IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection

Abstract

Background Chronic active Epstein Barr virus (EBV)-infection is characterized by mononucleosis like symptoms including fatigue, lymphadenopathy and/or hepatosplenomegaly and serologic evidence for ongoing EBV replication. Interferon-gamma (IFN-γ) triggers several antiviral mechanisms in target cells including the induction of indoleamine-2,3-dioxygenase (IDO), which degrades the essential amino acid tryptophan to kynurenine. Because tryptophan is a precursor of the neurotransmitter 5-hydroxytryptamine (serotonin), tryptophan depletion by IDO can cause mood disturbances in patients with chronic immune activation. Methods This study investigated the tryptophan metabolism in 20 patients with chronic active EBV-infection, who were followed up for 4 to 8 months and in 10 healthy age-matched controls. The clinical suspicion of chronic active EBV infection was verified by the presence of circulating antibodies against EBV early antigen (EA) and virus capsid antigen (VCA). Results Patients with detectable EBV–DNA had higher serum neopterin ( p < 0.01) and lower tryptophan concentrations ( p = 0.01) than EBV–DNA negative patients. Serum concentrations of neopterin, indicating Th-1 mediated immune activation via IFN-γ, were positively correlated to enhanced tryptophan degradation (rs = 0.650, p < 0.001) in patients, but not in healthy individuals. Patients suffering from more severe symptoms (as assessed by questionnaires) tended to have aggravated tryptophan degradation. Conclusion Our data show that EBV viremia is associated with cell-mediated immune activation and increased tryptophan degradation, which may partly account for the symptoms found in this disorder.