Specificity, Size, and Frequency of Spaces That Characterize the Mechanism of Bulk Transepithelial Transport of Prions in the Nasal Cavities of Hamsters and Mice

Abstract

Inhalation of infected brain homogenate results in transepithelial transport. Bulk transepithelial transport in the nasal cavity has not been studied to date. In the present study, we characterized the frequency, size, and specificity of the intercellular spaces that mediate the bulk transport of inhaled prions between cells of mice or hamsters following extranasal inoculation with mock-infected brain homogenate, different strains of prion-infected brain homogenate, or brain homogenate mixed with India ink. Infected or mock-infected inoculum was identified within lymphatic vessels of the lamina propria and in spaces of >5 m between a small number of cells of the nasal mucosa in >90% of animals from 5 to 60 min after inhalation. The width of the spaces between cells, the amount of the inoculum within the lumen of lymphatic vessels, and the timing of the transport indicate that this type of transport was taking place through preexisting spaces in the nasal cavity that were orders of magnitude wider than what is normally reported for paracellular transport. The indiscriminate rapid bulk transport of brain homogenate in the nasal cavity results in immediate entry into nasal cavity lymphatics following inhalation. This novel mechanism may underlie the recent report of the early detection of prions in blood following inhalation and has implications for horizontal prion transmission. IMPORTANCEThe results of these studies demonstrate that the nasal mucosa of mice and hamsters is not an absolute anatomical barrier to inhaled prion-infected or uninfected brain homogenate. Relatively large amounts of infected and uninfected brain homogenate rapidly cross the nasal mucosa and enter the lumen of lymphatic vessels following inhalation. These bulk transepithelial transport events were relatively rare but present in >90% of animals 5 to 60 min following inhalation. This novel mechanism of bulk transepithelial transport was seen in experimental and control hamsters and mice, indicating that it was not species specific or in response to prion exposure. The indiscriminate bulk intercellular transport of inhaled pathogens across the nasal mucosa followed by entry into the lymphatic system may be a mechanism that underlies the entry and spread of other toxins and pathogens in olfactory system-driven animals.T ransmissible spongiform encephalopathies (TSEs) are a group of fatal neurological disorders affecting a variety of animal species, including humans. TSEs have relatively long incubation periods, and although they are rare in humans, they are relatively common in some animal populations. The TSEs affecting animals include scrapie in sheep and goats and chronic wasting disease (CWD) in deer, elk, and moose. The infectious agent is thought to consist largely if not entirely of PrP Sc , a misfolded conformation of the naturally occurring prion protein (PrP), designated PrP C (1-6). Specific details of the transmission of these diseases are not known, but there is evidence for the horizontal transmission of PrP Sc that has...

PrPSc formation and clearance as determinants of prion tropism

“…In all infected animals, DY TME-infected brain homogenate was also detected in the lumen of lymphatic vessels located in the lamina propria of all 3 animals ( Fig 2 , panel B). A similar pattern of brain homogenate distribution was observed in both (n = 2) of the mock-infected hamsters, which is consistent with previous results [ 47 ].…”

Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease

“…In addition to potential cofactors that could influence CWD infectivity, such as particle binding [ 47 ] and compromised mucosal integrity [ 48 , 53 ], there is PRNP genotype, in which polymorphisms at codon 96 of the white-tailed deer are known to affect the temporal dynamics of CWD infections [ 23 , 41 , 45 ]. In the present studies, most cohorts of 96GG deer became CWD-positive before 96GS animals in the same exposure group [cohorts 1, 2, 4, 6].…”

Oral Prion Neuroinvasion Occurs Independently of PrP C Expression in the Gut Epithelium

“…Thus, it cannot be excluded that soil-bound prions might also be inhaled and infect the host as the animal forages for food. Although M cells are present in the epithelia covering the nasal-associated lymphoid tissue ( 60 ), studies in hamsters indicate that this prion uptake across the nasal epithelium occurs independently of M cells ( 61 ). Whether prion uptake across the mucosal surfaces in the upper gastrointestinal and upper respiratory tracts of natural host species is also PrP C independent remains to be determined.…”