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

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.

Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice

“…Consistent with previous studies (Donaldson et al, 2016; Rios et al, 2016), significantly fewer nanobeads were detected in the SED of Peyer’s patches from flagellin-treated RANK Δ mice compared to RANK mice ( Figures 4J ). Since flagellin treatment did not enhance the uptake of nanobeads in RANK ΔIEC mice, this suggests that the effect of flagellin on antigen uptake into aged Peyer’s patches was due to the flagellin-mediated increase in M cell density.…”

“…Aged mice were injected IP with 50 ng of flagellin for 3 d, consistent with similar protocols for enhancing M cell development via systemic RANKL administration (Donaldson et al, 2016; Kanaya et al, 2012; Knoop et al, 2009). Control aged mice were injected with PBS.…”

Impact of TGEV infection on the pig small intestine

“…We observed fewer IgA secretory cells, CD3 + T cells, and DCs in TGEV-infected pigs, indicating impaired immune function [19]. Certain pathogens, or exposure to inflammatory stimuli, can significantly enhance the density of M cells in the intestine [20]. Our experiments show that TGEV infection apparently increases M cell density.…”

Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance

“…RANK signaling activates TRAF6 and NF-KB in epithelial cells [160] and triggers the expression of the transcription factor Spi-B, which is required for the final maturation and accumulation of M cells in the dome epithelium [160]. Interestingly, the systemic administration of RANKL induces the ectopic differentiation of enterocytes into M cells throughout the villous epithelium [161], suggesting that any enterocyte is capable of differentiating into M cells but that the normal availability of RANK ligand is spatially restricted to the epithelium overlaying lymphoid clusters or FAE. In fact, RANK ligand is primarily expressed by subepithelial stromal cells in areas of lymphoid tissue (e.g., Peyer's patches) [162].…”