Investigation of Inoculation Routes on Chronic Wasting Disease Progression in Cervidized Mouse Model: A Foundation for Microbiota-Pathogenesis Research

Abstract

Chronic wasting disease (CWD) is an infectious and fatal prion disorder of cervids that is rapidly expanding across North America. Although extensively studied in natural hosts, the early tissue and route-specific events that govern prion seeding and amplification remain poorly defined. This thesis employed transgenic mice that express transgenic elk prion protein (TgElk) to investigate the effects of inoculation routes on CWD prion seeding and distribution in selected tissues. TgElkPrP mice were inoculated with CWD positive brain homogenate via the intragastric (IG) or intracerebral (IC) routes. Prion seeding activity and amplification were determined using real-time quaking-induced conversion (RT-QuIC), and the CWD positivity in animals was confirmed by immunohistochemistry. Prion seeding activity was detected in brain and spleen tissues as early as 8 weeks post-IC inoculation. In contrast, prion seeding activity was minimally expressed in mice by 56 weeks post-IG inoculation, suggesting a longer incubation time is required for disease manifestation. These findings indicate differential disease progression rates and incubation processes caused by different inoculation routes. This work also provides a foundation for future investigations into the interaction between CWD progression and the dynamics of gut microbiome composition, with the potential to identify gut microbial species as a biomarker for early detection of CWD and to understand how gut microbial communities influence animal susceptibility to CWD.