Mechanism of measles virus failure to activate NF-jB in neuronal cells

Lack of IFN-b and MHC class I expression in measles virus (MV) infected neurons could impair the host antiviral defense mechanism and result in virus escape from recognition by cytotoxic T-cells. Induction of IFN-b and MHC class I gene expression requires NF-jB activation which depends on degradation of IjBa, an inhibitory protein of NF-jB. In earlier studies we demonstrated that in contrast to glial cells, MV was unable to induce IjBa degradation in neuronal cells. It is unclear whether this failure is due to the presence of a neuron-speciŽc IjBa isoform or a defect in the MV signaling cascade that leads to IjBa phosphorylation and degradation. In this study, an IjBa-wild type (WT) expression vector was transfected into neuronal and glial cells and subsequently exposed to MV. In contrast to glial cells, IjBaWT was degraded in neuronal cells in response to TNFa but not MV. The Žndings eliminate the existence of an IjBa isoform in neuronal cells that is resistant to phosphorylation by MV. Blocking de novo protein synthesis with cyclohexamide had no effect on neuronal IjBa, indicating that lack of degradation rather than increased synthesis is responsible for IjBa accumulation in MV-stimulated neuronal cells. To determine if malfunction in the MV receptor CD46 is responsible for failure of IjBa phosphorylation and degradation, neuronal cells were transfected with a wild type CD46 (CD46-WT) expression vector. MV stimulation of CD46-WT transfected cells failed to induce IjBa degradation. Collectively these Žndings indicate that failure of MV to phosphorylate neuronal IjBa is not due to a presence of an IjBa isoform or malfunction of the MV receptor, and is more likely to be due to a defect in the signaling pathway that normally leads to IjBa phosphorylation and degradation. Journa l o f NeuroViro logy (2001) 7, 25 ± 34.