Role of distinct mononuclear phagocyte subsets in oral prion disease pathogenesis

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 GALT
2. To determine whether specific MNP subsets act to protect the body during prion disease by aiding the clearance of orally-acquired prions
3. To determine whether oral prion disease susceptibility is increased in the presence of greater numbers of MNP in the intestine

As 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.

This project aims to determine the role of distinct mononuclear phagocyte (MNP) subsets in oral prion disease. Prions cause fatal neurodegenerative diseases that affect animals and humans to which there are no cures, and can cause zoonoses, exerting high societal and economic costs. Many prion diseases are orally acquired. After oral exposure the prions replicate first within the gut-associated lymphoid tissues (GALT) as they spread from the gut to the brain. Prion replication within the GALT is essential for efficient infection. The prions then spread from the GALT via enteric nerves to the brain. The route by which orally-acquired prions are first delivered into the GALT is unclear. Prions are first transported across the gut epithelium into the GALT by specialised M cells. Our data show 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 may play a host-protective role by destroying prions. We have shown that treatments that prevent prion replication within the GALT block disease susceptibility. This study aims to identify the MNP subsets which enhance disease susceptibility by aiding the uptake of prions from the gut. This work will also identify MNP subsets which clear the prions from the body, and could be potentially targeted to provide protection against infection. As MNP have many important roles in immunity, immunopathology and homeostasis in the gastrointestinal tract, this work will have wide-ranging impact. A greater understanding of the role of distinct MNP subsets in Ag sampling within the GALT will help inform the design of novel adjuvants to improve the efficacy of mucosal vaccines. 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 intervention targets.

Researchers in industry and in academia will benefit from data in this project describing the influence of MNP and inflammation on the uptake of orally-acquired antigens and prions. A thorough analysis of the cellular and molecular factors that influence susceptibility to orally-acquired prions will improve our understanding of the factors which influence the risk of disease susceptibility, improve pre-clinical diagnosis and help identify novel targets for prophylactic and therapeutic intervention.

Prion diseases have had significant economic impact on the UK farming industry. Although many natural hosts such as sheep, deer and cattle can be infected with prions, little is known of the factors which influence disease susceptibility. Any future outbreaks of novel prion outbreaks are likely to have huge economical impact on the food and livestock industry. Since any novel prion outbreaks may most likely occur via the oral exposure, the farming and animal husbandry industries (farmers, breeders etc.), and food-security policy makers will have significant interest in the project's outputs.

Immunologists will be interested in data generated from this study describing the role of distinct MNP subsets in the uptake of orally-acquired antigens and prions from the gut lumen into the GALT.

UK policy makers will have interest in the project's findings on novel factors that may influence oral prion disease susceptibility. This may influence their assessments of the risk of prion disease transmission via oral exposure. Indeed, the impact of the applicant's data describing the effects of host age on TSE susceptibility (Brown et al. 2009 J. Immunol. 183, 5199) were discussed at the November 2009 meeting of the UK Spongiform Encephalopathies Advisory Committee (for minutes see http://www.seac.gov.uk/papers/103-2.pdf) and received significant media interest (eg: BBC website http://news.bbc.co.uk/1/hi/scotland/edinburgh_and_east/8307551.stm).

Depending on the data generated from this study it is plausible that pharmaceutical companies may have significant interest in data generated from this study. Therefore, during the course of the project the applicant will consult with the Institute's Business Development and Commercialisation Department to seek potential Industry partners to exploit the project's data (see pathways to impact).

This study will enable the scientists working on the project to acquire many transferable skills. Important skills will be gained in major disciplines: mucosal immunology, MNP immunobiology and prion diseases. During the course of this study the scientist will develop import skills in in vivo biology (a currently recognised priority for research) and high resolution bioimaging. The scientists will gain invaluable additional expertise and develop their team-working, networking and collaboration skills.

Data from this study will be disseminated to the scientific community through a combination of publication in quality peer-reviewed journals, data deposition in public databases (see data management) and presentation at international and national scientific conferences, seminars and lectures to undergraduates. Prof. Mabbott is regularly invited to present at these events. Opportunities will be taken to communicate the project's findings to the public. Prof. Mabbott was recently involved in Public Engagement activities for Brain Awareness Week (Univ. Edinburgh). This involved teaching primary school pupils some basic biology of the human brain through short practical examples. The release of potential news-worthy publications would be discussed with the Institute and BBSRC press officers and press releases issued when appropriate. Prof, Mabbott's published studies on prion pathogenesis were handled in such manner and attracted national and international media including: The Times newspaper, the BBC news and were also feature by the BBSRC on their website and in BBSRC Business magazine.