Our long term research goal remains the same: to understand the mechanisms of inflammation and immune-mediated injury of the central nervous system (CNS). We are specifically interested in how immune effectors, cytokines and chemokines are generated within the CNS compartment and what role they play in CNS tissue injury. This application focuses on investigating the mechanisms by which neurotropic viruses induce cytokine and chemokine gene expression in glial cells by studying TNF and RANTES genes. Pro-inflammatory cytokine TNF is a potent effector in primary demyelination. RANTES, a chemokine that attracts T cells, monocytes and dendritic cells, is expressed in EAE brains, and correlates with disease activity. RANTES was recently reported to inhibit HIV replication in CD4+ T cells, a finding that may be related to the relative resistance of CD4+ T cells to HIV-exposed but uninfected individuals. We will use Newcastle Disease virus (NDV) and measles virus (MV). We used NDV previously to study the transcription and mRNA stability of cytokines and MV will be especially useful to delineate the receptor-ligand induced, and dsRNA-mediated signaling for RANTES gene induction, because the MV receptor CD46 has been recently defined. Previous studies in our laboratory have shown that NDV induces a variety of cytokines/chemokines in primary rat astrocytes and microglia. We also showed that MV induces RANTES in a human glioma cell line and human primary monocytes. We want to investigate: (1) The mechanisms of virus-induced TNF mRNA stabilization in astrocytes by identifying the stabilizing RNA sequence, characterize the RNA-binding proteins, and investigating the role of virus-induced kinase activity in mRNA stability. (2) The mechanisms of virus-induced RNATES gene transcription in glial cells will be explored by defining the virus response elements (VRE) of RANTES promoter in astrocytes and the VRE-binding proteins required for the transcription. (3) Signaling required for MV-induced RANTES gene expression in glial cells will be examined by defining the requirement of CD46 receptor coupling by MV and intracellular signaling required for RANTES gene expression, using rat astrocytes expressing wild CD46 or CD46-GPI chimeric receptors through transfection. In addition, we will also explore the ability of RANTES to inhibit MV replication in astrocytes.
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