Congenital brain damage due to intrauterine virus infections is a significant pediatric problem. 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 nervous system 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 potential neuroanatomical damage and resultant behavioral abnormalities that may occur following infection of infants with neurovirulent wild type or vaccine strains of mumps virus can lead to the development of tests to identify neurovirulent potential before vaccine release, such as RT-PCR tests for genetic correlates to neurovirulence. Notably, the information obtained in these studies will not only be useful for the development of non-neurovirulent mumps vaccines, but will likely be generalizable to other potentially neurovirulent vaccines (e.g., measles, Japanese encephalitis). We study the mechanisms by which wild type and vaccine strains of mumps virus selectively target the central nervous system and may cause 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). 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. Jeryl-Lynn (JL, vaccine strain, non-neurovirulent) has been plaque purified to two plaque phenotypes (small and large plaques). The JL vaccine will be passaged in neonatal Lewis rat brain, and the animals will be studied at each passage to identify the growth of a neurovirulent variant. The neurovirulent variant and nonneurovirulent parent strain will undergo sequence comparison to identify genomic changes associated with neurovirulence. Correlation between genomic changes and specific neuroanatomical and behavioral damage will be identified and mechanisms for this damage elucidated.
