Effects of JC virus infection on anti-apoptotic protein survivin in progressive multifocal leukoencephalopathy.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system resulting from the productive infection of oligodendrocytes by the opportunistic polyomavirus JC virus (JCV). Apoptosis is a host defense mechanism to dispose of damaged cells; however, certain viruses have the ability to deregulate apoptotic pathways to complete their life cycles. One such pathway involves survivin, a member of the inhibitor of apoptosis family, which is abundantly expressed during development in proliferating tissues but should be absent in normal, terminally differentiated cells. Immunohistochemistry performed in 20 cases of PML revealed the presence of survivin in JCV-infected oligodendrocytes and bizarre astrocytes within demyelinated plaques. Survivin up-regulation was also found in oligodendroglial and astrocytic cultures infected with JCV. Cell cycle analysis and DNA laddering demonstrated a significantly lower number of cells undergoing apoptosis on JCV infection compared with noninfected cultures; small interfering RNA inhibition of survivin resulted in a dramatic increase in apoptotic cells in JCV-infected cultures. This is the first report describing the activation of survivin by JCV infection in vitro and in PML clinical cases. These observations provide new insights into the anti-apoptotic mechanisms used by JCV to complete its lytic cycle and may suggest new therapeutic targets for PML.
Piña-Oviedo
Sergio
S
Department of Neuroscience, Neuropathology Core, Temple University School of Medicine, 1900 North 12th St., Suite 240, Philadelphia, PA 19122, USA.
Urbanska
Katarzyna
K
Radhakrishnan
Sujatha
S
Sweet
Thersa
T
Reiss
Krzysztof
K
Khalili
Kamel
K
Del Valle
Luis
L
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001344:Autopsy; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D019311:Staurosporine