Oral prion neuroinvasion occurs independently of PrPC expression in the gut epithelium

The early replication of certain prion strains within the Peyer’s patches 20 in the small intestine is essential for the efficient spread of disease to the brain after 21 oral exposure. Our data show that orally-acquired prions utilise specialised gut 22 epithelial cells known as M cells to enter Peyer’s patches. M cells express the 23 cellular isoform of the prion protein, PrPC, and this may be exploited by some 24 pathogens as an uptake receptor to enter Peyer’s patches. This suggested that 25 PrPC might also mediate the uptake and transfer of prions across the gut epithelium 26 into Peyer’s patches in order to establish infection. Furthermore, the expression 27 level of PrPC in the gut epithelium could influence the uptake of prions from the 28 lumen of the small intestine. To test this hypothesis, transgenic mice were created 29 in which deficiency in PrPC was specifically restricted to epithelial cells throughout 30 the lining of the small intestine. Our data clearly show that efficient prion 31 neuroinvasion after oral exposure occurred independently of PrPC expression in 32 small intestinal epithelial cells. The specific absence of PrPC in the gut epithelium 33 did not influence the early replication of prions in the Peyer’s patches or disease 34 susceptibility. Acute mucosal inflammation can enhance PrPC expression in the 35 intestine, implying the potential to enhance oral prion disease pathogenesis and 36 susceptibility. However, our data suggest that the magnitude of PrPC expression in 37 the epithelium lining the small intestine is unlikely to be an important factor which 38 influences the risk of oral prion disease susceptibility.