Journal
PLOS PATHOGENS
Volume 7, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1002449
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Funding
- European Union [FOOD-CT-2006-023183, FOOD-CT-2006-023144, 222887]
- Biotechnology and Biological Research Council
- Biotechnology and Biological Sciences Research Council [BB/G003947/1, BB/D00831X/1, BBS/E/A/00001660, BBS/E/D/05241339, BBS/E/I/00000989, BBS/E/A/00001659, BB/D00831X/2] Funding Source: researchfish
- BBSRC [BBS/E/A/00001659, BBS/E/A/00001660, BB/D00831X/2, BBS/E/D/05241339, BB/D00831X/1, BB/G003947/1] Funding Source: UKRI
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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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