Location: Virus and Prion Research
Project Number: 5030-32000-228-025-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Aug 1, 2026
End Date: Jul 31, 2028
Objective:
This Non-Assistance Cooperative Agreement (NACA) supports collaborative research to address chronic wasting disease (CWD), a fatal prion disease of wild and farmed cervids. The continued geographic expansion of CWD, together with the long-term environmental persistence of infectious prions, poses increasing threats to U.S. agriculture, wildlife resources, and ecosystem health. Under this agreement, ARS and the Cooperator will investigate the genetic determinants of CWD susceptibility and resistance in white-tailed deer, elk, and moose to improve disease detection, risk assessment, and science-based management. The project integrates in vitro prion amplification assays, cell culture systems, novel gene-targeted mouse models, and natural host studies to define how naturally occurring PRNP polymorphisms influence CWD pathogenesis.
Approach:
Approach 1. Characterization of cervid PRNP gene-targeted mouse models. ARS and the Cooperator will characterize novel gene-targeted mouse models expressing naturally occurring cervid PRNP polymorphisms associated with CWD susceptibility or resistance. These models will represent both homozygous and naturally occurring heterozygous genotypes. Mouse lines will be systematically characterized to verify allele expression and to compare PRNP expression profiles with those of the corresponding cervid species.
Approach 2. In vitro assessment of genotype-dependent prion susceptibility. Brain homogenates from the gene-targeted mouse models will serve as substrates for ultrasensitive protein misfolding cyclic amplification (PMCA). These studies will quantify the susceptibility of individual PRNP genotypes to CWD prion conversion by comparing prion amplification efficiency and replication kinetics among polymorphic variants. The results will establish an initial assessment of genotype-dependent susceptibility and resistance.
Approach 3. Validation in gene-targeted mouse models. The in vitro findings will be validated using the gene-targeted mouse models. Representative CWD isolates from endemic regions across North America will be used to evaluate genotype-associated differences in disease susceptibility, incubation period, disease progression, and prion strain properties. Comprehensive analyses will integrate clinical observations, neuropathology, biochemical characterization of prions, and complementary cell culture and in vitro assays to define the biological consequences of naturally occurring PRNP variation.
Approach 4. Validation in natural cervid hosts. To determine the biological relevance of the PMCA and mouse model findings, corresponding studies will be performed in white-tailed deer carrying selected PRNP genotypes. Deer will be longitudinally monitored through clinical assessments and quarterly collection of rectal biopsy, saliva, blood, and fecal specimens to evaluate disease progression and prion dissemination. Following necropsy, brain, lymphoid tissues, and additional target organs will undergo comprehensive biochemical, pathological, and molecular analyses to define prion strain properties and disease pathogenesis.
Collectively, these complementary in vitro, mouse, and natural host studies will determine whether naturally occurring PRNP variants confer meaningful resistance to CWD and will provide a mechanistic framework for genetics-based surveillance, risk assessment, and disease management.