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.
Highlights
IntroductionPrion diseases (transmissible spongiform encephalopathies) are a unique group of subacute neurodegenerative diseases that affect humans and animals
Prion diseases are a unique group of subacute neurodegenerative diseases that affect humans and animals
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
Summary
Prion diseases (transmissible spongiform encephalopathies) are a unique group of subacute neurodegenerative diseases that affect humans and animals. Aggregations of PrPSc, an abnormally folded isoform of cellular PrP (PrPC), accumulate in affected tissues. The precise mechanism by which orallyacquired prions are propagated from the gut lumen across the epithelium to establish host infection is uncertain. Further studies are clearly necessary to precisely characterise the cellular route that prions exploit to establish infection after oral exposure, and how alterations to this cellular route, both intrinsic and extrinsic, can affect disease susceptibility. Treatments which prevent the accumulation and replication of prions in host lymphoid tissues can significantly reduce disease susceptibility [5,6,7,8,9]. Identification of the cellular route by which prions are first transported across the gut epithelium to achieve host infection will identify an important factor which influences oral prion disease susceptibility and to which intervention strategies can be developed
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