We study the mechanisms by which wild type and vaccine strains of mumps virus selectively target the central nervous system and damage the developing infant brain. Vaccine and wild type mumps strains are passaged in inbred neonatal rats in order to study anatomical damage to areas of the brain that undergo postnatal development (e.g., cerebellum and hippocampus). Mechanisms responsible for this damage are evaluated, including the death and functional damage to neurons and other brain cells, changes in expression of surface molecules and neurotrophin secretion important in neuronal migration and growth, and inflammatory mediators (e.g. cytokines, chemokines). Behavioral correlates of this damage are measured by specific neurobehavioral testing (e.g., activity levels, motor skills, spatial learning and memory). After characterization of neurovirulence potential, neurovirulent revertants of non-neurovirulent and non-neurovirulent revertants of neurovirulent vaccine and wild type mumps virus will undergo sequence analysis to identify molecular genetic correlates of neurovirulence. Brain damage due to intrauterine virus infections is the most common form of congenital disease. In addition, the brain continues to develop during the first year of postnatal life. Since the developing nervous system is uniquely sensitive to damage following virus infection, administering neurovirulent vaccines to infants can place the child's CNS at increased risk for vaccine related injury. Mumps virus, and certain strains of mumps vaccine (Urabe Am9, Leningrad 3), are among the most neurotropic of the early childhood viruses, and new MMR combinations continue to be proposed, including new strains of mumps vaccine virus. Identification of the specific neuroanatomical damage and resultant behavioral abnormalities that occur following infection of infants with wild type or vaccine strains of mumps virus can lead to sensitive tests to aid in vaccine strain selection. In addition, identification of molecular genetic correlates to neurovirulence can provide information to help eliminate neurovirulent vaccine strains before release to the public.
