Oral Prion Neuroinvasion via Cranial Nerves

NON-TECHNICAL SUMMARY: Prion diseases such as scrapie in sheep, chronic wasting disease in deer and elk, and bovine spongiform encephalopathy in cattle are caused by novel transmissible agents and results in a fatal degeneration of the central nervous system. The goal of this research is to define the route(s) of neuroinvasion following oral prion infection. Prion ingestion establishes infection of lymphoid and nervous system tissues in the gut prion to spread to the central nervous system. In this study, we will examine the ability of prions to infect the nervous system in the oral cavity as an alternate route of entry into the host. The route of prion spread to the central nervous system will be examined in order to determine the role of lymphoid tissue and cranial nerves in neuroinvasion following oral cavity infection. These studies can inmprove our understanding of how prions enter a host and spread within a host in order to reach the brain and infect peripheral tissues. The findings from this study will be relevant to U.S. agriculture by identifying 1) potential routes of prion infection in the oral cavity; 2) the ability of prions to infect tissues in the oral cavity that are used in food, such as the tongue; and 3) oral cavity tissues that could be used for prion detection in an antemortem diagnostic test for animal prion diseases.

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APPROACH: The chronological sequence of prion spread in the nervous system and lymphoreticular system following topical application of prions to a superficial tongue wound will be determined. These studies will investigate the site(s) of prions replication prior to neuroinvasion of the brainstem. Nervous system tissues, lymphoreticular tissues, and tongue will be collected each week and the initial sites of prion replication will be determined by PRP(Sc) detection. The ability of prions to cause disease after intratongue inoculation will be determined using a prion strain that does not replicate in the lymphoreticular system. Immunohistochemistry will be performed to demonstrate the presence of absence of PrP(Sc) in brainstem nuclei that innervate the tongue in order to determine whether prion spread along the tongue-associated cranial nerves is one possible route of neuroinvasion in these models. A pilot study of sheep will be conducted to determine the spread of scrapie to the tongue following oral ingestion and intracerebral inoculation of a nautral sheep scrapie isolate.