Role of distinct mononuclear phagocyte subsets in oral prion disease pathogenesis

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This project aims to determine the role of distinct mononuclear phagocyte (MNP) subsets in the establishment of oral prion infections. Prions cause fatal neurodegenerative diseases that affect animals and humans to which there are no cures. Prion diseases may also cause zoonoses, exerting high societal and economic costs. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in deer and elk, and variant Creutzfeldt-Jakob disease (vCJD) in humans can be orally acquired. After ingestion of prion-contaminated food, the prions replicate first within the gut-associated lymphoid tissues (GALT) in the intestine as they make their journey from the gut to the brain. Prion replication within the GALT is essential for the establishment of prion disease after oral exposure. The prions then spread from the GALT via peripheral nerves in the intestine, then spread via the spinal cord and vagus nerve to the brain where they cause damage to nerve cells and death. The route by which orally-acquired antigens (Ag) and prions are initially delivered to the GALT is unclear. We have shown that prions "hi-jack" cells of the immune system in order to infect the body. The prions are initially transported across the gut epithelium into Peyer's patches by specialised gut epithelial cells known as M cells. Our data also suggest that the prions are then taken up by MNP which they appear to use as "Trojan horses" to carry them into the GALT. However, whereas some MNP appear aid prion infection in the GALT, others appear to play a host-protective role by engulfing and destroying the prions. We have shown that treatments that prevent the initial replication of prions within the GALT can block prion disease transmission. Thus, a thorough understanding of the role of MNP in oral prion disease pathogenesis will reveal the MNP subsets which enhance susceptibility by aiding the uptake of prions from the intestine. This work will also help identify MNP subsets which help to clear the prions from the body, and which could be potentially targeted to provide protection against oral prion infections.The main aims and hypotheses of this project are:1. To determine whether specific MNP subsets play an important role in the uptake of prions from the intestine and delivery their into the GALT2. To determine whether specific MNP subsets act to protect the body during prion disease by aiding the clearance of orally-acquired prions3. To determine whether oral prion disease susceptibility is increased in the presence of greater numbers of MNP in the intestineAs MNP have many important roles in immunity, immunopathology and homeostasis in the intestine, this work will have wide-ranging impact. A greater understanding of the role of distinct MNP subsets in antigen sampling within the GALT will help inform the design of novel adjuvants to improve the mucosal vaccine efficacy. No effective therapies are available to treat prion diseases. A greater understanding of the factors that influence oral prion disease susceptibility will enhance our understanding of those that influence the risk of disease transmission and help identify novel targets for intervention in these devastating and currently untreatable diseases.