Prion pathogenesis and secondary lymphoid organs (SLO): tracking the SLO spread of prions to the brain

Abstract

Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrP (Sc), an abnormally folded isoform of the cellular prion protein (PrP (C)), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing feature of the prion diseases, when compared with other protein-misfolding diseases, is their transmissibility. Following peripheral exposure, some prion diseases accumulate to high levels within lymphoid tissues. The replication of prions within lymphoid tissue has been shown to be important for the efficient spread of disease to the brain. This article describes recent progress in our understanding of the cellular mechanisms that influence the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. A thorough understanding of these events will lead to the identification of important targets for therapeutic intervention, or alternatively, reveal additional processes that influence disease susceptibility to peripherally-acquired prion diseases.

Figure 1. FDC do not passively acquire PrP^C from other cell types. Whole embryonic day 15 spleen tissue from Prnp^−/− mice or wild-type (WT) controls was transplanted under the kidney capsule of WT recipient mice. Tissues were analyzed 6 weeks after transplant. FDC expressing high levels of PrP^C were detected in the B cell follicles of the WT donor spleens grafted into WT recipients (WT→WT; left-hand panels). However, no PrP^C was detected upon FDC within the Prnp^−/− spleens grafted into WT mice (Prnp^−/−→WT; right-hand panels). Upper panels, scale bar = 200 µm. Lower panels, scale bar = 50 µm. Adapted from Brown et al.

Figure 2. The specific ablation of PrP^C expression only on FDC blocks prion replication in the spleen. CD21-cre mice can be used to study FDC-specific gene function. (A and B), Using this approach we recently created a compound transgenic mouse in which PrP^C expression could be specifically “switched off” only on FDC. (C&E), Following peripheral prion exposure high levels of PrP^Sc accumulate upon the surfaces of FDC in the spleens of control mice. (D&F) However, prion replication is blocked in the spleens of mice in which PrP^C expression was specifically “switched off” only on FDC. Arrow heads in D show scavenged PrP within TBM. Arrows in E show PrP^Sc-positive FDC in the spleens of control mice. A&B, scale bar = 100 µm; C&D, scale bar = 20 µm; E&F, scale bar = 500 µm. Adapted from McCulloch et al.

Figure 3. The specific ablation of M cells blocks oral prion pathogenesis. (A&B), Whole-mount immunostaining shows that treatment of mice with anti-RANKL-mAb blocks RANKL-RANKL signaling and specifically depletes M cells (GP2⁺ UEA-1⁺ cells) in the FAE of Peyer’s patches. (C&D), In the specific absence of M cells at the time of oral exposure prion accumulation (PrP^Sc, black) upon FDC in Peyer’s patches is blocked. Adapted from Donaldson et al.

Figure 4. The microarchitecture of the splenic MZ is disrupted in the spleens of aged mice. Left-hand-panels; In the spleens of young mice MADCAM1-expressing sinus-lining cells form a distinct barrier between the MZ and the white pulp (WP, arrow). RP, red pulp; Fol, FDC-containing B cell follicle. Within the MZ abundant CD1d-expressing MZ B cells (upper panels, green) continually shuttle between MZ and B cell follicles as they transfer immune complexes to FDC. Two distinct populations of macrophages also reside in the MZ: SIGNR1-expressing MZ macrophages, and SIGLEC1/CD169-expressing MZ metallophilic macrophages (middle and lower panels, brown). In the spleens of aged mice the distribution and density of these cells are all severely disrupted when compared with young mice (right-hand panels). Upper panels, scale bar = 50 µm; middle and lower panels, scale bar = 100 µm. Adapted from Brown et al.

Figure 5. A potential cellular relay that mediates prion neuroinvasion after oral exposure. After ingestion of a contaminated meal, prions appear to be actively transcytosed into Peyer’s patches by M cells and enterocytes in the follicle-associated epithelium. In the absence of M cells neuroinvasion is blocked suggesting that M cells are the important sites of prion uptake from the gut lumen. The prions are subsequently acquired by mononuclear phagocytes (macrophages and classical DC) in the sub-epithelial dome of the Peyer’s patches. Current hypotheses suggest classical DC, in contrast to macrophages, act as ‘Trojan horses’ and carry the prions to the FDC in the B cell follicles. The prions then infect and replicate upon FDC. Following their expansion upon FDC, prions subsequently infect enteric nerves. The prions then spread to the CNS via the peripheral nervous system (both sympathetic and parasympathetic).