Viruses can enter the central nervous system (CNS) via the olfactory neuroepithelium. With one such virus, vesicular stomatitis virus, infection can result in lethal encephalitis or in the host's ability to activate both innate and acquired immune responses and clear the infection. Viral infections of the CNS occur in an immunologically privileged site. Further, neurons, which do not normally express major histocompatibility antigens, cannot be recognized by T lymphocytes performing immune surveillance for viral antigens. Viral replication can modify cellular metabolism, sometimes leading to initiation of apoptosis, resulting in the death of that cell. Infections in the CNS can directly or indirectly, through parenchymal cell products, alter the microenvironment. The new gene expression can be beneficial in alerting the innate and acquired immune system or can be pathologic, triggering physiological changes in CNS systems such as the permeability of the blood brain barrier (BBB). In this renewal application, the aims are: 1) the signals important for recruitment of inflammatory cells (sequentially NK, macrophages, and T cells) to the olfactory bulb, the site of infection, 2) the mechanisms by which VSV infection alters the BBB, and 3) further examination of the roles of distinct isotypes of NOS in mice infected with VSV. This work builds on previous studies on the recovery-promoting benefit of IL-12 administration and the mechanism of cytokine-mediated antiviral activities in neurons, funded by the application being renewed. The proposed studies will be carried out using molecular biological approaches (rt-PCR, RNAse protection, in situ hybridization), immunohistochemistry, knockout strains of mice, and drug treatment specific for enzyme systems to be explored such as production of leukotrienes and activation of C5a. Potentially important biological molecules, which will be investigated include IL-12, chemokines, prostaglandins, leukotrienes, vascular endothelial growth factor, and complement C5a. This work has both basic and clinical applications, as viral encephalitis and pathological changes in the BBB are important medical problems.
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