Orally Administered Prion Protein Is Incorporated by M Cells and Spreads into Lymphoid Tissues with Macrophages in Prion Protein Knockout Mice

Takakura, Ikuro; Miyazawa, Kohtaro; Kanaya, Takashi; Itani, Wataru; Watanabe, Kouichi; Ohwada, Shyuichi; Watanabe, Hitoshi; Hondo, Tetsuya; Rose, Michael T.; Mori, Tsuyoshi; Sakaguchi, Suehiro; Nishida, Naoshi; Katamine, Shigeru; Yamaguchi, Takahiro; Aso, Hisashi

doi:10.1016/j.ajpath.2011.05.058

Cited by 44 publications

(37 citation statements)

References 53 publications

(58 reference statements)

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“…Blood has been shown previously to harbor CWD infectivity, particularly associated with B cells and platelets (12,32). In contrast, in PRNP knockout mice orally inoculated with the Fukuoka-1 strain of CJD, macrophages were identified as the cells responsible for transporting prions from intestinal mucosa to mesenteric lymph nodes and spleen (33). Further studies are needed to illuminate which lymphoid cell or cells are responsible for systemic prion trafficking in subclinical CWD and other prion diseases.…”

Section: Figmentioning

confidence: 92%

“…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). Additionally, gastrointestinal-associated lymphoid tissue (GALT) uptake appears to be required for neuroinvasion, as depletion of M cells or decreased numbers of Peyer's patches, but not lymphocytes, blocked the development of prion disease in mice (33,(41)(42)(43). Other imaging studies have suggested prions can use a paracellular route to cross the epithelial mucosal epithelium (40).…”

Section: Figmentioning

confidence: 99%

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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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Section: Figmentioning

confidence: 92%

Section: Figmentioning

confidence: 99%

Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

Hoover

Davenport

Henderson

et al. 2017

J Virol

View full text Add to dashboard Cite

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“…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). The temporal parameters and the cell types mediating the transepithelial transport of prions within the nasal cavity have not been established.…”

mentioning

confidence: 99%

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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“…M cells are thought to be involved in the infections of various pathogens, such as pathogenic bacteria, viruses or prions (Brayden et al, 2005;Clark et al, 1998;Heppner et al, 2001;Takakura et al, 2011). In addition, we have recently demonstrated that bovine M cells possess a higher capacity for transporting the transmissible spongiform encephalopathies (TSE) agent than enterocytes in vitro (Miyazawa et al, 2010), suggesting a risk of bovine M cells as the entry site for some pathogens.…”

Section: Discussionmentioning

confidence: 99%