Abstract
In natural or experimental oral scrapie infection of sheep, disease associated prion protein (PrPd) often first accumulates in Peyer's patch (PP) follicles. The route by which infectivity reaches the follicles is unknown, however, intestinal epithelial cells may participate in intestinal antigenic presentation by delivering exosomes as vehicles of luminal antigens. In a previous study using an intestinal loop model, following inoculation of scrapie brain homogenate, inoculum associated PrPd was detected by light microscopy shortly (15 minutes to 3.5 hours) after inoculation in the villous lacteals and sub-mucosal lymphatics. No PrPd was located within the follicle-associated epithelium (FAE), sub-FAE domes or the PP follicles. To evaluate this gut loop model and the transportation routes in more detail, we used electron microscopy (EM) to study intestinal tissues exposed to scrapie or control homogenates for 15 minutes to 10 days. In addition, immuno-EM was used to investigate whether exosomes produced in the FAE may possess small amounts of PrPd that were not detectable by light microscopy. This study showed that the integrity of the intestinal epithelium was sustained in the intestinal loop model. Despite prominent transcytotic activity and exosome release from the FAE of the ileal PP in sheep, these structures were not associated with transportation of PrPd across the mucosa. The study did not determine how infectivity reaches the follicles of PPs. The possibility that the infectious agent is transported across the FAE remains a possibility if it occurs in a form that is undetectable by the methods used in this study. Infectivity may also be transported via lymph to the blood and further to all other lymphoid tissues including the PP follicles, but the early presence of PrPd in the PP follicles during scrapie infection argues against such a mechanism.
Highlights
The oral route of infection is considered to be important in the natural pathogenesis of transmissible spongiform encephalopathies (TSEs), which are fatal neurodegenerative disorders described in man, domestic and wild ruminants and carnivores [1]
Variations between intestinal tissues sampled at the earliest time points (15 minutes to 3.5 hours) and later time points (24 hours to 10 days) were observed (Table 1 provides a semi-quantitative summary of the primary features seen at electron microscopy (EM) in Peyer’s patch (PP) follicular tissues taken at different time points)
Vacuoles containing a few membrane-bounded vesicles corresponding to multivesicular bodies (MVBs) were observed infrequently, and the numbers of vacuolar and tubular structures including MVBs in the absorptive epithelium (AE) were much lower when compared with the apposing follicle-associated epithelium (FAE) (Fig. 2a)
Summary
The oral route of infection is considered to be important in the natural pathogenesis of transmissible spongiform encephalopathies (TSEs), which are fatal neurodegenerative disorders described in man, domestic and wild ruminants and carnivores [1]. TSEs are characterised by the accumulation of an abnormal form of the host coded prion protein (PrP) in brain and some viscera [2]. For diagnostic purposes disease associated forms of PrP (PrPd) may be detected by immunohistochemistry in tissue sections. In natural TSE infections such as scrapie in sheep and various experimental animal models, the early accumulation of PrPd occurs in the gut associated lymphoid tissues prior to clinical disease [8,9,10]. PrPd has been detected in the Peyer’s patch (PP) follicles as early as 21 days after inoculation in experimentally infected sheep [10]. The early presence of PrPd in gut associated lymphoid tissues provides circumstantial evidence for uptake from the gut but does not give any direct insight into the route of intestinal transport of infection
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