PROJECT SUMMARY / ABSTRACTOur broad, long-term objectives are to understand the fundamental properties andoperative mechanisms of infectious prion transmission, and ultimately to preventunpredictable recurrences of prion epidemics. This application focuses on chronicwasting disease (CWD), a burgeoning, highly contagious cervid prion disease which hasattained global epidemic status. Understanding the properties of North American,European, and Asian CWD prions is an important goal of this proposal. We proposethree Specific Aims to address our central hypothesis: that the conformationally proteanproperties of CWD prions results in the evolution of strains with novel host rangeproperties, and unpredictable zoonotic potential. Our Lead Aim seeks to characterize thetransmission properties of emergent Norwegian and South Korean CWD prions. It buildsupon our preliminary findings that the strain properties of Scandinavian and NorthAmerican CWD prions are distinct. We will comprehensively assess and compare thetransmission properties emergent CWD prions from different geographic locations andspecies using well characterized transgenic and novel gene-targeted mouse modelsexpressing prion protein (PrP) genes from susceptible species. In Aim II, we will assessthe conformational properties of novel CWD strains using innovative ELISA approachesand monoclonal antibodies recognizing defined conformational epitopes. We will assessthe properties of CWD strains in cell culture models, and using cell free conversionassays. We will define the amplitude and temporal accumulation of various CWD strainsin infected mice by titration in susceptible cells. Finally, using transgenic mousemodeling, we will assess the effects of PrP polymorphisms on strain selection andpathogenesis, and address the susceptibility of at risk species. In our final Aim, we willcompare the host-range properties, and zoonotic potential of CWD prions. Ourpreliminary data describing novel Nor-CWD strains, and the possibility of detectingadditional emergent CWD strains, provide additional uncertainty as to whether CWD-exposed humans, or species in contact with wild cervids, are at risk for developing novelprion diseases. We will assess a variety of species barriers by challenging conventionaltransgenic mouse models expressing PrP from various species including cattle, sheep,and humans, with CWD prions. We will also address the role of CWD adaptation inperipheral tissues on the human species barrier.