Prion uptake in the gut: identification of the first uptake and replication sites.
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.
Section of Cell Biology II, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Pekka
P
Kujala
Claudine R
CR
Raymond
Martijn
M
Romeijn
Susan F
SF
Godsave
Sander I
SI
van Kasteren
Holger
H
Wille
Stanley B
SB
Prusiner
Neil A
NA
Mabbott
Peter J
PJ
Peters
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D020566:Dendritic Cells, Follicular / Q000378:metabolism / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D017615:Enteric Nervous System / Q000378:metabolism* / Q000648:ultrastructure; D020895:Enterocytes / Q000378:metabolism* / Q000648:ultrastructure; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000378:metabolism* / Q000648:ultrastructure; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000635:transmission*; D011328:Prions / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D021381:Protein Transport; D013997:Time Factors; D052118:Lysosomal-Associated Membrane Protein 1
D051907:Lysosomal Membrane Proteins; D011328:Prions; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1