Journal article
Expression of anti-apoptotic survivin in glial cells of progressive multifocal leukoencephalopathy and activation of the survivin promoter in JCV infected cells
Journal of neurovirology, Vol.12
01 May 2006
Abstract
Progressive Multifocal Leukoencephalopathy (PML) is a sub-acute and fatal disease of the Central Nervous System, result of the productive infection of glial cells, particularly oligodendrocytes, by the opportunistic JC Virus. JCV is a human neurotropic virus, prevalent in the adult population world wide, with approximately 85 to 90% of the population exhibiting hemmaglutinating antibodies. Primary infection is sub-clinical and the virus remains in latent state presumably in the kidney, until its reactivation under immunosuppressive conditions, particularly in AIDS patients, to result in the lytic destruction of oligodendrocytes and in the development of PML. The lytic destruction of oligodendrocytes and the activation of astrocytes in response to the injury caused by JCV infection results in the characteristic histopathological landmarks of PML; extensive and confluent areas of myelin loss, in which numerous bizarre reactive astrocytes with atypical and pleomorphic nuclei, and enlarged oligodendrocytes harboring intra-nuclear eosinophilic inclusion bodies, which represent the site of active viral replication While apoptosis is a host defense mechanism to dispose of senescent or damaged cells, including virally infected cells, certain viruses have the ability to de-regulate apoptotic pathways in order to complete their vital cycles. One of these pathways involves a novel protein, Survivin, a member of the inhibitor of apoptosis gene family, which is abundantly expressed during development in embryonic proliferating tissues, but should be absent in terminally differentiated cells. Immunohistochemical experiments performed in a collection of 20 brain samples from patients with AIDS related PML and 2 cases of non-AIDS PML, revealed increased expression of Survivin in bizarre reactive astrocytes and in the intra-nuclear inclusion bodies of JCV infected oligodendrocytes. In addition, JCV infected primary astrocytic cell cultures demonstrated enhanced expression of Survivin by Westen Blot and immunocytochemistry compared to non-infected cultures, which lack expression of Survivin. Finally, in order to determine the activation of the Survivin promoter by JCV T-Antigen we performed Luciferase assays in human primary astrocytes co-transfected with either 1066 kb or 622 kb Survivin promoter constructs driving the Luciferase reporter gene, and two different amounts of a T-Antigen construct. Ectopic production of T-Antigen resulted in significant activation of the Survivin promoter transcription. Furthermore, it appears that activation of the Survivin promoter is directly proportional to the amount of T-Antigen present in the cells. This is the first time that expression of the anti-apoptotic Survivin is demonstrated in clinical samples of PML and in JCV infected glial cell cultures. Based on these observations we hypothesize that upon its reactivation, JCV attempts to prevent cells from entering the apoptosis pathway by activating the Survivin gene, which results in enhanced levels of Survivin expression. The presence of Survivin will in turn disrupt the apoptotic machinery and preventing infected cells from committing suicide, therefore allowing JCV to successfully complete its lytic cycle and resulting in the development of PML.
Metrics
2 Record Views
Details
- Title
- Expression of anti-apoptotic survivin in glial cells of progressive multifocal leukoencephalopathy and activation of the survivin promoter in JCV infected cells
- Creators
- T SweetS Pina-OviedoS RadhakrishnanK KhaliliL Del Valle
- Publication Details
- Journal of neurovirology, Vol.12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Epidemiology and Biostatistics
- Identifiers
- 991021448180204721