Early Growth Response Gene Upregulation in Epstein-Barr Virus (EBV)-Associated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease exhibiting a variety of symptoms and affecting multiple systems. Psychological stress and virus infection are important. Virus infection may trigger the onset, and psychological stress may reactivate latent viruses, for example, Epstein-Barr virus (EBV). It has recently been reported that EBV induced gene 2 (EBI2) was upregulated in blood in a subset of ME/CFS patients. The purpose of this study was to determine whether the pattern of expression of early growth response (EGR) genes, important in EBV infection and which have also been found to be upregulated in blood of ME/CFS patients, paralleled that of EBI2. EGR gene upregulation was found to be closely associated with that of EBI2 in ME/CFS, providing further evidence in support of ongoing EBV reactivation in a subset of ME/CFS patients. EGR1, EGR2, and EGR3 are part of the cellular immediate early gene response and are important in EBV transcription, reactivation, and B lymphocyte transformation. EGR1 is a regulator of immune function, and is important in vascular homeostasis, psychological stress, connective tissue disease, mitochondrial function, all of which are relevant to ME/CFS. EGR2 and EGR3 are negative regulators of T lymphocytes and are important in systemic autoimmunity.

Keywords: EBV-induced gene 2 (EBI2); EGR1; EGR2; EGR3; Epstein–Barr virus (EBV); early growth response; immediate early gene; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Figure 1

Expression of Epstein–Barr virus (EBV) induced gene 2 (EBI2) (open rectangle), early growth response gene 1 (EGR1) (cross symbol), early growth response gene 2 (EGR2) (open diamond), and early growth response gene 3 (EGR3) (solid circle) mRNAs in peripheral blood mononuclear cells (PBMC) of 11 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients with previously documented upregulation of EBI2 gene [3]. The figure shows that ME/CFS patients with a high level of EBI2, also exhibit upregulation of EGR1, EGR2, and EGR3, implying that the EGR gene upregulation is linked with that of EBI2. In those ME/CFS patients with marked upregulation of EBI2, there was similarly marked upregulation of the EGR genes, with level of mRNA expression occurring in the order, from highest to lowest, EGR1, EBI2, EGR2, EGR3.