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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Meegan, James M
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Scripps Research Institute
La Jolla
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Oldstone, M B A (2009) Modeling subacute sclerosing panencephalitis in a transgenic mouse system: uncoding pathogenesis of disease and illuminating components of immune control. Curr Top Microbiol Immunol 330:31-54
Zuniga, E I; Hahm, B; Oldstone, M B A (2007) Type I interferon during viral infections: multiple triggers for a multifunctional mediator. Curr Top Microbiol Immunol 316:337-57
Hahm, Bumsuk; Cho, Jae-Ho; Oldstone, Michael B A (2007) Measles virus-dendritic cell interaction via SLAM inhibits innate immunity: selective signaling through TLR4 but not other TLRs mediates suppression of IL-12 synthesis. Virology 358:251-7
Go, Eden P; Wikoff, William R; Shen, Zhouxin et al. (2006) Mass spectrometry reveals specific and global molecular transformations during viral infection. J Proteome Res 5:2405-16
Oldstone, Michael B A (2006) Viral persistence: parameters, mechanisms and future predictions. Virology 344:111-8
Tishon, Antoinette; Lewicki, Hanna; Andaya, Abegail et al. (2006) CD4 T cell control primary measles virus infection of the CNS: regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective. Virology 347:234-45
Trifilo, Matthew J; Hahm, Bumsuk; Zuniga, Elina I et al. (2006) Dendritic cell inhibition: memoirs from immunosuppressive viruses. J Infect Dis 194 Suppl 1:S3-10
Oldstone, M B A (2005) Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr Top Microbiol Immunol 296:1-17
Hahm, Bumsuk; Trifilo, Matthew J; Zuniga, Elina I et al. (2005) Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity 22:247-57
Oldstone, Michael B A; Dales, Samuel; Tishon, Antoinette et al. (2005) A role for dual viral hits in causation of subacute sclerosing panencephalitis. J Exp Med 202:1185-90

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