Advancing our understanding of human prions hinges on developing better models of disease. Human-to-human transmission of prions may occur following exposures through peripheral routes, and we need models that can mimic these disease outcomes. With this in mind, we continue to develop improved transgenic mouse models expressing the human prion protein that are susceptible not only to infection of the brain, but also exposures by peripheral routes. The goal of this project is to use these refined models to characterize susceptibility by medically-relevant routes of infection and to understand how prion strain properties influence these processes. This project will also focus on comparing the outcomes of infections with prions from the brain or peripheral tissues of the lymphoid system following exposures by different routes of inoculation. Through this project we aspire to improve our understanding of how prion strains and other factors influence the infectious transmission of human prions.