Prions efficiently cross the intestinal barrier after oral administration: Study of the bioavailability, and cellular and tissue distribution in vivo

Urayama, Akihiko; Concha‐Marambio, Luis; Khan, Uffaf; Bravo-Alegría, Javiera; Kharat, Vineetkumar; Soto, Claudio

doi:10.1038/srep32338

Cited by 17 publications

(21 citation statements)

References 42 publications

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“…Using extremely sensitive PrP Sc -based detection assays, two independent studies reported the presence of low/trace levels of prions in the blood-stream within minutes of oral exposure [81, 82]. The cellular route through which the prions initially gained access to the blood-stream was not determined in these studies.…”

Section: Discussionmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

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Section: Discussionmentioning

confidence: 99%

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

et al. 2016

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“…Studies with radioactively labeled scrapie prions in mice demonstrated prions can rapidly cross the intestinal mucosa in minutes, followed by distribution to systemic organs via the vascular system (38). Investigations of specific routes of intestinal uptake of transmissible mink encephalopathy and scrapie prion have identified M cells of the follicle-associated epithelium of Peyer's patches as a site of prion entry (39,40).…”

Section: Figmentioning

confidence: 99%

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

Hoover

Davenport

Henderson

et al. 2017

J Virol

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Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrP CWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrP CWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrP CWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrP CWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrP CWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrP CWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion accumulation and pathways of prion spread during early CWD infection remain unknown. To investigate the chronological events of early prion pathogenesis, we exposed deer to CWD prions and monitored the tissue distribution of PrP CWD over the first 4 months of infection. We show CWD uptake occurs in the oropharynx with initial prion replication in the draining oropharyngeal lymphoid tissues, rapidly followed by dissemination to systemic lymphoid tissues without evidence of neuroinvasion. These data highlight the two phases of CWD infection: a robust prion amplification in systemic lymphoid tissues prior to neuroinvasion and establishment of a carrier state.

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“…For these studies, we radiolabeled the protein with 125 -Iodine, a method that we have extensively used in previous studies and shown not to alter the biological and biochemical properties of PrP Sc (28)(29)(30)(31) (32,33). To assess the ability of surface-bound prions to self-propagate, beads were incubated with serially diluted 263K prion-infected brain homogenate, extensively washed and air-dried; then, used to seed PMCA as previously described (32).…”

Section: Binding and Release Of Prions From Environmental Surfacesmentioning

confidence: 99%

“…Sc was purified using detergent extraction and PK digestion, as previously described (31). Briefly, 10% (w/v) brain homogenate was prepared in PBS supplemented with proteinase inhibitor (complete, Roche) and 10% sarkosyl (final concentration).…”

Section: Prpmentioning

confidence: 99%

“…Only the protease-resistant core of PrP Sc was found by silver staining of the final material, compared side by side with western blot. Resulting material was proven to amplify in PMCA conditions, as well as remain infectious (31). Purified protease-resistant PrP Sc was radiolabeled with Iodine-125 ( 125 I), using the Cloramine T method, described elsewhere (30).…”

Section: Prpmentioning

confidence: 99%

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Efficient prion disease transmission through common environmental materials

Pritzkow

Morales

Lyon

et al. 2018

Journal of Biological Chemistry

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Prion diseases are a group of fatal neurodegenerative diseases associated with a protein-based infectious agent, termed prion. Compelling evidence suggests that natural transmission of prion diseases is mediated by environmental contamination with infectious prions. We hypothesized that several natural and man-made materials, commonly found in the environments of wild and captive animals, can bind prions and may act as vectors for disease transmission. To test our hypothesis, we exposed surfaces composed of various common environmental materials (i.e. wood, rocks, plastic, glass, cement, stainless steel, aluminum, and brass) to hamster-adapted 263K scrapie prions and studied their attachment and retention of infectivity in vitro and in vivo. Our results indicated that these surfaces, with the sole exception of brass, efficiently bind, retain, and release prions. Prion replication was studied in vitro using the protein misfolding cyclic amplification technology and infectivity of surface-bound prions was analyzed by intracerebrally challenging hamsters with contaminated implants. Our results revealed that virtually all prion-contaminated materials transmitted the disease at high rates. To investigate a more natural form of exposure to environmental contamination, we simply housed animals with large contaminated spheres made of the different materials under study, instead of injecting them with prion materials. Strikingly, most of the hamsters developed classical clinical signs of prion disease and typical disease-associated brain changes. Our findings suggest that prion contamination of surfaces commonly present in the environment can be a source of disease transmission, thus expanding our understanding of the mechanisms for prion spreading in nature. ________________________________________ Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are infectious and invariably fatal neurological disorders affecting various species of mammals, including sheep, deer, cattle and humans (1,2). The hallmarks of TSEs include spongiform degeneration of the brain and the accumulation of an infectious agent termed prion, which is composed of a misfolded version (PrP Sc ) of the http://www.jbc.org/cgi

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Prions efficiently cross the intestinal barrier after oral administration: Study of the bioavailability, and cellular and tissue distribution in vivo

Cited by 17 publications

References 42 publications

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

Efficient prion disease transmission through common environmental materials

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