The inflammatory response to acute Sindbis virus (SV) infection of the central nervous system (CNS) has been characterized in a murine model. This disease is representative of arboviral encephalitis, and it serves as a model to study immune reactions within the CNS. Cerebrospinal fluid inflammation during SV encephalitis, which reaches a peak early in infection, is composed of T cells and natural killer cells. Parenchymal inflammation is maximal later, and appears more complex in cellular composition. The virus is subsequently cleared from the CNS, and mice with the wild-type infection recover uneventfully. The primary goal of the proposed experiments is to characterize the development of the CNS T cell response during SV encephalitis over the full course of the infection. Specific investigations will focus on detailed phenotypic study of T cells that infiltrate the CNS, as well as characterization of their functional properties. These include cytokine production as well as anti-viral proliferative and cytotoxic responsiveness. Other experiments will investigate the significance of preliminary findings which have shown that gamma delta plus T cells accumulate preferentially within the CNS, especially early in infection. Since the specific molecular interactions between T cells and cerebral capillary endothelial cells likely regulate lymphocyte extravasation into the CNS and the development of perivascular inflammation, further goals of this proposal will be to explore the nature of adhesion events between these two cell populations during acute encephalitis. This will be performed using both an in vitro cell adhesion assay between lymphocytes and tissue sections of brain parenchyma from infected animals, as well as with an in vivo assay of T cell homing into the CNS. Blocking experiments with monoclonal antibodies are planned in order to determine the relevant molecular interactions between T cells and CNS microvascular endothelium both in vitro and in vivo. The in vitro assay may also serve to screen for and identify presently uncharacterized receptor-ligand interactions that mediate binding in this setting. Exploring these features of T cells will be important for understanding not only the pathogenesis of acute viral encephalitis, but also other inflammatory conditions of the CNS which are presumed to be T cell-mediated.
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