PROJECT SUMMARY / ABSTRACT
Our broad, long-term objectives are to understand the fundamental properties and
operative mechanisms of infectious prion transmission, and ultimately to prevent
unpredictable recurrences of prion epidemics. This application focuses on chronic
wasting disease (CWD), a burgeoning, highly contagious cervid prion disease which has
attained global epidemic status. Understanding the properties of North American,
European, and Asian CWD prions is an important goal of this proposal. We propose
three Specific Aims to address our central hypothesis: that the conformationally protean
properties of CWD prions results in the evolution of strains with novel host range
properties, and unpredictable zoonotic potential. Our Lead Aim seeks to characterize the
transmission properties of emergent Norwegian and South Korean CWD prions. It builds
upon our preliminary findings that the strain properties of Scandinavian and North
American CWD prions are distinct. We will comprehensively assess and compare the
transmission properties emergent CWD prions from different geographic locations and
species using well characterized transgenic and novel gene-targeted mouse models
expressing prion protein (PrP) genes from susceptible species. In Aim II, we will assess
the conformational properties of novel CWD strains using innovative ELISA approaches
and monoclonal antibodies recognizing defined conformational epitopes. We will assess
the properties of CWD strains in cell culture models, and using cell free conversion
assays. We will define the amplitude and temporal accumulation of various CWD strains
in infected mice by titration in susceptible cells. Finally, using transgenic mouse
modeling, we will assess the effects of PrP polymorphisms on strain selection and
pathogenesis, and address the susceptibility of at risk species. In our final Aim, we will
compare the host-range properties, and zoonotic potential of CWD prions. Our
preliminary data describing novel Nor-CWD strains, and the possibility of detecting
additional emergent CWD strains, provide additional uncertainty as to whether CWD-
exposed humans, or species in contact with wild cervids, are at risk for developing novel
prion diseases. We will assess a variety of species barriers by challenging conventional
transgenic mouse models expressing PrP from various species including cattle, sheep,
and humans, with CWD prions. We will also address the role of CWD adaptation in
peripheral tissues on the human species barrier.