Entry versus blockade of brain infection following oral or intraperitonealscrapie administration: Role of prion protein expression in peripheral nerves and spleen

Naturally occurring transmissible spongiform encephalopathy (TSE) diseases such as bovine spongiform encephalopathy in cattle are probably transmitted by oral or other peripheral routes of infection. While prion protein (PrP) is required for susceptibility, the mechanism of spread of infection to th e brain is not clear. Two prominent possibilities include hematogenous spre ad by leukocytes and neural spread by axonal transport. In the present expe riments, following oral or intraperitoneal infection of transgenic mice wit h hamster scrapie strain 263K, hamster PrP expression in peripheral nerves was sufficient for successful infection of the brain, and cells of the sple en were not required either as a site of amplification or as transporters o f infectivity. The role of tissue-specific PrP expression of foreign PrP in interference with scrapie infection was also studied in these transgenic m ice. Peripheral expression of heterologous PrP completely protected the maj ority of mice from clinical disease after oral or intraperitoneal scrapie i nfection. Such extensive protection has not been seen in earlier studies on interference, and these results suggested that gene therapy with mutant Pr P may be effective in preventing TSE diseases.