PDF(Pubmed)
Abstract：
Infection by Japanese Encephalitis Virus (JEV) in humans is primarily characterized by signs and symptoms including non-specific febrile illness, arthralgia, myalgia etc. followed by its resolution due to joint action of host innate and adaptive immunity. However, in selective cases, complications arise owing to invasion of central nervous system (CNS) by JEV. Patients being unable to control peripheral viral replication owing to differences in host genetics and immunity experience JEV-associated neurological complications manifested in the form of headache, nausea, meningoencephalitis, coma and eventual death. Entry of JEV into CNS activates complex cascade of events resulting in loss of neuronal physiology and thus CNS tissue integrity. In present study, we have demonstrated role played by JEV in modulation of neuronal pyruvate dehydrogenase kinase 1 (PDK1) abundance and its effect upon neuronal health. Infection of neuron by JEV culminates into upregulation of PDK1 abundance. Albeit inhibition of JEV-induced PDK1-upregulation was accompanied by enhanced JEV propagation in neurons, abrogation of PDK1-upregulation was demonstrated to ameliorate neuronal apoptosis. PDK1 inhibition-associated reduction in neuronal death was observed to be associated with reduced generation of reactive oxygen species (ROS) in neurons. Our study hence provides a possible therapeutic target which upon modulation might help combat JEV infection-associated neuronal apoptosis via restoration of JEV-associated ROS generation.
摘要：
日本脑炎病毒（JEV）在人类中的感染主要表现为体征和症状，包括非特异性发热疾病，关节痛,肌痛等.其次是由于宿主先天免疫和适应性免疫的共同作用而导致的分辨率。然而,在选择性的情况下，JEV侵犯中枢神经系统（CNS）引起并发症。由于宿主遗传和免疫差异而无法控制外周病毒复制的患者会经历以头痛形式表现的JEV相关神经系统并发症，恶心,脑膜脑炎,昏迷和最终死亡。JEV进入CNS激活事件的复杂级联,导致神经元生理学丧失,从而导致CNS组织完整性丧失。在目前的研究中,我们已经证明了JEV在调节神经元丙酮酸脱氢酶激酶1（PDK1）丰度及其对神经元健康的影响中的作用。JEV对神经元的感染最终导致PDK1丰度的上调。尽管抑制JEV诱导的PDK1上调伴随着JEV在神经元中的传播增强，PDK1上调的废除被证明可以改善神经元凋亡。观察到PDK1抑制相关的神经元死亡减少与神经元中活性氧（ROS）的产生减少有关。因此，我们的研究提供了可能的治疗靶标，该靶标在调节后可能有助于通过恢复JEV相关的ROS生成来对抗JEV感染相关的神经元凋亡。
