Molecular Neurobiology

, Volume 53, Issue 4, pp 2550–2571 | Cite as

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

  • Gerwyn Morris
  • Michael Berk
  • Ken Walder
  • Michael Maes


Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.


Immune Inflammation Oxidative stress Toll-like receptor Cognition Depression Chronic fatigue syndrome Neurology Psychiatry 



Chronic fatigue syndrome


Tumor necrosis factor




Nuclear factor-ΚB




Toll-like receptors


Pathogen-associated molecular patterns


Damage-associated molecular patterns


Mitogen-activated protein kinase


Reactive oxygen species


Reactive nitrogen species






Epstein-Barr virus


Chronic activated Epstein-Barr virus syndrome


Myalgic encephalomyelitis


Chronic EBV syndrome


Multiple sclerosis


MS retrovirus


Human herpes virus


T helper 2


Dendritic cells


B cell lymphoma 2


Bcl-2-associated X protein


Polymerase chain reaction


Nonstructural protein


Central nervous system


Cerebrospinal fluid


Transforming growth factor β1


Magnetic resonance imaging


Human cytomegalovirus


Nuclear factor erythroid 2 [NF-E2]-related factor 2


Mammalian target of rapamycin protein


Borrelia burgdorferi




Extracellular signal-regulated kinase


Cyclooxygenase 2


Stachybotrys chartarum


Reduced nicotinamide adenine dinucleotide


c-Jun N-terminal kinase


Forkhead box P3


Vomitoxin or deoxynivalenol


Signal transducer and activator of transcription 3


Inducible nitric oxide synthase



Conflict of Interest

The authors do not report any conflict of interest.


All authors contributed equally to the paper.


There was no specific funding for this specific study.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Gerwyn Morris
    • 1
  • Michael Berk
    • 2
    • 3
  • Ken Walder
    • 4
  • Michael Maes
    • 2
    • 5
  1. 1.Tir Na NogLlanelliUK
  2. 2.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  3. 3.Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  4. 4.Centre for Molecular and Medical Research, School of MedicineDeakin UniversityGeelongAustralia
  5. 5.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand

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