scholarly journals Transmission of scrapie and sheep-passaged bovine spongiform encephalopathy prions to transgenic mice expressing elk prion protein

2009 ◽  
Vol 90 (4) ◽  
pp. 1035-1047 ◽  
Author(s):  
Gültekin Tamgüney ◽  
Michael W. Miller ◽  
Kurt Giles ◽  
Azucena Lemus ◽  
David V. Glidden ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Incubation Time ◽  
Transmitted Disease ◽  
Cerebellar Nuclei ◽  
Infected Sheep ◽  
Neurological Dysfunction ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Naturally Occurring

Chronic wasting disease (CWD) is a transmissible, fatal prion disease of cervids and is largely confined to North America. The origin of CWD continues to pose a conundrum: does the disease arise spontaneously or result from some other naturally occurring reservoir? To address whether prions from sheep might be able to cause disease in cervids, we inoculated mice expressing the elk prion protein (PrP) transgene [Tg(ElkPrP) mice] with two scrapie prion isolates. The SSBP/1 scrapie isolate transmitted disease to Tg(ElkPrP) mice with a median incubation time of 270 days, but a second isolate failed to produce neurological dysfunction in these mice. Although prions from cattle with bovine spongiform encephalopathy (BSE) did not transmit to the Tg(ElkPrP) mice, they did transmit after being passaged through sheep. In Tg(ElkPrP) mice, the sheep-passaged BSE prions exhibited an incubation time of approximately 300 days. SSBP/1 prions produced abundant deposits of the disease-causing PrP isoform, denoted PrPSc, in the cerebellum and pons of Tg(ElkPrP) mice, whereas PrPSc accumulation in Tg mice inoculated with sheep-passaged BSE prions was confined to the deep cerebellar nuclei, habenula and the brainstem. The susceptibility of ‘cervidized’ mice to ‘ovinized’ prions raises the question about why CWD has not been reported in other parts of the world where cervids and scrapie-infected sheep coexist.

scholarly journals Pathological Prion Protein in the Tongues of Sheep Infected with Naturally Occurring Scrapie

2005 ◽  
Vol 79 (9) ◽  
pp. 5847-5849 ◽  
Author(s):  
Cristina Casalone ◽  
Cristiano Corona ◽  
Maria Ines Crescio ◽  
Francesca Martucci ◽  
Maria Mazza ◽  
...  
Keyword(s):  
Food Safety ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Western Blotting ◽  
Infected Sheep ◽  
Spongiform Encephalopathy ◽  
Rodent Models ◽  
Naturally Occurring ◽  
Transmissible Mink Encephalopathy ◽  
Experimental Challenge

ABSTRACT Tongue involvement by prion spreading was shown to be a common outcome after oral or intracranial experimental challenge with scrapie and transmissible mink encephalopathy sources in rodent models. It is also known that bovine spongiform encephalopathy, which is pathogenic for humans, is experimentally transmissible to sheep and can lead to a disease indistinguishable from scrapie. A recent European Food Safety Authority opinion recommended research into PrPsc accumulation in the tongues of ruminants. We report on the detection of PrPsc in the tongues of seven scrapie-infected sheep by immunohistochemistry and Western blotting.

scholarly journals Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep

2005 ◽  
Vol 86 (3) ◽  
pp. 827-838 ◽  
Author(s):  
Lorenzo González ◽  
Stuart Martin ◽  
Fiona E. Houston ◽  
Nora Hunter ◽  
Hugh W. Reid ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Incubation Period ◽  
Prion Protein ◽  
Neurological Disease ◽  
Infected Sheep ◽  
Spongiform Encephalopathy ◽  
Brain Areas ◽  
Naturally Occurring ◽  
Jakob Disease ◽  
The Brain

In view of the established link between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob disease and of the susceptibility of sheep to experimental BSE, the detection of potential cases of naturally occurring BSE in sheep has become of great importance. In this study, the immunohistochemical (IHC) phenotype of disease-associated prion protein (PrPd) accumulation has been determined in the brain of 64 sheep, of various breeds and PrP genotypes, that had developed neurological disease after experimental BSE challenge with different inocula by a range of routes. Sheep BSE was characterized by neuron-associated intra- and extracellular PrPd aggregates and by conspicuous and consistent deposits in the cytoplasm of microglia-like cells. The stellate PrPd type was also prominent in most brain areas and marked linear deposits in the striatum and midbrain were distinctive. Sheep of the ARR/ARR and ARQ/AHQ genotypes displayed lower levels of PrPd than other sheep, and intracerebral BSE challenge resulted in higher levels of PrPd accumulating in the brain compared with other routes. The PrP genotype and the route of challenge also appeared to affect the incubation period of the disease, giving rise to complex combinations of magnitude of PrPd accumulation and incubation period. Despite these differences, the phenotype of PrPd accumulation was found to be very consistent across the different factors tested (notably after subpassage of BSE in sheep), thus highlighting the importance of detailed IHC examination of the brain of clinically affected sheep for the identification of potential naturally occurring ovine BSE.

scholarly journals Prion Type-Dependent Deposition ofPRNPAllelic Products in Heterozygous Sheep

2015 ◽  
Vol 90 (2) ◽  
pp. 805-812 ◽  
Author(s):  
J. P. M. Langeveld ◽  
J. G. Jacobs ◽  
N. Hunter ◽  
L. J. M. van Keulen ◽  
F. Lantier ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Transmissible Spongiform Encephalopathy ◽  
Infected Sheep ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Sequence Variants ◽  
Spongiform Encephalopathies

ABSTRACTSusceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrPres) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrPresmaterial from BSE-infected ARR/VRQ sheep. PrPresin BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ-PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrPresaccumulation process in prion formation as well as the disease-associated phenotypic expressions in the host.IMPORTANCETransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R-PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation.

scholarly journals Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein

2012 ◽  
Vol 93 (7) ◽  
pp. 1624-1629 ◽  
Author(s):  
Rona Wilson ◽  
Chris Plinston ◽  
Nora Hunter ◽  
Cristina Casalone ◽  
Cristiano Corona ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Human Prion Protein

The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

scholarly journals Comparative Molecular Analysis of the Abnormal Prion Protein in Field Scrapie Cases and Experimental Bovine Spongiform Encephalopathy in Sheep by Use of Western Blotting and Immunohistochemical Methods

2004 ◽  
Vol 78 (7) ◽  
pp. 3654-3662 ◽  
Author(s):  
Stéphane Lezmi ◽  
Stuart Martin ◽  
Stéphanie Simon ◽  
Emmanuel Comoy ◽  
Anna Bencsik ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Western Blotting ◽  
Molecular Analysis ◽  
Infected Sheep ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spongiform Encephalopathy ◽  
Protease Cleavage ◽  
Two Samples ◽  
Immunohistochemical Methods

ABSTRACT Since the appearance of bovine spongiform encephalopathy (BSE) in cattle and its linkage with the human variant of Creutzfeldt-Jakob disease, the possible spread of this agent to sheep flocks has been of concern as a potential new source of contamination. Molecular analysis of the protease cleavage of the abnormal prion protein (PrP), by Western blotting (PrPres) or by immunohistochemical methods (PrPd), has shown some potential to distinguish BSE and scrapie in sheep. Using a newly developed enzyme-linked immunosorbent assay, we identified 18 infected sheep in which PrPres showed an increased sensitivity to proteinase K digestion. When analyzed by Western blotting, two of them showed a low molecular mass of unglycosylated PrPres as found in BSE-infected sheep, in contrast to other naturally infected sheep. A decrease of the labeling by P4 monoclonal antibody, which recognizes an epitope close to the protease cleavage site, was also found by Western blotting in the former two samples, but this was less marked than in BSE-infected sheep. These two samples, and all of the other natural scrapie cases studied, were clearly distinguishable from those from sheep inoculated with the BSE agent from either French or British cattle by immunohistochemical analysis of PrPd labeling in the brain and lymphoid tissues. Final characterization of the strain involved in these samples will require analysis of the features of the disease following infection of mice, but our data already emphasize the need to use the different available methods to define the molecular properties of abnormal PrP and its possible similarities with the BSE agent.

scholarly journals Comparison of Abnormal Prion Protein Glycoform Patterns from Transmissible Spongiform Encephalopathy Agent-Infected Deer, Elk, Sheep, and Cattle

2002 ◽  
Vol 76 (23) ◽  
pp. 12365-12368 ◽  
Author(s):  
Richard E. Race ◽  
Anne Raines ◽  
Thierry G. M. Baron ◽  
Michael W. Miller ◽  
Allen Jenny ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathy ◽  
Spongiform Encephalopathy ◽  
Wasting Disease

ABSTRACT Analysis of abnormal prion protein glycoform patterns from chronic wasting disease (CWD)-affected deer and elk, scrapie-affected sheep and cattle, and cattle with bovine spongiform encephalopathy failed to identify patterns capable of reliably distinguishing these transmissible spongiform encephalopathy diseases. However, PrP-res patterns sometimes differed among individual animals, suggesting infection by different or multiple CWD strains in some species.

scholarly journals Characterization of two distinct prion strains derived from bovine spongiform encephalopathy transmissions to inbred mice

2004 ◽  
Vol 85 (8) ◽  
pp. 2471-2478 ◽  
Author(s):  
Sarah E. Lloyd ◽  
Jacqueline M. Linehan ◽  
Melanie Desbruslais ◽  
Susan Joiner ◽  
Jennifer Buckell ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Incubation Time ◽  
Inbred Mice ◽  
Biochemical Properties ◽  
Distinct Pattern ◽  
Spongiform Encephalopathy ◽  
Prion Strain ◽  
Disease Phenotypes ◽  
Prion Strains

Distinct prion strains can be distinguished by differences in incubation period, neuropathology and biochemical properties of disease-associated prion protein (PrPSc) in inoculated mice. Reliable comparisons of mouse prion strain properties can only be achieved after passage in genetically identical mice, as host prion protein sequence and genetic background are known to modulate prion disease phenotypes. While multiple prion strains have been identified in sheep scrapie and Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (BSE) is thought to be caused by a single prion strain. Primary passage of BSE prions to different lines of inbred mice resulted in the propagation of two distinct PrPSc types, suggesting that two prion strains may have been isolated. To investigate this further, these isolates were subpassaged in a single line of inbred mice (SJL) and it was confirmed that two distinct prion strains had been identified. MRC1 was characterized by a short incubation time (110±3 days), a mono-glycosylated-dominant PrPSc type and a generalized diffuse pattern of PrP-immunoreactive deposits, while MRC2 displayed a much longer incubation time (155±1 days), a di-glycosylated-dominant PrPSc type and a distinct pattern of PrP-immunoreactive deposits and neuronal loss. These data indicate a crucial involvement of the host genome in modulating prion strain selection and propagation in mice. It is possible that multiple disease phenotypes may also be possible in BSE prion infection in humans and other animals.

scholarly journals Resistance to Chronic Wasting Disease in Transgenic Mice Expressing a Naturally Occurring Allelic Variant of Deer Prion Protein

2007 ◽  
Vol 81 (9) ◽  
pp. 4533-4539 ◽  
Author(s):  
Kimberly Meade-White ◽  
Brent Race ◽  
Matthew Trifilo ◽  
Alex Bossers ◽  
Cynthia Favara ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Prion Disease ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathy ◽  
Brain Regions ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Intestinal Tissue ◽  
Naturally Occurring

ABSTRACT Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer or elk PrP in transgenic mice has induced susceptibility to chronic wasting disease (CWD), the prion disease of cervids. In the current experiments, transgenic mice expressing two naturally occurring allelic variants of deer PrP with either glycine (G) or serine (S) at residue 96 were found to differ in susceptibility to CWD infection. G96 mice were highly susceptible to infection, and disease appeared starting as early as 160 days postinfection. In contrast, S96 mice showed no evidence of disease or generation of disease-associated protease-resistant PrP (PrPres) over a 600-day period. At the time of clinical disease, G96 mice showed typical vacuolar pathology and deposition of PrPres in many brain regions, and in some individuals, extensive neuronal loss and apoptosis were noted in the hippocampus and cerebellum. Extraneural accumulation of PrPres was also noted in spleen and intestinal tissue of clinically ill G96 mice. These results demonstrate the importance of deer PrP polymorphisms in susceptibility to CWD infection. Furthermore, this deer PrP transgenic model is the first to demonstrate extraneural accumulation of PrPres in spleen and intestinal tissue and thus may prove useful in studies of CWD pathogenesis and transmission by oral or other natural routes of infection.

scholarly journals Insights into Chronic Wasting Disease and Bovine Spongiform Encephalopathy Species Barriers by Use of Real-Time Conversion

2015 ◽  
Vol 89 (18) ◽  
pp. 9524-9531 ◽  
Author(s):  
Kristen A. Davenport ◽  
Davin M. Henderson ◽  
Jifeng Bian ◽  
Glenn C. Telling ◽  
Candace K. Mathiason ◽  
...  
Keyword(s):  
New Species ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Protein Interactions ◽  
Chronic Wasting Disease ◽  
Spongiform Encephalopathy ◽  
Protein Protein Interactions ◽  
Wasting Disease ◽  
Prion Transmission ◽  
A New Species

ABSTRACTThe propensity for transspecies prion transmission is related to the structural characteristics of the enciphering and new host PrP, although the exact mechanism remains incompletely understood. The effects of variability in prion protein on cross-species prion transmission have been studied with animal bioassays, but the influence of prion protein structure versus that of host cofactors (e.g., cellular constituents, trafficking, and innate immune interactions) remains difficult to dissect. To isolate the effects of protein-protein interactions on transspecies conversion, we used recombinant PrPCand real-time quaking-induced conversion (RT-QuIC) and compared chronic wasting disease (CWD) and classical bovine spongiform encephalopathy (cBSE) prions. To assess the impact of transmission to a new species, we studied feline CWD (fCWD) and feline BSE (i.e., feline spongiform encephalopathy [FSE]). We cross-seeded fCWD and FSE into each species' full-length, recombinant PrPCand measured the time required for conversion to the amyloid (PrPRes) form, which we describe here as the rate of amyloid conversion. These studies revealed the following: (i) CWD and BSE seeded their homologous species' PrP best; (ii) fCWD was a more efficient seed for feline rPrP than for white-tailed deer rPrP; (iii) conversely, FSE more efficiently converted bovine than feline rPrP; (iv) and CWD, fCWD, BSE, and FSE all converted human rPrP, although not as efficiently as homologous sCJD prions. These results suggest that (i) at the level of protein-protein interactions, CWD adapts to a new species more readily than does BSE and (ii) the barrier preventing transmission of CWD to humans may be less robust than estimated.IMPORTANCEWe demonstrate that bovine spongiform encephalopathy prions maintain their transspecies conversion characteristics upon passage to cats but that chronic wasting disease prions adapt to the cat and are distinguishable from the original prion. Additionally, we showed that chronic wasting disease prions are effective at seeding the conversion of normal human prion protein to an amyloid conformation, perhaps the first step in crossing the species barrier.

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