Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy

Brown, Karen; Mabbott, Neil A.

doi:10.1099/vir.0.058958-0

Cited by 26 publications

(46 citation statements)

References 53 publications

(88 reference statements)

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“…Although many of these changes were most prominent in mice ≥ 18 months old, significant disruption to the MAdCAM‐1 + MZ sinus lining cells was evident from as early as 9 months old and preceded the changes to MZ B cells observed at 12 months. Hence these data show that significant ageing‐related changes are evident in the splenic MZ much earlier than has been previously described 6, 7, 8. The timing of the changes observed also suggests that the ageing‐related disturbances to the distribution of the MAdCAM‐1 + MZ sinus lining cells may lead to subsequent disturbances to the distribution of MZ B cells and MZ metallophilic macrophages.…”

Section: Resultssupporting

confidence: 67%

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Ageing adversely affects the migration and function of marginal zone B cells

Turner

Mabbott

2017

Immunology

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SummaryMarginal zone (MZ) B cells are positioned within the spleen to capture blood‐borne antigen and immune complexes and deliver them to follicular dendritic cells in the B‐cell follicles. We show that within the spleens of aged mice antigen capture by MZ B cells, and their ability to shuttle between the follicle and MZ, were impaired. The ability of aged MZ B cells to migrate towards the MZ chemoattractant sphingosine‐1‐phosphate was increased, suggesting that aged MZ B cells had a greater propensity to be retained within the MZ. An extrinsic impairment in aged B‐cell migration towards the MZ was demonstrated using bone marrow chimeras. The follicular shuttling of MZ B cells derived from either young or aged bone marrow was similarly reduced in aged recipient spleens, showing that ageing effects on splenic stromal cells were responsible for the impaired follicular shuttling of MZ B cells. MZ B cells rapidly mount T‐cell‐independent (TI) antibody‐responses to microbial polysaccharide antigen. In aged mice the ability to produce immunoglobulins in response to the TI type 1 antigen TNP‐LPS was impaired. These ageing‐related changes to the MZ and MZ B cells have implications for the clearance of blood‐borne pathogens. Indeed elderly people have increased susceptibility to Streptococcus pneumoniae, a TI antigen, and decreased responses to vaccination. A thorough analysis of the mechanisms that underpin the ageing‐related decline in the status of the MZ and MZ B cells will help the design of novel treatments to improve immunity in the elderly.

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Section: Resultssupporting

confidence: 67%

“…Our laboratory has previously demonstrated this in 20‐month‐old C57BL/Dk and RIII mice,6, 7 and an independent study has reported disturbances to the MZ in C57BL/6 mice > 12 months old 9. Others have also demonstrated changes to the MZ of 17‐ to 18‐month‐old BALB/c mice 8.…”

Section: Resultsmentioning

confidence: 67%

Ageing adversely affects the migration and function of marginal zone B cells

Turner

Mabbott

2017

Immunology

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“…Studies using transgenic mice expressing human PrP C suggest that the transmission of BSE to humans is restricted by a significant species barrier [74]. After interspecies prion exposure, the processing and amplification of prions upon FDC in lymphoid tissues is important for their adaptation to the new host and to achieve neuroinvasion [75, 76]. Thus, it is plausible that factors which increase the density of M cells in the small intestine may enable a greater burden of prions to enter Peyer’s patches, increasing the probability that more will be able to avoid clearance by cells such as macrophages, [11, 77].…”

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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“…Although the mechanisms behind high permissiveness of lymphoid tissues to prions are not known, prions acquired via cross-species transmission can persist stably and silently in SLOs for a long time in the absence of neuroinvasion (15,56,57). Aged animals that are known to be less susceptible to prion infection than young animals can also accumulate prions within their lymphoid tissues, despite lack of prions in their brains (58). Moreover, the lymphoid tissues display a higher capacity than nerve tissues to replicate prions after low-dose infection (59).…”

Section: Discussionmentioning

confidence: 99%

Post-conversion sialylation of prions in lymphoid tissues

Srivastava

Makarava

Katorcha

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Sialylated glycans on the surface of mammalian cells act as part of a "self-associated molecular pattern," helping the immune system to recognize "self" from "altered self" or "nonself." To escape the host immune system, some bacterial pathogens have evolved biosynthetic pathways for host-like sialic acids, whereas others recruited host sialic acids for decorating their surfaces. Prions lack nucleic acids and are not conventional pathogens. Nevertheless, prions might use a similar strategy for invading and colonizing the lymphoreticular system. Here we show that the sialylation status of the infectious, disease-associated state of the prion protein (PrP Sc ) changes with colonization of secondary lymphoid organs (SLOs). As a result, spleen-derived PrP Sc is more sialylated than brain-derived PrP Sc . Enhanced sialylation of PrPSc is recapitulated in vitro by incubating brain-derived PrP Sc with primary splenocytes or cultured macrophage RAW 264.7 cells. General inhibitors of sialyltranserases (STs), the enzymes that transfer sialic acid residues onto terminal positions of glycans, suppressed extrasialylation of PrP Sc . A fluorescently labeled precursor of sialic acid revealed ST activity associated with RAW macrophages. This study illustrates that, upon colonization of SLOs, the sialylation status of prions changes by host STs. We propose that this mechanism is responsible for camouflaging prions in SLOs and has broad implications.prions | prion diseases | sialic acid | sialylated glycans | macrophages

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Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy

Cited by 26 publications

References 53 publications

Ageing adversely affects the migration and function of marginal zone B cells

Ageing adversely affects the migration and function of marginal zone B cells

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

Post-conversion sialylation of prions in lymphoid tissues

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