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

Abstract

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.

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Fig. 1

Abbreviations

CFS:

Chronic fatigue syndrome

TNFα:

Tumor necrosis factor

IL:

Interleukin

NF-ΚB:

Nuclear factor-ΚB

IFN:

Interferons

TLR:

Toll-like receptors

PAMPs:

Pathogen-associated molecular patterns

DAMPs:

Damage-associated molecular patterns

MAPK:

Mitogen-activated protein kinase

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

4-HNE:

4-Hydroxynonenal

MDA:

Malondialdehyde

EBV:

Epstein-Barr virus

CAEBV:

Chronic activated Epstein-Barr virus syndrome

ME:

Myalgic encephalomyelitis

CEBVS:

Chronic EBV syndrome

MS:

Multiple sclerosis

MSRV:

MS retrovirus

HHV:

Human herpes virus

Th2:

T helper 2

DCs:

Dendritic cells

Bcl2:

B cell lymphoma 2

BAX:

Bcl-2-associated X protein

PCR:

Polymerase chain reaction

NS1:

Nonstructural protein

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

TGF-β1:

Transforming growth factor β1

MRI:

Magnetic resonance imaging

HCMV:

Human cytomegalovirus

Nrf2:

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

mTOR:

Mammalian target of rapamycin protein

Bf:

Borrelia burgdorferi

PG:

Prostaglandin

ERK:

Extracellular signal-regulated kinase

COX-2:

Cyclooxygenase 2

SC:

Stachybotrys chartarum

NADH:

Reduced nicotinamide adenine dinucleotide

JNK:

c-Jun N-terminal kinase

FoxP3:

Forkhead box P3

DON:

Vomitoxin or deoxynivalenol

STAT3:

Signal transducer and activator of transcription 3

iNOS:

Inducible nitric oxide synthase

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Morris, G., Berk, M., Walder, K. et al. The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability. Mol Neurobiol 53, 2550–2571 (2016). https://doi.org/10.1007/s12035-015-9262-7

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Keywords

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