infection, usually viral. One study found that almost two-thirds of the ME/CFS patients reported an infection-related onset.[ref] Not all ME/CFS cases seem to be infection-triggered, though.

An autoimmune component likely exists for some ME/CFS patients. Research shows genetic variants with links to autoimmune diseases also have links to ME/CFS in patients with an initial viral cause.[ref]

Other recent studies point to latent or reactivated Epstein-Barr virus being implicated for a portion of ME/CFS patients. One study published in Dec. 2020 found that 24% of chronic fatigue patients had DNA from the Epstein-Barr virus in their plasma, in comparison with only 4% of the control group.[ref] Other studies point to a variety of other possible viral triggers for ME/CFS including herpes simplex or cytomegalovirus, but not all studies agree.[ref]

Natural Killer cells and Calcium channels in ME/CFS:

One fairly consistent finding for ME/CFS patients is a reduction in natural killer cells. A type of white blood cell, natural killer (NK) cells are part of the innate immune response. They target tumor cells for destruction and are also vital for responding to viral infections by destroying infected cells.[ref]

Calcium ions play numerous roles in the activation of different cellular processes. Researchers have found that patients with ME/CFS are likely to have impaired calcium ion channel function via the TRPM3 channel. They link this to reduced TRMP3 function on natural killer cells in people with ME/CFS compared to healthy controls. Several variants in the TRPM3 gene are more often found in people with ME/CFS.[ref]

NK cell cytotoxic activity. CC license. Read PMC4821384

 

NLRP3 and fatigue:

Another innate immune system component, NLRP3, is also implemented in fatigue syndromes including ME/CFS and MS.[ref][ref]

NLRP3 is a lynchpin at the start of the immune cascade. Essentially, when NLRP3 activates, it causes caspase-1 activation, which in turn activates interleukin-1β (IL-1β) and interleukin-18 (IL-18). IL-1β and IL-18 are proinflammatory cytokines that cause rapid cell death (pyroptosis) as well as initiating other inflammatory responses. IL-1B also alters the integrity of the blood-brain barrier.[ref]

NLRP3 activation can develop due to microbes (including coronaviruses) as well as ethanol, amyloid-beta (Alzheimer’s), and alpha-synuclein (Parkinson’s).

Researchers often use animal models in chronic fatigue research, and animal studies point to the continued activation of NLRP3.

Using a mouse model with the NLRP3 gene inactivated, researchers showed that the mice had reduced fatigue behavior after forced exercise. The knock-out model also showed decreased IL-1β. On the other hand, the mice with NLRP3 intact had increased fatigue behavior and increased IL-1β after repeated forced exercise.[ref]

In addition to NLRP3 being activated by viral pathogens, it can also be triggered by mitochondrial dysfunction.[ref] This brings us to the next topic of mitochondrial dysfunction in chronic fatigue…

Mitochondria, cellular energy, and interferon:

Mitochondria are the organelles responsible for the majority of cellular energy — the ‘powerhouse’ of the cell.

When you learn about mitochondria, the Krebs’ cycle, and the electron transport chain in biology class, a dimensional picture forms of a cellular battery cranking out energy in the form of ATP.

Cellular energy is, of course, vital to wellbeing. Your muscles and brain can’t work well when lacking energy. So a mitochondrial connection to fatigue is common sense. But why would the fatigue continue after an illness resolves?

The role of mitochondria in the cell goes beyond just generating energy. Mitochondria are constantly changing – fusing together and splitting into two. When a mitochondrion is no longer functioning correctly, it degrades and recycles via a process called mitophagy (autophagy of mitochondria).

In addition to activating the NLRP3 inflammasome cascade (IL-1β and IL-18), damaged mitochondria can trigger interferons and other pro-inflammatory cytokines. Specifically, when mitochondrial DNA leaks, it triggers the immune response, including interferon activation, as a danger signal from the damaged mitochondria.[ref]

Some viral infections also trigger mitophagy, or mitochondrial destruction, which works to help the virus evade the immune response.[ref]

Thus, we have immune system activation causing mitochondrial damage as well as mitochondrial damage-causing immune system activation. In a trap of decreased cellular energy, fatigue persists.

Fibromyalgia, chronic post-SARS, and persistent fatigue

A small study in 2011 looked at the similarities between what the authors called chronic post-SARS (SARS-CoV-1) and fibromyalgia patients. The study found that people with chronic post-SARS had persistent fatigue, muscle pain, weakness, depression, and non-restorative sleep – which overlapped with the symptoms of people diagnosed with fibromyalgia and ME/CFS.  Interestingly, the fibromyalgia and post-SARS patients had a high EEG cyclical alternating sleep pattern rate.[ref]

Transposable Elements: beyond viruses to infection mimicry

Getting a little deeper in the science here…  stick with me. This stuff is interesting.

One area of research in ME/CFS ties the immune system activation to the viral DNA encoded in our human genome.

Not everyone with ME/CFS, fibromyalgia, or similar diagnoses has altered levels of viruses or a known viral onset. A possible answer may lie in the ‘fossil viruses’ encoded into the human genome.

Your DNA – your genome – is the ‘code’ for your genes, but most of your DNA doesn’t code for protein-coding genes.  In fact, about 45% of the genome is made up of transposable elements. These sections of DNA move around within the genome and were sometimes called ‘jumping genes’.

Methylation represents one method of controlling which genes – or which sections of the genome – get transcribed into RNA. This is just one epigenetic way cells control which genes turn off or on. In methylation, a methyl tag that binds to the right spot on your DNA turns off a gene.

A recent study looked at methylation patterns in people with fibromyalgia and ME/CFS. The researchers found that methylation patterns were different from the healthy control group, and one large difference is in the methylation patterns in the transposable elements.

The study focused on a section known as HERV-K, which is an endogenous retrovirus found in the non-coding part of the genome. An endogenous retrovirus is a section of our human DNA that was a likely integration of a virus or provirus incorporated into the genome millions of years ago. Researchers estimate about 4-8% of the human genome’s composition includes endogenous retroviruses. (Here’s a good article on HERVs, if you’re interested)

The results showed that people with fibromyalgia had increased expression of the HERV-H, HERV-K, and HERV-K.  This corresponded with increased interferon-beta and interferon-gamma. The researchers theorize that an infection mimicry state could be a cause of fibromyalgia and CFS/ME.[ref]

Study on endogenous retroviruses in fibromyalgia. PMC7072917

Chronic Active Epstein-Barr virus:

Switching gears from ancient retrovirus viruses in our genes to the current virus that almost every has in their body…

Epstein-Barr is a herpes virus that causes few symptoms in children, but in teens and young adults, it causes mononucleosis. The virus is spread through contact with saliva, and almost everyone (>90% of people) has it by the time they are an adult. The virus sticks around in a latent form for the rest of your life. For a few people, Epstein-Barr can reactivate later in life, causing various problems for people.

Symptoms of mono include extreme fatigue, head and body aches, fever, malaise, and swollen glands.  For most teens and young adults, the symptoms will subside within a few weeks.

Chronic active Epstein-Barr virus (CAEBV) is a rare syndrome where the virus stays active, causing long-term illness. Patients have prolonged mono-like symptoms, and most show unusual T-cells or natural killer cells. Due to the prevalence in certain population groups, researchers think there is a genetic susceptibility component.[ref] Rare mutations linked to immunodeficiency have been tied to chronic active Epstein-Barr.[ref]

For most people, though, the Epstein-Barr virus hangs out in a latent state and avoids immune system detection in unique ways. One of the proteins coded for by the virus is very similar to human IL-10, which is an immune system molecule that dampens the immune response. Additionally, Epstein-Barr is an enveloped virus, and the host’s cell membrane creates the envelope. So it escapes detection by looking like ‘self’.[ref]

Many autoimmune diseases, such as lupus, rheumatoid arthritis, and Sjögren’s syndrome, are linked to Epstein-Barr as a contributing factor.[ref]

Prolonged fatigue after West Nile Virus :

Research shows that a lot of people experience prolonged fatigue for 6 months or more after having West Nile virus. West Nile is a mosquito-borne illness that is prevalent across the US some years, with an estimated 3 million people in the US with the disease by 2010.[ref]  West Nile virus is transmitted to humans from birds via mosquitoes, and a number of other animals can also carry the disease.

While the majority of people with West Nile virus are asymptomatic, about 20% of people will experience fever, headache, weakness, and muscle ache.  Around 1% of people will develop severe neurological symptoms including encephalitis and myocarditis. Risk factors include being over 60 and having co-morbidities. The case fatality rate for people with symptomatic West Nile virus is 3-13%, according to the CDC.[ref][ref]

In a study of people with West Nile in Houston, TX, about 20% of the symptomatic people in the study still had continuing fatigue up to 8 years later. The study participants with continuing symptoms also had elevated cytokine levels.[ref]

Other research points to almost half of people with more severe cases of West Nile having long-term symptoms from it. The NLRP3 inflammasome activation is important in fighting off West Nile, as is interferon.[ref]

Long-haul COVID-19:

Research is beginning to emerge about post-infection lingering symptoms for the SARS-CoV-2 virus.

A recent follow-up study of people hospitalized for COVID-19 pneumonia show many having lingering symptoms including anxiety, fatigue, and muscle pain. Women were affected more than men. The researchers concluded “We suggest that the phenomenon of Long-COVID may not be directly attributable to the effect of SARS-CoV-2, and believe the biopsychosocial effects of COVID-19 may play a greater role in its aetiology.”  The researchers go on to say “we question whether Long-COVID exists as a new disease with distinct pathophysiology. We suggest it is a new manifestation of a well-recognized phenomenon that can be observed after other traumatic events, as opposed to the persistent effect of COVID-19.”[ref]

Hmmm…that reminds me a lot of initial assumptions about chronic fatigue syndrome being a psychiatric condition or the ‘yuppie flu’.

Another research study found that about 17% of COVID-19 patients continued to have fatigue symptoms after their illness. About 3% met the criteria for CFS/ME. The researchers also included PTSD in the study and found no overlap between the patient with PTSD and CFS/ME.[ref]

A May 2021 study sheds more light on the similarity between Long COVID, ME/CFS, and chronic viral fatigue.  The study found that 67% of the long COVID patients had reactivated Epstein-Barr virus titers (compared to only 10% in the control group). Symptoms of Epstein-Barr virus (fatigue, brain fog, sleep problems, muscle aches, headaches, gastrointestinal issues, and skin rash) overlap completely with long COVID symptoms.[ref]


Genetic variants related to fatigue syndromes after a viral infection:

The research studies for CFS/ME, fibromyalgia, and other post-viral conditions show a theme of an altered immune system response. That theme is carried out further when you look at the genetic variants linked to an increased susceptibility to those conditions. Some of these immune system genetic variants also overlap with autoimmune diseases and the response to different pathogens.

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Genes related to chronic fatigue syndrome:

PTPN22 gene: regulates the immune system through impacting T cell activation and B cell auto-reactivity. It acts as a negative regulator, dampening T cell activation. Additionally, PTPN22 impacts innate immunity through promoting interferon I production. (Read more about PTPN22)

The rs2476601 R620W variant is a well-studied link to autoimmune diseases with over 1,000 studies that reference it. The variant increases susceptibility to vitiligo[ref], Graves’ disease, type 1 diabetes[ref], Meniere’s disease[ref], juvenile arthritis[ref] psoriasis[ref] and endometriosis[ref]

Check your genetic data for rs2476601 R620W (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: increased risk of autoimmune diseases, increased susceptibility to CFS/ME (in patients with infectious disease onset)
  • A/A: increased risk of autoimmune diseases,  increased susceptibility to CFS/ME (in patients with infectious disease onset)[ref]

Members: Your genotype for rs2476601 is .

CTLA4 gene: codes for a protein that acts as a checkpoint that can downregulate your immune system response. CTLA4 is active in regulatory T cells (Tregs), which are the part of the immune system that maintains your tolerance to self-antigens. The variant below is linked to an increased risk of Grave’s[ref], myasthenia gravis[ref], type 1 diabetes[ref][ref], and celiac[ref].

(Read more about CTLA4)

Check your genetic data for rs3087243 60C/T (23andMe v4, v5; AncestryDNA):

  • A/A: typical risk of autoimmune conditions
  • A/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased risk  of CFS/ME (patients with infectious disease onset only)
  • G/G: increased risk of autoimmune conditions, decrease CTLA4 expression; increased susceptibility to CFS/ME (patients with infectious disease onset)[ref]

Members: Your genotype for rs3087243 is .

TNF gene: codes for an inflammatory cytokine produced by the immune system cells (macrophages) during acute inflammation. The main role of this cytokine involves signaling for ‘apoptosis’ meaning the cell needs to be destroyed. (Read more about TNF-alpha)

Check your genetic data for rs1799724 -857C/T (23andMe v4, v5):

  • T/T: (generally) higher TNF-alpha levels[ref][ref], increased susceptibility to CFS/ME[ref]
  • C/T: somewhat higher TNF-alpha levels, increased susceptibility to CFS/ME
  • C/C: typical – generally not at higher risk for inflammatory diseases

Members: Your genotype for rs1799724 is .

INFG gene: interferon-gamma is part of the innate defense against viral pathogens

Check your genetic data for rs2430561 +874T>A (23andMe v5; AncestryDNA):

  • T/T: common genotype, lower IFN producers; increased susceptibility to CFS/ME[ref]
  • A/T: higher interferon-gamma producers
  • A/A: higher interferon-gamma producers[ref] increase inflammatory response to EBV[ref]

Members: Your genotype for rs2430561 is .

NRLP3 Inflammasome Related Variants:

Activation of the NLRP3 inflammasome includes the release of  IL-1β and IL-18.[ref] The NLRP3 inflammasome is activated by various stimuli that include viruses (coronavirus, influenza), fungi (Candida), and certain bacteria. Additionally, it is activated by β-amyloid plaques (Alzheimer’s), uric acid crystals, and extracellular ATP (tissue damage).[ref][ref]

NLRP3 gene: codes for NLR family pyrin domain containing 3, a part of the innate immune system. This protein is found in macrophages and when activated triggers an immune response.

Check your genetic data for rs35829419 (AncestryDNA):

  • C/C: typical
  • A/C: more likely to have fatigue and pain after EBV or Q fever virus[ref]; greater severity in sickle cell[ref]; increased susceptibility to  leprosy, colorectal cancer, HIV-1 infection, rheumatoid arthritis, abdominal aortic aneurysms, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis[ref]
  • A/A: more likely to have fatigue and pain after EBV or Q fever virus[ref]; greater severity in sickle cell[ref]; increased susceptibility to  leprosy, colorectal cancer, HIV-1 infection, rheumatoid arthritis, abdominal aortic aneurysms, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis[ref]

Members: Your genotype for rs35829419 is .

Check your genetic data for rs121908147 V20M (AncestryDNA):

  • G/G: typical
  • A/G: carrier of one copy of a mutation linked to autoinflammatory disease in combination with other mutation[ref]

Members: Your genotype for rs121908147 is .

Natural killer cell-related variants:

Research on CFS/ME, regardless of cause, points towards natural killer cells being off-kilter.

TRPM8 gene: Transient receptor potential cation channel subfamily M (melastatin) member 8 (cold menthol receptor) that is a sodium and calcium ion channel. Its activation occurs both by menthol and by cold exposure.

Check your genetic data for rs11563204 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: increased risk of CFS/ME
  • A/A: increased risk of CFS/ME[ref]

Members: Your genotype for rs11563204 is .

TRPM3 gene: calcium ion channel that impacts function on natural killer cells

Check your genetic data from rs6560200 (23andMe v4):

  • C/C: (common genotype) higher risk of CFS/ME[ref][ref] *see lifehacks: Naltrexone
  • C/T: typical risk
  • T/T: typical risk

Members: Your genotype for rs6560200 is .

Check your genetic data for rs1891301 (AncestryDNA):

  • T/T: higher risk of CFS/ME[ref][ref] *see lifehacks: Naltrexone
  • C/T: typical risk
  • C/C: typical risk

Members: Your genotype for rs1891301 is .

Complement system genetic variants

Note that these variants in the complement system, part of the innate immune system, also impact the risk of age-related macular degeneration (AMD). Overactivation of the complement system causes damage in AMD, while the alleles with links to lower complement system activation have links to CFS/ME.

CFB gene:

Check your genetic data for rs4151667 (23andMe v4, v5):

  • A/A: half the risk of AMD[ref] increased risk of CFS/ME[ref]
  • A/T: reduced risk of AMD, increased risk of CFS/ME
  • T/T: normal risk of AMD

Members: Your genotype for rs4151667 is .

CFH gene: codes for complement factor H, the ‘stop’ that regulates the activation of the complement system.

Check your genetic data for rs1061170 Y402H (23andMe v4, v5; AncestryDNA):

  • T/T: not at an increased risk for AMD; increased risk of CFS/ME[ref]
  • C/T: increased risk for AMD
  • C/C: increased risk for AMD (most common genotype in many population groups)[ref]

Members: Your genotype for rs1061170 is .


Lifehacks:

Please talk with your doctor before starting any diet or supplements. What works in research studies may not be right for your individual case!

Specific interventions:

TNF Inhibitors (PTPN22 variant): It may be that inhibiting TNF-alpha could help with autoimmune diseases or CFS/ME for some people with the PTPN22 variants. Read more about TNF-alpha and natural inhibitors.

Naltrexone (TRMP3 variant): A 2019 cell study using CFS/ME cells from 8 different patients showed that Naltrexone restored TRPM3 function.[ref]  Keep in mind that this is just a cell study (not a randomized, double-blind placebo-controlled trial), but it may be worth talking with your doctor about this study, especially if you carry a TRPM3 variant linked to CFS.

Ketone metabolites (NLRP3 variant): β-hydroxybutyrate, a metabolite formed in ketosis, blocks the NLRP3 inflammasome.[ref] The body produces β-hydroxybutyrate on a ketogenic diet (low carb, high fat). Additionally, you can buy β-hydroxybutyrate supplements.

Parthenolide(NLRP3): Parthenolide, a plant compound found in feverfew, is a medicinal plant traditionally used to treat fever and inflammation.  Parthenolide has been shown to inhibit the activation of the NLRP3 inflammasome.[ref]

Boosting overall mitochondrial function:

L-carnitine: Carnitine is important in producing energy in the mitochondria, and people with CFS/ME often have low carnitine levels.  A clinical trial showed that l-carnitine supplementation improved the studied parameters in people with CFS/ME after a month.[ref]

CoQ10: People with CFS/ME often have lower levels of CoQ10, another molecule important in mitochondrial health. Supplementing with 150mg of ubiquinol, a form of CoQ10, improved cognitive function in people with CFS/ME.[ref]

Sleep / Circadian Rhythm: Sleep disruption is often a component of ME/CFS, fibromyalgia, and other long-term fatigue and pain syndromes. Important here: blocking blue-light before bedtime, sleeping on a regular schedule, and getting outside or exposure to bright light in the morning.  (Read more about circadian rhythm genes)

 


Related Articles and Genes:

Is inflammation causing your depression or anxiety?
Research over the past two decades clearly shows a causal link between increased inflammatory markers and depression. Genetic variant in the inflammatory-related genes can increase the risk of depression and anxiety.

Circadian Rhythm and Your Immune Response to Viruses
Our immune system’s response varies over the course of 24-hours. At certain times, we may be more resilient to fighting off viruses; at other times of the day, we may be more susceptible to pathogens.

Cortisol and HPA Axis Dysfunction
Cortisol is a hormone produced by the adrenal glands in times of stress, and it also plays many roles in your normal bodily functions. It is a multi-purpose hormone that needs to be in the right amount (not too high, not too low) and at the right time. Your genes play a big role in how likely you are to have problems with cortisol.

Top 10 Genes to Check in Your Genetic Raw Data
Wondering what is actually important in your genetic data? These 10 genes have important variants with a big impact on health. Check your genes (free article).

 


Videos:

Jackson Labs video on their current research

 

Video on research on ME/CFS diagnostic tests:

 

 

Central sensitization…



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.