Failure of measles virus to activate nuclear factor-kappa B in neuronal cells: implications on the immune response to viral infections in the central nervous system.
Neurons are postmitotic cells that foster virus persistence. These cells lack the HLA class I molecules required for clearance of infected cells. Previously, we showed that HLA class I is induced by measles virus (MV) on glial cells, which is primarily mediated by IFN-beta. In contrast, MV was unable to induce HLA class I or IFN-beta in neuronal cells. This failure was associated with lack of NF-kappa B binding to the positive regulatory domain II element of the IFN-beta promoter, which is essential for virus-induced IFN-beta gene activity. In this study, we demonstrate that the failure to activate NF-kappa B in neuronal cells is due to the inability of MV to induce phosphorylation and degradation of I kappa B, the inhibitor of NF-kappa B. In contrast, TNF-alpha induced degradation of I kappa B alpha in the neuronal cells, suggesting that failure to induce I kappa B alpha degradation is likely due to a defect in virus-mediated signaling rather than to a defect involving neuronal I kappa B alpha. Like MV, mumps virus and dsRNA failed to induce I kappa B alpha degradation in the neuronal cells, suggesting that this defect may be specific to viruses. Autophosphorylation of the dsRNA-dependent protein kinase, a kinase possibly involved in virus-mediated I kappa B alpha phosphorylation, was intact in both cell types. The failure of virus to induce I kappa B alpha phosphorylation and consequently to activate NF-kappa B in neuronal cells could explain the repression of IFN-beta and class I gene expression in virus-infected cells. These findings provide a potential mechanism for the ability of virus to persist in neurons and to escape immune surveillance.
Dhib-Jalbut
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Department of Neurology, University of Maryland at Baltimore, MD 21201, USA. sjalbut@umaryland.edu
Xia
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Rangaviggula
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H
Fang
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Lee
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D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D008459:Measles virus / Q000276:immunology* / Q000502:physiology* / Q000528:radiation effects; D009109:Mumps virus / Q000276:immunology / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009457:Neuroglia / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D019892:eIF-2 Kinase / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D019892:eIF-2 Kinase