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, PrPC, and this may be 
exploited by some pathogens as an uptake receptor to enter Peyer's patches. This 
suggested that PrPC 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 PrPC 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 PrPC 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 PrPC expression in small intestinal 
epithelial cells. The specific absence of PrPC in the gut epithelium did not 
influence the early replication of prions in Peyer's patches or disease 
susceptibility. Acute mucosal inflammation can enhance PrPC expression in the 
intestine, implying the potential to enhance oral prion disease pathogenesis and 
susceptibility. However, our data suggest that the magnitude of PrPC 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 PrPC, expressed on gut epithelial cells to enter Peyer's patches. Acute 
mucosal inflammation can enhance PrPC 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 PrPC expression in the gut epithelium. We show that orally acquired prions 
can establish infection in Peyer's patches independently of PrPC expression in 
gut epithelial cells. Our data suggest that the magnitude of PrPC expression in 
the epithelium lining the small intestine is unlikely to be an important factor 
which influences oral prion disease susceptibility.