In addition to published articles listed below, manuscripts are submitted or in preparation for: a) Influenza virus neurotoxicity in humans correlates with in vivo replication and spread in neonatal rat brain. b) Vaccinia virus smallpox vaccine neurotoxicity can be identified with a newborn mouse assay using endpoints of day of death and percent survival. Vaccinia virus replicates persistently in the brain of surviving mice until anti vaccinia antibody rises in serum. c) Identification of mumps genomic changes associated with differences in neurovirulence have been identified on the N, P, M, F, HN and L genes. d) Identification of host brain responses to neurovirulent mumps virus strains: Molecular Markers of Neurotoxicity: We have identified mumps virus-related perturbations in CNS gene expression by standard semiquantitative RT-PCR and by differential display techniques, including endogenous immune mediators of the CNS. We have recovered un-characterized gene products from new genes that are altered by virus infection of the brain. We used RNase protection assay to compare changes in endogenous immune mediators in the CNS in animals infected with low and high neurotoxic strains of mumps virus, and demonstrated differences in cytokine expression that correlate with known neurotoxicity. e) Animal Models of CNS Diseases Following Childhood Virus Infection: Autism. Viruses are known etiologic agents of autism (e.g., rubella). Therefore, concerns are raised regarding a possible relationship between childhood vaccines and autism. Because no valid animal models existed to study the pathogenesis of the neuroanatomical and behavioral signs of autism, we developed a rat model of autism using neonatal infection with neurotropic viruse, Borna disease virus. We have characterized autistic-like changes in neuroanatomy, neurochemistry, neurological disease and behavior in these rats. In addition, we have identified regional and developmental changes in neurotransmitters, including serotonin and norepinephrine. A developmental study of damage to developing brain (e.g., cerebellum)in virus infected rats was performed demonstrating anatomical, behavioral and neurological consequences. We have now identified host genetic background features that affect neurotoxic outcomes.We have identified genomic changes in the G and L proteins associated with changes in neurotoxicity outcomes. f) We have begun establishing a mouse neurotoxicity assay for measles virus using mice transgenic for the human measles receptor, CD 46.
