Stress effects on virus protein induced inflammation and sickness behavior

项目摘要/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，其特征是 严重的疲劳，以及免疫和神经认知功能障碍。ME/CFS的病因和驱动因素 仍然未知，并且没有有用的生物标记物来区分不同的亚群。我们的创新 该奖项前十年的研究表明，脱氧尿苷三磷酸 EB病毒编码的核苷酸水解酶(DUTPase)，最近由人类编码 疱疹病毒6型(HHV-6)具有新的免疫调节和神经调节功能，有助于 观察了ME/CFS患者亚组的病理生理学。在本次续费申请中，我们将继续 我们的机制研究确定了EBV和HHV-6 dUTP酶在ME/CFS中的作用。我们的整体 假设EBV在浆母细胞/浆细胞中的流产复制增加 发生ME/CFS的遗传易感性患者诱导EBV合成和释放增加 外切体中的dUTP酶。含EB病毒dUTP酶外切体与抗原TLR2的连接 局部微环境中的递呈细胞(APC)触发促炎TH1的产生 细胞因子和激活素A，进而刺激卵泡辅助T细胞的分化和增殖 (TFH)细胞，导致IL-21的产生，从而导致在这些患者中观察到的免疫功能障碍 病人。激活素A也是肌肉生长的负调节因子，我们建议它改变功能 骨骼肌中的关键酶导致氧化应激和低能量水平，从而有助于 ME/CFS患者的劳后疲劳特征。含有EBV dUTPase的贩运 外切体进入大脑和靶细胞上的TLR2连接导致小胶质细胞激活，血脑屏障破坏， 神经炎症和突触可塑性改变最终导致这些患者的认知障碍。 最后，EBV dUTPase的这些生理效应会因慢性应激而增强。这样做的结果 研究将证明EBV/HHV-6 dUTPase可能是免疫激活的驱动因素 在ME/CFS中。它还可以将EBV/HHV-6 dUTPase蛋白鉴定为诊断生物标志物 ME/CFS患者亚组。最后，这些研究将证明EBV/HHV-6的参与 DUTPase蛋白与TLR2是诱导神经免疫功能障碍所必需的，因此，这种相互作用可以 可作为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.