Despite an effective vaccine, measles virus (MV) infects more than 40 million persons per year, killing over one million annually. Issues imperfectly understood are MV induced-immunity, -immunosuppression and -persistent infection of the CNS (SSPE). Humans are the only natural host for MV and the unavailability of small animal models limits understanding its pathogenesis. Such a model would also be of value for designing strategies to modify and/or develop anti-MV therapies. The CD46 molecule has been identified as the high affinity receptor for MV. The P.I.'s hypothesis is that appropriate expression of the CD46 molecules in mice using transgenic (tg) technology will create a small animal model for study of MV pathogenesis. This hypothesis is based on three observations. First, cultured rodent cells not susceptible to MV infection can replicate MV, form syncytia and make infectious virus if they are transfected with and express the CD46 molecule. Second, tissues taken from CD46 tg mice and explanted in vitro are infectible and replicate MV progeny. Third, MV replicates and spreads in vivo in NSE-CD46 tg mice. The research plan is first to establish a small animal model for MV and second, to utilize it to study MV pathogenesis. With just over two years of NIH support, the P.I. developed two distinct tg models. In one mice express CD46 in neurons under control of the NSE promoter. Infection of these mice with MVs leads to viral replication and spread in neurons associated with tremors, seizures and paralysis leading uniformly to death. The P.I. proposes to use NSE-CD46 tgs with a variety of ko (destruction of interferon, CD4, CD8 and B lymphocyte genes) mice in concert with MV mutants made by reverse genetics to directly assess the role of individual MV genes, of the immune system and of interferons in MV pathogenesis. The other newly made tg mice express CD46 widely (genomic CD46, CD46 driven by CMV promoter). The P.I. anticipates that these mice will be of value for similar studies.
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