Since the developing nervous system is uniquely sensitive to damage following virus infection, postnatal CNS development during the first year of life provides continued susceptibility of the infant CNS to damage by viral infection after birth. Administering neurovirulent vaccines to infants also places the child's CNS at increased risk for injury. However, it is very difficult to predict which vaccines have significant neurovirulence potential for human CNS. Wild type mumps viruses are among the most neurotropic of the early childhood viruses. Mumps vaccine virus strains also have neurovirulence potential (e.g., Urabe Am9) and new MMR combinations continue to be proposed that include new strains of mumps vaccine virus. Thus, it is important to develop valid molecular biological, in vitro and in vivo models to evaluate the pathogenesis of the neurotoxic effects of vaccine viruses. Development of these models will lead to cost saving and improved predictability of neurovirulence testing, and information obtained in these studies about mumps virus vaccines will likely be useful in generalizing to other potentially neurovirulent vaccines (e.g., measles, Japanese encephalitis). Progress: 1. Molecular Markers of Neurotoxicity: We have identified vaccine virus-related perturbations in CNS gene expression by standard semiquantitative RT-PCR and by differential display techniques: CNS genes that are altered by the presence of viruses in the CNS include neurotrophic hormones, cellular adhesion molecules and molecules involved in metabolism. In addition, we have identified several genes, not previously known to be affected by CNS virus infection, that are responsible for immunological responses, nucleotide synthesis and cell migration in the CNS. We have sequenced gene products from new genes that are altered by virus infection of the brain. 2. 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 viruses. We have characterized autistic-like changes in neuroanatomy, neurological disease and behavior in these rats. 3. Pathogenesis of neurotoxicity of neurovirulent vaccine virus infections. We have documented a relationship between state of CNS maturity and neurotoxic effects of virus infection. 4. Pathogenesis of behavioral and anatomical developmental brain disease following neonatal virus infection. We have identified regional abnormalities in cytokines, cytokine receptors, neuropeptides and neurotransmitters in neonatally virus-infected rat brain.
