Transcytosis of Murine-Adapted Bovine Spongiform Encephalopathy Agents in an<i>In Vitro</i>Bovine M Cell Model

Miyazawa, Kohtaro; Kanaya, Takashi; Takakura, Ikuro; Tanaka, Sadao; Hondo, Tetsuya; Watanabe, Hitoshi; Rose, Michael T.; Kitazawa, Haruki; Yamaguchi, Takahiro; Katamine, Shigeru; Nishida, Naoshi; Aso, Hisashi

doi:10.1128/jvi.00969-10

Cited by 26 publications

(20 citation statements)

References 46 publications

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“…M cells have the ability to transport bacteria, [15][16][17][18] viruses, [19][20][21][22][23][24] parasites 25 and non-infectious particles 26 through the apical membrane to the basolateral surface. When bacteria and large particles get into the mucosal lumen, M cells undergo apical membrane ruffling, actin cytoskeleton rearrangements, 27 and interdigitation, and then phagocytose these large particles.…”

Section: Function Of M Cellsmentioning

confidence: 99%

Roles of M cells in infection and mucosal vaccines

Wang

Gao

Zhang

et al. 2014

Human Vaccines & Immunotherapeutics

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Section: Function Of M Cellsmentioning

confidence: 99%

Roles of M cells in infection and mucosal vaccines

Wang

Gao

Zhang

et al. 2014

Human Vaccines & Immunotherapeutics

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“…There is disagreement about the location and mechanism of the transepithelial transport of prions following ingestion, with in vitro evidence for M cell transport (35), cotransport of prions with ferritin (58,80), and laminin-mediated binding and endocytosis of prions (60), all across Caco-2 human epithelial cells. A second in vitro model of prion transport demonstrated that a mouse-adapted BSE agent crossed bovine M cells efficiently (59). In vivo experiments have demonstrated evidence for both M-cell-mediated and non-M-cell-mediated transepithelial transport of prion proteins following oral ingestion in mice and sheep, respectively (2,20,25,36,38,46,64,83).…”

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Rapid Transepithelial Transport of Prions following Inhalation

Kincaid

Hudson

Richey

et al. 2012

J Virol

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Prion infection and pathogenesis are dependent on the agent crossing an epithelial barrier to gain access to the recipient nervous system. Several routes of infection have been identified, but the mechanism(s) and timing of in vivo prion transport across an epithelium have not been determined. The hamster model of nasal cavity infection was used to determine the temporal and spatial parameters of prion-infected brain homogenate uptake following inhalation and to test the hypothesis that prions cross the nasal mucosa via M cells. A small drop of infected or uninfected brain homogenate was placed below each nostril, where it was immediately inhaled into the nasal cavity. Regularly spaced tissue sections through the entire extent of the nasal cavity were processed immunohistochemically to identify brain homogenate and the disease-associated isoform of the prion protein (PrP d ). Infected or uninfected brain homogenate was identified adhering to M cells, passing between cells of the nasal mucosa, and within lymphatic vessels of the nasal cavity at all time points examined. PrP d was identified within a limited number of M cells 15 to 180 min following inoculation, but not in the adjacent nasal mucosa-associated lymphoid tissue (NALT). While these results support M cell transport of prions, larger amounts of infected brain homogenate were transported paracellularly across the respiratory, olfactory, and follicle-associated epithelia of the nasal cavity. These results indicate that prions can immediately cross the nasal mucosa via multiple routes and quickly enter lymphatics, where they can spread systemically via lymph draining the nasal cavity.

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“…Transport of inhaled prions across the nasal mucosa was demonstrated by the detection of hyper (HY) strain transmissible mink encephalopathy (TME)-infected brain homogenate (BH) within the lumen of lymphatic vessels in the lamina propria of the nasal cavity and involved both M cell transport and transport between epithelial cells of the NC (20). While there have been previous reports of M cell transport of prions in vitro (21)(22)(23)(24)(25) and in vivo (26)(27)(28), the in vivo bulk transport of HY TME-infected inoculum between cells of the NC was unexpected, as this mechanism of transepithelial transport had not been reported previously. The purpose of the following study was to characterize this novel mechanism of transepithelial transport by determining (i) whether this was a species-or prion strainspecific process, (ii) the frequency of these bulk intercellular transport events, and (iii) and the size of the spaces between the cells that mediate this transport.…”

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

Kincaid

Ayers

Bartz

2016

J Virol

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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...

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Transcytosis of Murine-Adapted Bovine Spongiform Encephalopathy Agents in anIn VitroBovine M Cell Model

Cited by 26 publications

References 46 publications

Roles of M cells in infection and mucosal vaccines

Roles of M cells in infection and mucosal vaccines

Rapid Transepithelial Transport of Prions following Inhalation

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

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