Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

• David S. Donaldson,

Affiliation The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom

ORCID http://orcid.org/0000-0002-8523-7853

• Anuj Sehgal,

Affiliation The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom

• Daniel Rios,

Current address: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America

Affiliation Dept. Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America

• Ifor R. Williams,

Affiliation Dept. Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America

ORCID http://orcid.org/0000-0002-8810-2911

• Neil A. Mabbott

* E-mail: neil.mabbott@roslin.ed.ac.uk

Affiliation The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom

ORCID http://orcid.org/0000-0001-7395-1796

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Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

• David S. Donaldson, 
• Anuj Sehgal, 
• Daniel Rios, 
• Ifor R. Williams, 
• Neil A. Mabbott

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• Published: December 14, 2016
•  
• http://dx.doi.org/10.1371/journal.ppat.1006075

Abstract

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

Author Summary

Prion diseases are infectious neurodegenerative disorders that affect humans and animals. Many natural prion diseases are orally acquired through consumption of contaminated food or pasture. An understanding of how prions infect the intestine will help identify factors that influence disease susceptibility and allow the development of new treatments. After oral infection prions first accumulate within the lymphoid tissues that line the intestine (known as Peyer’s patches) before they spread to the brain where they cause neurodegeneration. To do this, the prions must first cross the intestinal epithelium, a single layer of cells that separates the body from the gut contents. M cells are found within the epithelium that covers the Peyer’s patches and are specialised to transport large particles and whole bacteria across the gut epithelium. We show that M cells act as the gatekeepers of oral prion infection. In the absence of M cells, oral prion infection is blocked, whereas an increase in M cells increases the risk of prion infection and shortens the disease duration. Therefore, our data demonstrate that factors such as pathogen infection, inflammation and aging, which alter the abundance of M cells in the intestine, may be important risk factors which influence susceptibility to orally-acquired prion infections.

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In conclusion, we show that the initial uptake and transfer of prions across the gut epithelium in association with M cells is essential to establish host infection. Importantly, we also demonstrate that the density of M cells in the FAE overlying the Peyer’s patches in the small intestine directly controls the efficiency of oral prion infection. In the specific absence of M cells, the uptake and accumulation of prions in Peyer’s patches and their subsequent spread to the MLN and spleen is blocked. In contrast, oral prion disease susceptibility was enhanced approximately 10-fold in mice in which M cell-deficiency in the gut epithelium was increased. Thus, M cells could be considered as the gatekeepers of oral prion infection whose density directly limits or enhances disease susceptibility. Further studies are necessary to determine whether most orally acquired prion strains similarly exploit intestinal M cells to establish host infection after oral exposure, but data from independent in vivo and in vitro studies using mouse-passaged RML scrapie prions [30], Fukuoka-1 prions [31], BSE prions [32] and 263K hamster prions [17] imply a similar requirement. Antigen sampling M cells are also present in the FAE overlying the NALT in the nasal cavity [44, 45], but data from the analysis of prion disease pathogenesis in hamsters implies that the requirement for M cell-mediated uptake may vary depending on the route of exposure [85]. After intra-nasal exposure some transient uptake of 263K prions was observed in M cells within the FAE overlying the NALT, but a greater magnitude of paracellular transport across the epithelia within the nasal cavity was also noted [85]. Although certain concurrent pathogen infections, inflammatory stimuli and aging may have multiple effects on the gut epithelium, our data suggest that factors such as these that can modify M cell-density in the small intestine [25, 39, 40, 71] may represent important risk factors which can significantly influence susceptibility to orally-acquired prion infections. Our data also raise the possibility that the density of M cells in the gut epithelium may similarly influence susceptibility to other important orally-acquired bacterial and viral pathogens which are considered to exploit M cells to infect the host [24–28].

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006075

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