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Prion uptake in the gut: identification of the first uptake and replication sites

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  • P. Kujala
  • C.R. Raymond
  • M. Romeijn
  • S.F. Godsave
  • S.I. van Kasteren
  • H. Wille
  • S.B. Prusiner
  • N.A. Mabbott
  • P.J. Peters

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http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002449
Original languageEnglish
Article numbere1002449
JournalPlos pathogens
Volume7
Issue number12
DOIs
Publication statusPublished - 2011

Abstract

After oral exposure, prions are thought to enter Peyer's patches via M cells and accumulate first upon follicular dendritic cells (FDCs) before spreading to the nervous system. How prions are actually initially acquired from the gut lumen is not known. Using high-resolution immunofluorescence and cryo-immunogold electron microscopy, we report the trafficking of the prion protein (PrP) toward Peyer's patches of wild-type and PrP-deficient mice. PrP was transiently detectable at 1 day post feeding (dpf) within large multivesicular LAMP1-positive endosomes of enterocytes in the follicle-associated epithelium (FAE) and at much lower levels within M cells. Subsequently, PrP was detected on vesicles in the late endosomal compartments of macrophages in the subepithelial dome. At 7-21 dpf, increased PrP labelling was observed on the plasma membranes of FDCs in germinal centres of Peyer's patches from wild-type mice only, identifying FDCs as the first sites of PrP conversion and replication. Detection of PrP on extracellular vesicles displaying FAE enterocyte-derived A33 protein implied transport towards FDCs in association with FAE-derived vesicles. By 21 dpf, PrP was observed on the plasma membranes of neurons within neighbouring myenteric plexi. Together, these data identify a novel potential M cell-independent mechanism for prion transport, mediated by FAE enterocytes, which acts to initiate conversion and replication upon FDCs and subsequent infection of enteric nerves.

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