Foodborne transmission of
bovine spongiform encephalopathy (BSE) to humans as
variant Creutzfeldt-Jakob disease (CJD) has affected over 100 individuals, and probably millions of others have been exposed to BSE-contaminated food substances. Despite these obvious public health concerns, surprisingly little is known about the mechanism by which PrP-
scrapie (PrP(Sc)), the most reliable
surrogate marker of
infection in BSE-contaminated food, crosses the human intestinal epithelial cell barrier. Here we show that digestive
enzyme (DE) treatment of
sporadic CJD brain homogenate generates a C-terminal fragment similar to the
proteinase K-resistant PrP(Sc) core of 27-30 kDa implicated in
prion disease transmission and pathogenesis. Notably, DE treatment results in a PrP(Sc)-
protein complex that is avidly transcytosed in vesicular structures across an in vitro model of the human intestinal epithelial cell barrier, regardless of the amount of endogenous PrP(C) expression. Unexpectedly, PrP(Sc) is cotransported with
ferritin, a prominent component of the DE-treated PrP(Sc)-
protein complex. The transport of PrP(Sc)-
ferritin is sensitive to low temperature,
brefeldin-A, and
nocodazole treatment and is inhibited by excess free
ferritin, implicating a receptor- or transporter-mediated pathway. Because
ferritin shares considerable homology across species, these data suggest that PrP(Sc)-associated
proteins, in particular
ferritin, may facilitate PrP(Sc) uptake in the intestine from distant species, leading to a carrier state in humans.