Comprehensive Phenotypic Profiling of Chronic Wasting Disease to Assess Transmissibility and Species Barriers

Project IV: Summary Background: Chronic wasting disease (CWD) is an infectious prion disease of cervids (elk, deer, moose, and reindeer) with no current treatment, few management tools, and lack of clarity regarding potential for transmissibility to humans. Overall goal: In this project, we will establish comprehensive phenotypic profiling in CWD diseased mouse models and investigate zoonotic barriers. Proposal: This project will expand critical scientific knowledge in an underexplored field of zoonotic diseases. Limited phenotypic analyses have made definitive diagnosis of CWD difficult, even though early diagnosis is crucial to reducing spread of disease in wildlife and aiding in understanding the zoonotic capabilities. We propose two aims to address this deficit of knowledge. In the first, we will establish comprehensive phenotyping profiling in cervidized mouse models (with CWD modulating genetics of mule deer). Extensive behavioral assessments will be performed, clinical biomarkers tracked, and a peripheral organ study will be performed to understand the course of disease better, thereby, contributing new strain information and early diagnostic tools which may inform strategies for management and therapies in the future. In the second, we will probe transmissibility of CWD to humans using novel knock-in mice carrying human PRNP inoculated with CWD. Innovation: We will develop new clinical capabilities in mouse models to explore the mechanisms, progression, and transmissibility of CWD. The uniqueness of this project is twofold. First, phenotyping assessments have been limited for CWD mouse models and have not translated to better or earlier diagnosis in wildlife. Due to the limitations with current methods, it is also still unknown if this disease is zoonotic. This will be the first comprehensive investigation of this type regarding CWD. Second, a limited number of studies in mouse models have been performed on the PRNP variant chosen, a particularly highly disease resistant polymorphism found in wild mule deer. Our studies of PRNP variants will aid in determining mechanisms of disease resistance and transmissibility factors. Significance: Immediate significance is in providing guidelines for earlier and efficient detection of prion disease manifestations. Additional significance: Investigating the phenotypes of mice with CWD modulating genetics may contribute vital information regarding disease characteristics already occurring in wild mule deer which may affect species barriers and disease outcomes.