Finally our data found that the EBV dUTPase protein modulate
Finally, our data found that the EBV dUTPase protein modulates tryptophan, serotonin, and DA metabolism and use in vitro and in vivo. The EBV dUTPase may alter kynurenine catabolism in microglia in vitro, suggesting that there is an increase synthesis of quinolinic acid. Quinolinic acid, an agonist of NMDAR, can cause overstimulation that results in neuronal toxicity. The dopaminergic and serotonergic neurotransmitter systems are reported to play a critical role in the regulation of emotion and mood, and they have been implicated in a spectrum of neuropsychiatric disorders.59, 60
EBV replicates primarily in the tonsils/nasopharynx and sheds in the saliva. A number of reports have found that physical and/or psychosocial stress induces the reactivation of latent EBV. Burning mouth syndrome (BMS) is a chronic condition characterized by a burning sensation of the oral cavity that affects menopausal or postmenopausal women (50–70 years of age). In addition, these patients exhibit high levels of anxiety and depression.62, 63 Idiopathic BMS can occur spontaneously and without any identifiable precipitating factors. Although the exact mechanism or mechanisms involved in the pathophysiology of idiopathic BMS is unknown, evidence suggests that it may be a neuropathic condition affecting the peripheral nervous system and CNS. Clonazepam, a member of the benzodiazepine family, which is used for treatment of anxiety, is the preferred treatment option for patients with BMS because of its effect on the peripheral GABA A receptor. It has been found that nerve fibers on the tongue have high Estradiol Benzoate of GABA A receptors. Our study indicates that EBV dUTPase upregulates a subunit of the GABA A receptor and suggests a possible involvement of EBV in this syndrome, especially in an older population with a decreased immune capacity to control the virus.
Conclusions We are proposing that in a subset of patients with ME/CFS there is an increase in abortive lytic replication of EBV, especially in those patients exhibiting a diminished EBV-specific B and T-cell response, resulting in the increased release of EBV dUTPase possibly in exosomes. Activation of TLR2 by the EBV dUTPase in cerebral microvascular endothelial cells can disrupt the integrity of the BBB by inducing the downregulation of genes in cerebral microvascular endothelial cells that encode for products important for maintaining tight junctions between these cells and simultaneously inducing the upregulation IL-1β, IL-6, and TNF-α proinflammatory cytokines that disrupt the BBB. Disruption of the BBB allows the dUTPase protein to enter the CNS where ligation and activation of TLR2 by the dUTPase on astrocytes, microglia, mast cells, and possibly neurons would result in altered excitatory glutamatergic synapses and expression of genes whose products are involved in fatigue, pain, and cognitive responses all of which are altered in patients with ME/CFS. Recent studies have also found that secretion of IL-33 by microglia cells activates mast cells, resulting in the rapid secretion of TNF and sensitization of meningeal nociceptors. This cross-talk between microglia and mast cells may be an important process for explaining stress-induced neuroinflammation, a common feature in many neurologic conditions such as depression and anxiety. Although these findings are exciting, further studies are necessary to confirm that changes in gene expression equates with changes in protein levels and altered functionality. In addition, multiple test correction was not used, which may affect statistical comparisons. The results of this study provide exciting new data at the molecular level, suggesting a mechanism by which EBV dUTPase may modulate immune activation, disrupt the BBB, and alter the structure/function of neurologic synapses, resulting in loss of neurocognitive functions in a cohort of patients with ME/CFS.
Conflicts of interest