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Chronic Fatigue
Syndrome Research

Research in our lab has led us to the conclusion that CFS is not a problem with energy “deficiency”. It is a problem with cellular energy “distribution” and reserve capacity regulated by changes in mitochondrial function.

What is ME/CFS?

Research in our laboratory supports the hypothesis that,  “ME/CFS is a human dauer syndrome that is maintained by persistent activation of the cell danger response (CDR) through purinergic signaling.”  Dauer syndromes are common in Nature as a hypometabolic response to life-threatening environmental factors like infection, trauma, famine, hypoxia, and seasonal change. The biology of dauer is mutlifaceted and ancient and overlaps with hibernation, torpor, estivation, and diapause.  Post-chemotherapy and post-COVID (long-hauler) fatigue syndromes, and post-treatment Lyme disease syndrome (PTLDS) tap into the same biology.  Mitochondria are located at the hub of the wheel of metabolism and help coordinate and maintain the metabolic changes found in ME/CFS and dauer.   All stressed cells release ATP through channels in the cell membrane. Once outside the cell, ATP binds to receptors called “purinergic receptors” to change gene expression, trigger inflammation, initiate the healing cycle, and decrease mitochondrial oxygen consumption by decreasing oxidative phosphorylation.  Direct injection of ATP in mice has been shown to decrease mitochondrial oxygen consumption and energy production by 74% and triggers changes in over 30 different metabolic pathways. Our research suggests that the repeating loop ME/CFS symptoms might be broken by treatment with a new class of medicines called antipurinergic drugs.  One of these is a drug called suramin, which will be tested in a randomized clinical trial in ME/CFS patients in 2022.

 

Commonly used clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) include the Fukuda1, Canadian2, and Institute of Medicine, now known as the National Academy of Medicine (NAM)3 criteria (Box 1). These clinical criteria are essential for accurately identifying possible cases ME/CFS. However, the accuracy of clinical diagnosis is improved when additional objective testing is available. In our studies of genetic forms of mitochondrial disease we developed a novel mass spectrometry-based method that allows us to measure over 500 molecules in the blood. Some people have likened these NextGen metabolomics methods to a new lens, like the Hubble telescope, that allow us to see deeper and with greater clarity into the universe of the cell than has been possible before.

 

Box 1

Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

All 3 of the following core symptoms must be present:

  1. Life altering fatigue lasting for more than 6 months
  2. Post-exertional malaise
  3. Unrefreshing sleep

One of the following two symptoms must be present:

  1. Episodes of cognitive impairment (sometimes called “brain fog”)
  2. Postural orthostatic tachycardia syndrome (POTS)

In our first studies of CFS4 we answered 3 basic questions:

  1. Can NextGen Metabolomics be used to assist with the diagnosis of CFS? A: Yes.
  2. Can the chemical information provided by metabolomics be used to help with the development of treatment plans that are tailored to the individual? A: Not yet.  A new method of dynamic metabolomic analysis (DMA) is needed. See below.
  3. Does a systems analysis of the metabolic abnormalities found in CFS lead us to a better understanding of the root biology underlying the disease? A: Yes.  ME/CFS is a chronic physiologic reaction to a perfect storm of severe environmental threats.  It is a dauer-like metabolic syndrome that can be caused by at least 50 different triggers.  ME/CFS prevents the orderly progression of the normal steps of healing5, and causes life-long pain and disability4. If ME/CFS is truly like dauer6, then the biological clock of aging is slowed during illness7, but in a perverse twist of medical fate, without relief from long-term disabling symptoms.

(Open Access link) (PDF) (UC San Diego Press Release).

In our next studies of ME/CFS8 we showed:
 
  1. The serum of patients with ME/CFS contains an activity that fragments mitochondria and depletes cellular ATP, causing energy depletion.  This activity can be detected in a new assay system that was developed in collaboration with Dr. Bhupesh Prusty in Würzburg, Germany.
  2. The cell danger response (CDR) can be triggered in cultured cells in the lab by exposing them to environmental chemicals or metabolic stress.  When the CDR is triggered in cells that contain an integrated copy of human herpes virus 6 (iHHV-6), a small piece of the HHV-6 RNA can be reactivated. This causes cells in the laboratory to secrete an activity that is indistinguishable from the energy-depleting activity found in ME/CFS serum.
  3. Although the secreted CDR-factors cause energy depletion and mitochondrial fragmentation, they also lead to a profound antiviral effect, protecting cells from many kinds of viral infection.  This was measured in laboratory cells by challenging them with influenza virus and herpes simplex virus 1 (HSV1).
  4. We think the CDR-activating factors that can be transferred to healthy cells in the lab from ME/CFS patient serum, and from the medium from iHHV-6 containing cells in the lab, are responsible for the post-exertional malaise (PEM) that is so devastating to patients with ME/CFS.

 

Video Links

NIH ME/CFS Symposium, “Accelerating ME/CFS Research”, April 4, 2019

Day 1: https://www.youtube.com/watch?v=1emsA2CcRK4

Day 2:  https://www.youtube.com/watch?v=7bEuwoo3s3s

Dr. Naviaux’s Talk on ME/CFS, Book 2 of Medicine, and the healing cycle is time stamped: 55:00 to 1:28:15 on Day 1.

Dr. Komaroff’s ME/CFS research summary is time stamped: 6:02:43 to 6:51:15 on Day 2

New Research

In new research funded by the Steven and Alexandra Cohen Foundation and private donors, we will be using advanced methods in targeted metabolomics and exposomics to answer the following questions:

  1. Can metabolomics and exposomics be used to diagnose acute Lyme disease?
  2. Can these methods predict who is at increased risk to develop PTLDS?
  3. Is there an overlapping chemical signature in PTLDS and ME/CFS?
  4. Can a new test called “Serial Metabolomic Analysis” be used to personalize metabolomic results, identify subtypes, and predict outcomes in Lyme or ME/CFS?
  5. Rules of treatment discovery in complex disease

References

  1. Fukuda, K., et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 121, 953-959 (1994).
  2. Carruthers, B.M., et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of chronic fatigue syndrome 11, 7-115 (2003).
  3. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Vol. http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx (The National Academies Press, Washington, DC, 2015).
  4. Naviaux, R.K., et al. Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America 113, E5472-5480 (2016).
  5. Naviaux, R.K. Metabolic features and regulation of the healing cycle-A new model for chronic disease pathogenesis and treatment. Mitochondrion 46, 278-297 (2019).
  6. Ewald, C.Y., Castillo-Quan, J.I. & Blackwell, T.K. Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling. Gerontology 64, 96-104 (2018).
  7. Naviaux, R.K. Incomplete Healing as a Cause of Aging: The Role of Mitochondria and the Cell Danger Response. Biology (Basel) 8(2019).
  8. Schreiner P, Harrer T, Scheibenbogen C, Lamer S, Schlosser A, Naviaux RK, Prusty BK (2020) Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Immunohorizons 4:201-215 (2020).
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