The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases

Abstract

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a class of fatal neurodegenerative diseases caused by the entry and spread of infectious prion proteins (PrP^Sc) in the central nervous system (CNS). These diseases are endemic to certain mammalian animal species that use their sense of smell for a variety of purposes and therefore expose their nasal cavity (NC) to PrP^Sc in the environment. Prion diseases that affect humans are either inherited due to a mutation of the gene that encodes the prion protein, acquired by exposure to contaminated tissues or medical devices, or develop without a known cause (referred to as sporadic). The purpose of this review is to identify components of the NC that are involved in prion transport and to summarize the evidence that the NC serves as a route of entry (centripetal spread) and/or a source of shedding (centrifugal spread) of PrP^Sc, and thus plays a role in the pathogenesis of the TSEs.

Keywords: PrPSc; TSE; centrifugal; centripetal; nasal cavity; olfactory system; prion pathogenesis; prionemia; prions.

Figure 1

Anatomy of mammalian nasal cavity. (A) H&E-stained coronal section of a decalcified hamster nasal cavity showing the bony and cartilaginous nasal septum in midline (NS) and the turbinate bones (T) that increase contact between inhaled material and the epithelia that line the cavity. Note the presence of extensive mucus glands (MGs) in the lamina propria surrounding the maxillary sinus (MS) and the unencapsulated nasal associated lymphoid tissue (NALT) in the floor of the NC. Asterisks mark airspaces. Boxes 1–3 are enlarged in panels B–D, respectively. (B) Olfactory epithelium (OE) lines the upper part of the NC and contains olfactory sensory neurons with dendrites that extend into the mucus layer of the NC airspace and axons that collect into nerve fascicles that form the olfactory nerve and project directly into the olfactory bulb of the brain. (C) Respiratory epithelium (RE) contains a single layer of pseudostratified ciliated columnar epithelial cells that overlay a loose connective tissue layer, the lamina propria (LP), that contains mucus glands and blood vessels. (D) Follicle-associated epithelium (FAE) contains microfold cells (M cells; indicated by arrows) that transport antigens in the NC to underlying lymphatic cells in intraepithelial pockets (dotted lines) and the nasal associated lymphoid tissue (NALT). Scale bars: A = 400 µm; B, C, and D = 20 µm.

Figure 2

Route for centripetal and centrifugal transport between the olfactory epithelium and olfactory bulbs. A decalcified coronal section of the bony cribriform plate (CP) of the skull, the bony nasal septum (NS), and the superior part of the NC stained with periodic acid–Schiff reagent (asterisks indicate airspace of the NC). The olfactory nerve fascicles (OFs) pass through holes of the CP connecting the olfactory sensory neurons of the olfactory epithelium (OE) to the glomeruli (GL) of the olfactory bulbs in the CNS. The axons of the olfactory sensory neurons collect into nerve fascicles in the lamina propria (LP) of the superior NC. Note the relatively short and direct route these axons take from the epithelium to the brain. The arrow on the left indicates the direction of centripetal spread, while the arrow on the right indicates the direction of centrifugal spread. GCL = granule-cell layer; MCL = mitral-cell layer; EPL = external plexiform layer; GL = glomerular layer; ONL = olfactory-nerve-fiber layer. Scale bar = 400 µm.

Figure 3

PrP^Sc in the NC of clinically ill hamsters following inhalation of prions into the NC (asterisks indicate airspace of the NC). (A,C,E) Periodic acid Schiff-stained sections, and (B,D,F) near-adjacent immunohistochemically processed tissue sections for the presence of PrP^Sc using the 3F4 antibody. (A,B) PrP^Sc in intraepithelial pockets (indicated by dotted lines) of the follicle-associated epithelium (FAE) and the underlying nasal associated lymphoid tissue (NALT). (C,D) PrP^Sc in the vomeronasal epithelium (VNE), in both the cell bodies (indicated by arrowheads) and apical surfaces of the sensory neurons (indicated by solid arrows). (E,F) PrP^Sc can be seen in the OE, in the OSN cell bodies (indicated by arrowheads), and in dendrites at the apical surfaces of the cells (indicated by solid arrows). Scale bars = 10 µm.