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

Abstract

Lack of IFN-β 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-β and MHC class I gene expression requires NF-κB activation which depends on degradation of IκBα, an inhibitory protein of NF-κB. In earlier studies we demonstrated that in contrast to glial cells, MV was unable to induce IκBα degradation in neuronal cells. It is unclear whether this failure is due to the presence of a neuron-specific IκBα isoform or a defect in the MV signaling cascade that leads to IκBα phosphorylation and degradation. In this study, an IκBα-wild type (WT) expression vector was transfected into neuronal and glial cells and subsequently exposed to MV. In contrast to glial cells, IκBα-WT was degraded in neuronal cells in response to TNFα but not MV. The findings eliminate the existence of an IκBα isoform in neuronal cells that is resistant to phosphorylation by MV. Blocking de novo protein synthesis with cyclohexamide had no effect on neuronal IκBα, indicating that lack of degradation rather than increased synthesis is responsible for IκBα accumulation in MV-stimulated neuronal cells. To determine if malfunction in the MV receptor CD46 is responsible for failure of IκBα 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 IκBα degradation. Collectively these findings indicate that failure of MV to phosphorylate neuronal IκBα is not due to a presence of an IκBα 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 IκBα phosphorylation and degradation.