Rubella virus-induced apoptosis varies among cell lines and is modulated by Bcl-X-L and caspase inhibitors

Rubella virus (RV) causes multisystem birth defects in the fetuses of infec ted women. To investigate the cellular basis of this pathology, we examined the cytopathic effect of RV in three permissive cell lines: Vero 76, RK13, and BHK21. Electron microscopy and the TUNEL assay showed that the cytopat hic effect resulted from RV-induced programmed cell death (apoptosis) in al l three cell lines, but the extent of apoptosis varied among these cells. A t 48 h postinfection, the RK13 cell line showed the greatest number of apop totic cells, the Vero 76 cell line was similar to 3-fold less, and BHK21 ha d very few. An increased multiplicity of infection and longer time postinfe ction were required for the BHK21 cell line to reach the level of apoptotic cells in Vero 76 at 48 h. Purified RV induced apoptosis in a dose-dependen t fashion, but not UV-inactivated RV or virus-depleted culture supernatant Specific inhibitors of the apoptosis-specific proteases caspases reduced RV -induced apoptosis and led to higher levels of RV components in infected ce lls. To address the role of regulatory proteins in RV-induced apoptosis, th e antiapoptotic gene Bcl-2 or Bcl-X-L was transfected into RK13 cells. Alth ough a high level of Bcl-2 family proteins was expressed, no protection was observed from apoptosis induced by RV, Sindbis virus, or staurosporine in RK13 cells. In BHK21 cells, however, increased expression of Bcl-X-L protec ted cells from apoptosis. The observed variability in apoptotic response to RV of these cell lines demonstrates that programmed cell death is dependen t on the unique properties of each cell and may be indicative of how select ive organ damage occurs in a congenital rubella syndrome fetus.