Neuroimmunologic Disorders Induced by Chronic Viral Infection

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DESCRIPTION (provided by applicant): Chronic viral infections of the central nervous system (CNS) can affect neuronal function resulting in behavioral and cognitive impairment. These virally induced CNS disturbances can occur in the absence of cytolysis and inflammation, an observation that has led to the hypothesis that viruses may contribute to a variety of CNS disorders of unknown etiology. Therefore, the interest in understanding the mechanisms whereby noncytolytic persistent viruses can contribute to CNS dysfunction. The prototypic Arenavirus lymphocytic choriomeningitis virus (LCMV) provides us with an important model system for the investigation of this problem. Mice with congenially acquired LCMV persistent infection (LCMV-cgPi) have impaired learning and memory associated with altered CNS gene expression in the absence of overt histopathological signs. Our overall hypothesis is that noncytolytic persistent viral brain infections can cause chronic activation of the host's innate immune defense mechanism, especially interferon-mediated responses, within the CNS. These host's responses fail to clear the virus, but their chronic activation causes changes in CNS gene expression that lead to disturbances in neuronal function, thus contributing to abnormal CNS function. Our specific aims are: 1. Determine the correlation between viral activity and altered gene expression in the brain of LCMV-cgPi mice. CNS gene expression profiling will be done using RNA isolated from individual LCMV-cgPi mice with similar brain viral distribution and load, both high and low, and compared to mock-infected control mice. Changes in CNS gene expression will be correlated with levels of infection. 2. Characterize LCMV-induced changes in brain gene expression. The regional and cellular expression pattern of identified candidate genes with altered CNS expression in LCMV-cgPi mice will be determined using IHC and ISH procedures, and correlated with infection at the single cell level. 3. Determine neuronal damage associated with long-term LCMV-cgPi. Synaptic and dendritic structures will be quantitatively evaluated using antibodies to synaptophysine and MAP2, and confocal laser scanning microscopy to assess abnormalities associated with LCMV-cgPi.