Measles virus causes significant morbidity and mortality in the human population. Despite a successful attenuated vaccine, measles virus still kills over one million children a year. The problem being that the vaccine is inefficient in children infected prior to their ninth month of age. This is believed due to the presence of maternal antibody and/or virus induced immunosuppression or other late effects following vaccination. Further, measles causes a hyperacute allergic disease and a chronic persistent (subacute sclerosing panencephalitis) neuronal disorder. Yet our understanding and knowledge of the molecular features of measles virus, the immunologic and immunopathologic responses to both infection and vaccination and how the virus persists in neurons are poorly understood. In order to understand the pathogenesis of measles virus infection and to identify the immune protective response, including B and T cell epitopes, we will develop and exploit a novel small animal model. We and our colleagues have identified the putative receptor for measles virus, the membrane cofactor protein (MCP, CD46). Measles virus is permissive for human and simian but not murine cells. However, murine MC57 and 3T3 cells barely permissive to measles virus become permissive and produce progeny virus when stably expressing any of the four CD46 isoforms, although isoform BC1 and BC2 are associated with a higher degree of syncytial formation. We propose expressing the cDNA of CD46 in mice under its own, a beta actin (universal) and cell-specific (neuron specific enolase, RIP) promoters. This will allow us to generate a transgenic model of measles virus in a small, inexpensive, genetically manipulable host, the mouse, whose immunologic response(s) can be easily manipulated. Transgenic mice expressing the measles virus receptor will be useful for studying measles virus pathogenesis including virulence, tissue tropism, eliciting immune responses in the presence or absence of adoptively transferred antibodies, for mapping human HLA restricted CTL epitopes using double transgenic mice expressing CD46 and HLA class I molecules, creating a subunit vaccine and for testing of newly developed vaccines.
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