br Conclusions br Conflicts of Interest br Introduction

Conclusions
Conflicts of Interest
Introduction Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem illness of unconfirmed cause. ME/CFS has largely been diagnosed from Fukuda CFS criteria and/or the Canadian ME/CFS criteria. The Institute of Medicine in 2015 proposed, in addition to a new name of systemic exertion intolerance disease, a new case criteria focused on chronic fatigue, postexertional fatigue, and orthostatic intolerance/cognitive deficits for patients with this disease. Neurocognitive dysfunction has been reported to occur in 85%–90% of patients with ME/CFS. Self-reporting and assessment by objective task performance tests have found that the cognitive problems include declining attention and concentration, slow information processing, and declining memory and learning of complex information. Several neuroimaging studies that used magnetic resonance imaging, functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography, and single photon emission computerized tomography have found structural and functional alterations in the brains of patients with ME/CFS.5, 6, 7, 8, 9 Studies that used positron emission tomography and whole-brain magnetic resonance spectroscopy found evidence of widespread neuroinflammation in the brains of patients with ME/CFS, which was associated with the severity of neuropsychologic symptoms. Although numerous models and hypotheses have been proposed to explain the neuroinflammation observed in patients with ME/CFS, the underlying mechanisms that contribute to this neuroinflammatory reaction(s) remain largely undefined.8, 12, 13, 14, 15 In more than one-half of patients with ME/CFS, onset is associated with acute flu-like symptoms, and multiple reports in the literature have suggested a role for viruses in ME/CFS,17, 18, 19 particularly Epstein-Barr (-)-p-Bromotetramisole Oxalate australia (EBV). However, further mechanistic studies to address a causal relationship between a virus and ME/CFS are missing and would be of high importance. In support of this premise, several studies have found that EBV can infect and undergo lytic replication in neuronal cell lines as well as primary human neurons and abortively replicates in human astrocytes. Although acute infections of EBV are known to cause neurologic complications in immunocompetent patients with infectious mononucleosis, generally, they are benign. Conversely, in patients co-infected with HIV-1, EBV is associated with primary central nervous system (CNS) lymphoma, which has a poor prognosis. EBV is also a risk factor in the development of multiple sclerosis,23, 24 a claim further supported by a recent study that found significant levels of EBV genomic DNA in B cells, astrocytes, and microglia cells in the brains of patients with multiple sclerosis. These studies focused on the virus, and none have addressed the possibility of a virus-encoded protein rather than the virus itself as the cause or driver of the pathologic features observed in these diseases. We have previously reported that the EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) protein, which is encoded by the BLLF3 gene and expressed during lytic/abortive-lytic replication of the virus, possesses functions that act as a pathogen-associated molecular pattern for Toll-like receptor (TLR) 2. Engagement of TLR2 by EBV dUTPase leads to the activation of nuclear factor κ light chain enhancer of activated B cells (NF-κB) and subsequent modulation of downstream genes involved in several cellular processes, including chronic inflammation, effector T-cell function, and neurotransmitter function.25, 26, 27, 28, 29, 30 We have also found that the EBV dUTPase can be secreted from B cells in exosomes, which function as intracellular messengers and can cross the blood–brain barrier (BBB). More important, we have found that EBV dUTPase induces anxiety and sickness behaviors in mice31, 32 and that patients with ME/CFS have increased serum levels of antibodies to the EBV dUTPase. The present study explored the contribution of EBV dUTPase protein, if any, in the neuroimmune dysfunction associated with ME/CFS with the use of in vitro and in vivo model systems.