Genetic Susceptibility and Biological Characterization of Chronic Wasting Disease

The Principal Investigator (PI) of this Investigator-Initiated Research Award proposal intends to study the variability in the prion protein gene. Such variability in the amino acid sequence can affect prion disease infections in two ways. First, the prion protein gene is the major genetic susceptibility factor for prion diseases. Thus, allelic variability in whitetail deer may result in varying susceptibility to chronic wasting disease (CWD). Second, deer expressing different prion proteins (PrPC)may produce, upon infection with CWD, abnonnal prion proteins with different biological properties. The PI proposes (1) to determine the prion protein sequence in infected and uninfected deer and the biochemical and transmission characteristics of resistance to the disease, and (2) to see if there are any signature glycofonns detectible, as has been done with bovine spongifonn encephalopathy. There are major strengths in the proposal. These are the first studies aimed at identifying potential transmission of CWD from deer to humans using transgenic mice expressing human PrP, and they are thus potentially highly relevant. Moreover, since CWD is epidemic in the area of investigation, the proposed research offers the hope of being able to select herds that may be resistant to infection. The investigators are in a unique position to have access to tissue samples from culled wild deer within Wisconsin. The proposal is well written. In addition, the technical expertise of one of the Coinvestigators in creating and utilizing murine transgenic PrP strains-coupled with the PI's experience with CWD in deerensures success on the technical level. A weakness is that, at this writing, although different PrP alleles have been identified in both CWD-infected and noninfected deer, there is no promise that the alleles, or those putatively identified in the study, will correlate to resistance or increased susceptibility to CWD in deer. If an absence of allelic resistance turns out to be true, it is not clear what the impact of the study will be. On balance, however, the panel rated the proposal as excellent. ThIS very strong proposal wIll address a number of quite significant questions regading CWD susceptibility within deer and the possibility of CWD crossing the species bamer.