Perinatal infections, including intrauterine viral and parasitic infections are major causes of central nervous system (CNS) disease in infants and children. In some instances, such as congenital human cytomegalovirus (HCMV), these infections occur relatively frequently. Current estimates suggest that congenital HCMV is the most common viral cause of CNS disease and mental retardation in the United States. Although HCMV is a well-described causes of perinatal infections, the pathogenesis of this infection is poorly understood. Studies in humans have been limited to observational studies and current animal models have provided few clues to the mechanism of CNS disease. We have developed a small animal model of perinatal infection that recapitulates several of the more distinct findings of CNS HCMV infection. In particular, we have shown that non-lytic viral infection of the brain is associated with maldevelopment of the newborn brain, including cerebellar hypoplasia and loss of normal granular neuron migration. Disease induction in these animals appears to require both virus replication in the brain and an inflammatory infiltrate in the meninges and parenchyma. In this proposal we will define the mechanisms of disease, including loss of normal cerebellar development that are associated with CNS virus infection. These studies will provide a greater understanding of the pathogenesis of perinatal infections and could lead to improved therapy of these potentially treatable causes of mental retardation.
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