Neuroteratogenic Mechanism of LCM Virus Infection

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DESCRIPTION (provided by applicant): This Research Career Award is a plan to foster the development of Dr. Daniel Bonthius into an independent neuroscientist. This Award is a two-year extension of a three-year parent Award. Dr. Bonthius is a pediatric neurologist with a special interest in the adverse effects of environmental agents, including congenital viral infections, on fetal brain development. His long-term career goal is to become a physician-scientist capable of making meaningful contributions in neuroteratology. The research techniques on which he will focus are those of molecular neurobiology, which are of key importance in the field of neuroteratology. Dr. Bonthius will acquire his new research skills through a combination of didactic courses, skills workshops, technical seminars, and through his research into the neuroteratology of lymphocytic choriomeningitis virus (LCMV) infection. LCMV is a prevalent virus, which can severely damage the developing human fetal brain. Injection of LCMV into the neonatal rat brain provides an excellent model system of human congenital LCMV infection. Dr. Bonthius will utilize this model system to study the neuroteratogenic mechanisms of the viral infection. Following inoculation of the neonatal rat, LCMV selectively infects four brain regions, which include the cerebellum, olfactory bulb, hippocampus, and periventricular region. In each of the four regions, LCMV induces unique forms of pathology with unique time courses. In the cerebellum, LCMV induces an acute destructive process, while in the olfactory bulb, the virus induces an acute hypoplasia. In the hippocampus, LCMV induces no acute pathology, but causes a delayed and severe dropout of dentate granule cells. In the periventricular region, LCMV induces no acute or delayed-onset pathology. The principal goal of this research is to identify the cellular and molecular mechanisms underlying these diverse pathologic changes. The types of immune cells involved in the pathologic processes will be identified. The role of cytokines, chemokines and nitric oxide overproduction will be explored. A second goal of the project is to explore the possibility that alpha-dystroglycan (alpha-DG) is the cellular receptor for LCMV. The topography of alpha-DG expression will be compared with the spatial distribution of LCMV infection. The importance of a-DG in influencing the tropism and infectivity of LCMV will be examined by blocking alpha-DG with an antibody prior to exposure of brain slices to LCMV.