Damage to the CNS by exogenous insults during critical periods in intrauterine, perinatal or early postnatal CNS development may lead to subtle or severe behavioral abnormalities. Viral pathogens constitute a significant portion of the defined teratogens to the nervous system; among the most devastating of human viral infections, HIV causes significant perinatal nervous system morbidity in children. Many congenital neurological or behavioral diseases of the CNS may have an as yet unidentified viral etiology. In this application we will enhance our understanding of the effects of perinatal virus infections on neuroanatomical development and behavior by studying an animal model of a virus infection of the developing nervous system: Lewis rats infected with Boma disease virus (BDV) as neonates. BDV infection in the perinatal period (up to the second postnatal day of life) is associated with persistent virus replication without encephalitis, and produces behavioral abnormalities (e.g. hyperactivity, hyper-reactivity and learning and memory disorders) neuroanatomical abnormalities in the hippocampus and cerebellum, and stunted growth. This model allows a unique opportunity to test the effects of virus replication in the developing nervous system in the absence of generalized nervous system destruction due to encephalitis. In this application we will evaluate the effects of neonatal BDV infection on morphological development of brain regions which undergo postnatal neurogenesis, the hippocampus and cerebellum, and determine BDV's effects on neuroblast division and neuronal migration in these areas. Behaviors specific to the cerebellum (e.g. motor) and hippocampus (e.g. memory and learning) will be tested in neonatally BDV-infected rats. We will discern the relative contributions of neonatal BDV infection upon abnormal brain development and abnormal neural function of persistently infected neurons by utilizing a model developed in our laboratory. Using the immunosuppressive drug, Cyclosporine A, to suppress encephalitic response to the virus, we can infect rats at or beyond critical points in brain and behavior development. We will also determine mechanisms for the pathogenesis of the anatomical and behavioral abnormalities in these rats, including viral tropism for the hippocampus on neonatal cerebellum. Finally, we will present evidence for BDV infection in humans and propose a new approach for the recovery of BDV from BDV-seropositive humans. Based on our work in the immunocompromised animal, bone marrow from HIV- infected BDV seropositive humans is a likely source from which to recover a human BDV-like agent. Finding a human BDV-like pathogen would make the study of BDV infection of direct medical relevance, in addition to its value as a model system.
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