Oral Prion Neuroinvasion Occurs Independently of PrP(C) Expression in the Gut Epithelium

The early replication of certain prion strains within Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain after oral exposure. Our data show that orally acquired prions utilize specialized gut epithelial cells known as M cells to enter Peyer's patches. M cells express the cellular isoform of the prion protein, PrP(C), and this may be exploited by some pathogens as an uptake receptor to enter Peyer's patches. This suggested that PrP(C) might also mediate the uptake and transfer of prions across the gut epithelium into Peyer's patches in order to establish infection. Furthermore, the expression level of PrP(C) in the gut epithelium could influence the uptake of prions from the lumen of the small intestine. To test this hypothesis, transgenic mice were created in which deficiency in PrP(C) was specifically restricted to epithelial cells throughout the lining of the small intestine. Our data clearly show that efficient prion neuroinvasion after oral exposure occurred independently of PrP(C) expression in small intestinal epithelial cells. The specific absence of PrP(C) in the gut epithelium did not influence the early replication of prions in Peyer's patches or disease susceptibility. Acute mucosal inflammation can enhance PrP(C) expression in the intestine, implying the potential to enhance oral prion disease pathogenesis and susceptibility. However, our data suggest that the magnitude of PrP(C) expression in the epithelium lining the small intestine is unlikely to be an important factor which influences the risk of oral prion disease susceptibility. IMPORTANCE The accumulation of orally acquired prions within Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. Little is known of how the prions initially establish infection within Peyer's patches. Some gastrointestinal pathogens utilize molecules, such as the cellular prion protein PrP(C), expressed on gut epithelial cells to enter Peyer's patches. Acute mucosal inflammation can enhance PrP(C) expression in the intestine, implying the potential to enhance oral prion disease susceptibility. We used transgenic mice to determine whether the uptake of prions into Peyer's patches was dependent upon PrP(C) expression in the gut epithelium. We show that orally acquired prions can establish infection in Peyer's patches independently of PrP(C) expression in gut epithelial cells. Our data suggest that the magnitude of PrP(C) expression in the epithelium lining the small intestine is unlikely to be an important factor which influences oral prion disease susceptibility.