Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Keywords: BLLF3; BRRF1; deoxyuridine triphosphate nucleotidohydrolase (dUTPase); epstein-barr virus (EBV); human herpesvirus 6 (HHV-6); immune dysfunction; myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 1

Model depicting how the combined effect of environmental insults, and stress in genetically susceptible individuals can trigger neurological, immune and metabolic dysfunction, which together could contribute to the symptomology observed in ME/CFS [4].

Figure 2

Hypothetical model depicting potential interactions between the EBV early proteins Na and dUTPase, encoded by BRRF1 and BLLF3, respectively, and their contribution to the immune dysfunction observed in patients with ME/CFS.

Figure 3

Effects of EBV dUTPase on gene expression in brains of female C57Bl/6 mice (6–8 weeks old) and the potential neurological circuits modulated with direct implications in ME/CFS. Genes in blue were significantly upregulated while those in red were significantly downregulated [120].

Figure 4

Diagram demonstrating the effect of EBV dUTPase on gene expression in immortalized primary human cerebral microvascular endothelial cells, astrocytes and microglia cells. Genes in blue were significantly upregulated while those in red were significantly downregulated when compared to controls [120].