Stress effects on virus protein induced inflammation and sickness behavior

项目总结/摘要 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种复杂的疾病，其特征在于： 深度疲劳，以及免疫和神经认知功能障碍。ME/CFS的病因和驱动因素 仍然是未知的，并且没有用于区分各种亚组的有用的生物标志物。我们的创新 该奖项前十年的研究表明，脱氧尿苷三磷酸 由EB病毒（EBV）编码的核苷酸水解酶（dUTR）和最近由人的核苷酸水解酶（dUTR）编码的核苷酸水解酶（dUTR）。 疱疹病毒6型（HHV-6）具有新的免疫调节和神经调节功能， 在ME/CFS患者亚组中观察到的病理生理学。在这次更新申请中，我们将继续 我们的机制研究，以确定的作用，EBV和HHV-6 dUTPases在ME/CFS。我们的整体 一种假设是，在一个亚组中，浆母细胞/浆细胞中EBV的失败复制增加， 遗传上易患ME/CFS的患者诱导EBV合成和释放增加 外泌体中的脱氧核糖核酸。含EBV dUTPaseexosomes与抗原上存在的TLR 2的连接- 局部微环境中的呈递细胞（APC）触发促炎性TH 1的产生 细胞因子以及激活素A，这反过来又刺激滤泡辅助性T细胞的分化和增殖， (TFH)细胞，导致IL-21的产生，这有助于在这些细胞中观察到的免疫功能障碍。 患者激活素A也是肌肉生长的负调节剂，我们认为它改变了肌肉生长的功能。 骨骼肌中的关键酶导致氧化应激和低能量水平，因此，有助于 ME/CFS患者的运动后疲劳特征。贩运含EBV dUTR的 外泌体进入脑和靶细胞上的TLR 2连接导致小胶质细胞活化，BBB破坏， 神经炎症和改变的突触可塑性最终导致这些患者的认知障碍。 最后，慢性应激会增强EB病毒dUTPase的这些生理作用。的结果 这项研究将证明EBV/HHV-6 dUTPases可能作为免疫激活的驱动因素， 在ME/CFS。它还可以鉴定EBV/HHV-6 dUTR蛋白作为诊断生物标志物，用于鉴定 ME/CFS患者亚组。最后，这些研究将证明EBV/HHV-6的参与 dUTR蛋白与TLR 2对于诱导神经免疫功能障碍是必需的，因此，这种相互作用可以 可用作开发替代治疗方法的新靶点。

Project Summary/Abstract Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disorder characterized by profound fatigue, as well as immune and neurocognitive dysfunction. The etiologies and the drivers of ME/CFS remain unknown and there are no useful biomarkers for distinguishing the various subgroups. Our innovative studies over the ten previous years of this award have demonstrated that the deoxyuridine triphosphate nucleotidohydrolases (dUTPase) encoded by the Epstein-Barr virus (EBV) and more recently by the human herpesvirus 6 (HHV-6) have novel immunoregulatory and neuroregulatory functions that contribute to the pathophysiology observed in a subgroup of patients with ME/CFS. In this renewal application, we will continue our mechanistic studies to define the role that the EBV and HHV-6 dUTPases have in ME/CFS. Our overall hypothesis is that the increased abortive replication of EBV in plasmablasts/plasma cells in a subgroup of patients genetically susceptible to developing ME/CFS induces the increased synthesis and release of EBV dUTPase in exosomes. Ligation of EBV dUTPase-containing exosomes with TLR2 present on antigen- presenting cells (APCs) in the local microenvironment triggers the production of pro-inflammatory TH1 cytokines as well as activin A, which in turn stimulates the differentiation and proliferation of follicular helper T (TFH) cells, resulting in IL-21 production, which contributes to the immune dysfunction observed in these patients. Activin A is also a negative regulator of muscle growth and we are proposing that it alters the function of key enzymes in skeletal muscle leading to oxidative stress and low energy levels thus, contributing to the post-exertional fatigue characteristic of patients with ME/CFS. Trafficking of EBV dUTPase containing exosomes to the brain and TLR2 ligation on target cells results in microglia activation, disruption of the BBB, neuroinflammation and altered synaptic plasticity ultimately leading to cognitive impairment in these patients. Finally, these physiological effects of the EBV dUTPase are enhanced by chronic stress. The results of this study, will demonstrate that the EBV/HHV-6 dUTPases may act as drivers of the immune activation that occurs in ME/CFS. It may also identify EBV/HHV-6 dUTPase proteins as diagnostic biomarkers for identifying a subset of patients with ME/CFS. Finally, these studies will demonstrate that engagement of EBV/HHV-6 dUTPase proteins with TLR2 is essential for inducing neuroimmune dysfunction and thus, this interaction can be used as a novel target for the development of alternative therapeutic approaches.