The long-term objective of the proposed research is to define the route(s) of neuroinvasion following oral prion infection. Food borne transmission of prions has been linked to the bovine spongiform encephalophy epidemic in the United Kingdom and is a likely route of BSE transmission to humans who acquire variant Creutzfeldt-Jakob disease. Oral prion ingestion can establish infection of the gut-associated lymphoid tissues and the vagus cranial nerve. Infection at these sites results in two separate pathways of brain invasion. The oral cavity is also innervated by cranial nerves but their role in prion neuroinvasion has not been investigated. The hypothesis to be tested in this study is that spread of the prion agent from the tongue to the brainstem can proceed by axonal transport within the tongue-associated cranial nerves and this route of neuroinvasion is independent of infection of the lymphoreticular system. Lesions or microbial infections that expose nerve endings on the surface of the tongue or oral cavity could be an alternate site of infection upon oral exposure to prions. The oral pathogenesis of prion infection will be investigated following intratongue inoculation of rodent-adapted prions. To determine the route(s) of prion neuroinvasion, the chronology of prion spread in the tongue, lymphoreticular system, and nervous system will be examined following intratongue inoculation of prions (Aim 1). Te investigate the role of the lymphoreticular system in prion neuroinvasion, the ability of prions to cause disease will be examined following intratongue inoculation of 1) a prion strain that does not replicate in lymphoreticular tissues, and 2) prion inoculation of immunodeficient mice that are not permissive for prion replication in the lymphoreticular system, but can replicate prions in the nervous system (Aim 2). The site(s) of prion replication and spread in the tongue will be examined in order to identify the cellular location of replication in skeletal muscle. The mechanism of prion transport from the tongue to the brainstem will be investigated using experimental models that establish neuromuscular blockade, inhibit axonal transport, or selectively ablate neurons that innervate the tongue (Aim 3). ? ?
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