Involvement of Survivin in the Development of PML

描述（由申请方提供）：JC病毒是多瘤病毒家族的成员，是进行性多灶性白质脑病（PML）的公认病原体，PML是一种中枢神经系统（CNS）的致死性脱髓鞘疾病，常见于基础免疫抑制疾病患者。艾滋病大流行后，PML病例急剧增加，PML曾被认为是一种与白血病和淋巴瘤相关的罕见疾病，现在，PML被认为是艾滋病的定义条件。初次感染后，病毒最可能在肾脏中保持潜伏状态，在免疫抑制下进入大脑并在少突胶质细胞中有效复制，CNS的髓鞘产生细胞主动感染星形胶质细胞。响应于γ JCV感染引起的损伤，少突胶质细胞的溶解性破坏和星形胶质细胞的活化导致PML的特征性组织病理学标志，广泛的髓鞘丢失区域，其中许多具有非典型和多形性核的奇异星形胶质细胞，和增大的少突胶质细胞细胞核内可见嗜酸性包涵体。处理受损或感染细胞的自然反应是程序性细胞死亡。决定细胞死亡和存活的内在机制取决于促凋亡蛋白和凋亡抑制剂之间的微妙平衡。我们在PML患者脑样本中的初步免疫组化数据显示，在奇异星形胶质细胞和JCV感染的少突胶质细胞的核内包涵体中，凋亡抑制剂家族的成员Survivin表达增加。这种蛋白质在胚胎增殖组织的发育过程中大量表达，但在终末分化细胞中不存在。据信，凋亡抑制的机制涉及半胱天冬酶（caspase）的失活，半胱天冬酶是程序性细胞死亡执行蛋白。我们的研究结果还表明，JCV感染的原代少突胶质细胞培养物显示增强表达的Survivin蛋白质印迹和免疫细胞化学。此外，感染细胞的细胞周期分析表明凋亡细胞的数量减少，并且Survivin的siRNA抑制导致凋亡的急剧增加。这些结果表明，JCV感染刺激Survivin的表达，其防止细胞凋亡，并刺激细胞存活以竞争其感染周期。

DESCRIPTION (provided by applicant): JC Virus, a member of the Polyomaviridiae family, is the well-established etiological agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease of the Central Nervous System (CNS), frequently seen in patients with underlying immunosuppressive conditions. After the AIDS pandemic, cases of PML, once considered a rare disease associated with leukemias and lymphomas, has dramatically ncreased and now, PML is considered and AIDS defining condition. After primary infection the virus remains in latent state most likely in the kidney, and under immunosuppression enters the brain and efficiently replicates in oligodendrocytes, the myelin producing cells of the CNS ad abortively infects astrocytes. The lytic destruction of oligodendrocytes and the activation of astrocytes in response to injury caused y JCV infection, result in the characteristic histopathological landmarks of PML, extensive areas of myelin loss, in which numerous bizarre astrocytes with atypical and pleomorphic nuclei, and enlarged oligodendrocytes harboring intra-nuclear eosinophilic inclusion bodies can be found. The natural response to dispose of damaged or infected cells is programmed cell death. The intrincate mechanisms that will decide between cell death and cell survival depend on the delicate balance between pro-apoptotic proteins and inhibitor of apoptosis. Our preliminary immunohistochemical data in brain samples from patients with PML revealed increased expression of Survivin, a member of the inhibitors of apoptosis family, in bizarre astrocytes and in the intra-nuclear inclusion bodies of JCV infected oligodendrocytes. This protein is abundantly expressed during development in embryonic proliferating tissues, but is absent in terminally differenciated cells. It is believed that the mechanism of apoptosis inhibition involves the inactivation of caspases, the programmed cell death executioner proteins. Our results also show that JCV infected primary oligodendroglial cell cultures show enhanced expression of Survivin by Western blot and immunocytochemistry. In addition cell cycle analysis of infected cells demonstrated a reduction in the number of apoptotic cells and siRNA inhibition of Survivin resulted in a dramatic increase in apoptosis. These results suggest that JCV infection stimulates the expression of Survivin, which prevents apoptosis, and stimulates cell survival in order to compete its infectious cycle.