Follicular Dendritic Cell-Specific Prion Protein (PrPc) Expression Alone Is Sufficient to Sustain Prion Infection in the Spleen

McCulloch, Laura; Brown, Karen; Bradford, Barry; Hopkins, John; Bailey, Mick; Rajewsky, Klaus; Manson, Jean; Mabbott, Neil A.

doi:10.1371/journal.ppat.1002402

Cited by 94 publications

(151 citation statements)

References 65 publications

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“…Sc accumulation occurs in FDC of lymphoid tissues prior to in the neural tissues [29,30]. These results support that Ki+Tg#40 mice showing PrP Sc accumulation in FDC should develop BSE at preclinical stage after IP inoculation.…”

Section: It Is Reported In Other Tses Following Peripheral Routes Of supporting

confidence: 54%

A Rapid Bioassay for Classical and L-Type Bovine Spongiform Encephalopathies

Matsuura¹,

Ishikawa²,

Somerville³

et al. 2013

OJVM

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The rapid detection of infectivity of several agents that cause Creutzfeldt-Jakob disease has previously been achieved by assaying for deposits of abnormal prion protein (PrP Sc ) in follicular dendritic cells in the spleens of transgenic mice carrying the human prion protein gene. In this study, transgenic mice expressing the bovine prion protein were inoculated intraperitoneally with classical (C-type) or atypical L-type bovine spongiform encephalopathies (BSE). Proteinase-resistant PrP Sc were detected in the spleens of all transgenic mice at 75 days after inoculation with both types of BSE. Infectivity in PrP Sc -positive spleens of the transgenic mice revealed that prions of C-and L-type BSE replicated. These results suggest that bioassay system by the transgenic mice could be useful for the rapid detection of BSE infectivity with discriminating between C-and L-type BSEs.

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Section: It Is Reported In Other Tses Following Peripheral Routes Of supporting

confidence: 54%

A Rapid Bioassay for Classical and L-Type Bovine Spongiform Encephalopathies

Matsuura¹,

Ishikawa²,

Somerville³

et al. 2013

OJVM

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“…However, in the current study aged mice were refractory to clinical prion disease after injection with primary BSE prions by combined intracerebral and intraperitoneal injection. After peripheral exposure FDCs are considered to amplify prions above the threshold required to achieve neuroinvasion (Mabbott, 2012;McCulloch et al, 2011). We have shown previously that young SCID mice which lack mature FDCs in their spleens are also refractory to prion disease after intracerebral injection with primary BSE prions (Brown et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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

Brown

Mabbott

2014

Journal of General Virology

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The occurrence of variant Creutzfeldt–Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the ‘species barrier’, which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6–8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

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“…Although the central nervous system (CNS) represents the main site of PrP Sc replication and deposition, PrP Sc is also found in peripheral organs, including cells and organs of the lymphoreticular system (4-7). Not only does PrP Sc colonize secondary lymphoid organs (SLOs), the germinal centers of spleen and lymph nodes offer suitable environments for replicating PrP Sc autonomously from the CNS (8)(9)(10)(11). Prion colonization and replication in SLOs is important for several reasons.…”

Section: Enhanced Sialylation Of Prpmentioning

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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Follicular Dendritic Cell-Specific Prion Protein (PrPc) Expression Alone Is Sufficient to Sustain Prion Infection in the Spleen

Cited by 94 publications

References 65 publications

A Rapid Bioassay for Classical and L-Type Bovine Spongiform Encephalopathies

A Rapid Bioassay for Classical and L-Type Bovine Spongiform Encephalopathies

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

Post-conversion sialylation of prions in lymphoid tissues

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