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In mammals, susceptibility to prion infection is primarily modulated by the host's cellular prion protein (PrP(C)) sequence. In the sheep scrapie model, a graded scale of susceptibility has been established both in vivo and in vitro based on PrP(C) amino acids 136, 154 and 171, leading to global breeding programmes to reduce the prevalence of scrap...
Development of mice expressing either ovine (Tg338) or cervid (TgElk) prion protein (PrP) have aided in characterization of scrapie and chronic wasting disease (CWD), respectively. Experimental inoculation of sheep with CWD prions has demonstrated the potential for interspecies transmission but, infection with CWD versus classical scrapie prions ma...
To assess scrapie infectivity associated with caprine-origin tissues, bioassay can be performed using kids, lambs or transgenic mice expressing caprine or ovine prion (PRNP) alleles, but the incubation periods are fairly long. Although several classical ovine scrapie prion permissive cell lines with the ability to detect brain-derived scrapie prion...
The purpose of our study was to describe the progressive accumulation of the abnormal conformer of the prion protein (PrP(CWD)) and spongiform degeneration in a single section of brain stem in Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease (CWD). A section of obex from 85 CWD-positive elk was scored using the presence and...
Figure S1 Detection of PrPSc immunolabeling in lymph nodes and brainstem at the obex of G/S127 goats intracerebrally inoculated with classical caprine scrapie.
Appendix S1 Supplementary Methods.
Table S1 Intracerebral inoculation of goat kids with homozygous (G/G127) or heterozygous (G/S127) brain‐derived inocula prepared from clinically affected goats with naturally acquired classical caprine scrapie.
Diagnostic analyses often employ single antibody systems but are potentially limited by epitope sequence variation. United States regulatory testing for scrapie primarily uses antibody F99/97.6.1 for immunohistochemistry (IHC) of the prion protein associated with scrapie (PrP(Sc)). Whereas the epitope bound by F99/97.6.1 is highly conserved in shee...
The placenta of domestic sheep plays a key role in horizontal transmission of classical scrapie. Domestic goats are frequently raised with sheep and are susceptible to classical scrapie, yet potential routes of transmission from goats to sheep are not fully defined. Sparse accumulation of disease-associated prion protein in cotyledons casts doubt a...
Although antemortem scrapie diagnosis in sheep is determined by the detection of misfolded isoforms of prion protein (PrP(Sc)) in lymphoid follicles of the rectal mucosa and nictitating membranes, assay sensitivity is limited if (a) the biopsy is collected early during the disease, (b) insufficient number of follicles are collected or (c) periphera...
Chronic wasting disease (CWD) adversely affects both wild and captive cervid populations. A vaccine to prevent CWD would be a highly desirable tool to aid in disease management. To this end, we tested in mule deer a combination of CWD vaccines consisting of cervid prion peptide sequences 168-VDQYNNQNTFVHDC-182 and 145-NDYEDRYYRENMYRYPNQ-164 that ha...
Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal ro...
A reliable antemortem test is needed to understand the ecology of chronic wasting disease (CWD) in elk (Cervus elaphus nelsoni). We measured the ability of antemortem biopsy samples from the rectal mucosa to detect the abnormal prion protein associated with CWD (PrP(CWD)), the relationship between test results from the obex and rectal biopsies at v...
An effective live animal diagnostic test is needed to assist in the control of chronic wasting disease (CWD), which has spread through captive and wild herds of white-tailed deer (Odocoileus virginianus) in Canada and the United States. In the present study, the diagnostic accuracy of rectal mucosa biopsy sample testing was determined in white-tail...
Chronic wasting disease (CWD), a transmissible spongiform encephalopathy of cervids, remains prevalent in North American elk, white-tailed deer and mule deer. A natural case of CWD in reindeer (Rangifer tarandus tarandus) has not been reported despite potential habitat overlap with CWD-infected deer or elk herds. This study investigates the experim...
The protein misfolding cyclic amplification (PMCA) assay allows for detection of prion protein misfolding activity in tissues and fluids from sheep with scrapie where it was previously undetected by conventional western blot and immunohistochemistry assays. Studies of goats with scrapie have yet to take advantage of PMCA, which could aid in discern...
Transmissible spongiform encephalopathies (TSEs) are diagnosed by immunodetection of disease-associated prion protein (PrP(d)). The distribution of PrP(d) within the body varies with the time-course of infection and between species, during interspecies transmission, as well as with prion strain. Mink are susceptible to a form of TSE known as transm...
Scrapie is the transmissible spongiform encephalopathy (TSE) of sheep and goats, and scrapie eradication in sheep is based in part on strong genetic resistance to classical scrapie. Goats may serve as a scrapie reservoir, and to date there has been no experimental inoculation confirming strong genetic resistance in goats. Two prion protein variants...
Background
The United States control program for classical ovine scrapie is based in part on the finding that infection is typically spread through exposure to shed placentas from infected ewes. Transmission from goats to sheep is less well described. A suitable rodent model for examining the effect of caprine scrapie isolates in the ovine host wil...
Chronic wasting disease (CWD) is a major concern for the management of North American cervid populations. This fatal prion disease has led to declines in populations which have high CWD prevalence and areas with both high and low infection rates have experienced economic losses in wildlife recreation and fears of potential spill-over into livestock...
Although host-encoded prion protein (PrP(C)) expression in ovine PBMCs and prion infectivity in scrapie-infected sheep blood have been demonstrated, such studies have not been reported in goats. Therefore, this study characterized cell-surface expression of PrP(C) on PBMC subsets derived from normal goats and sheep, by flow cytometry, and determine...
Classical scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats characterized by cellular accumulation of abnormal isoforms of prion protein (PrPSc) in the central nervous system and the follicles of peripheral lymphoid tissues. Previous studies have shown that the whole blood and buffy coat blood fraction of s...
Scrapie is a prion-associated transmissible spongiform encephalopathy (TSE) of sheep and goats, and frequently serves as a comparative model for other prion diseases, such as chronic wasting disease and bovine spongiform encephalopathy. TSEs are unique neurologic disorders that do not appear to be accompanied by robust systemic immunologic response...
We monitored a herd of fallow deer (Dama dama) for evidence of prion infection for 7 yr by periodic postmortem examination of animals from the herd. The fallow deer were exposed to the chronic wasting disease (CWD) agent from mule deer by living in a paddock considered contaminated with infectivity from its history of housing CWD infected deer and,...
Domestic goats (Capra hircus) are a natural and experimental host of scrapie and bovine spongiform encephalopathy, the transmissible spongiform encephalopathies (TSE) of sheep and cattle. Goats are also susceptible to experimental infection with the agents of TSEs of deer and elk (chronic wasting disease) and humans (Creutzfeldt Jakob disease). Dis...
Tissues unsuitable for standard immunohistochemical and histopathological examinations for chronic wasting disease (CWD) in cervids and for scrapie in sheep are frequently submitted for testing. This study investigated the effects of experimental autolysis on the detection of abnormal prion protein (PrPsc) in lymphoid and central nervous system (CN...
Amplification primers and conditions. Primer sequences, strand directions, base positions relative to reference sequences, annealing temperatures, and included region descriptions.
Sequencing primers. Primer sequences, strand directions, base positions relative to reference sequences, and descriptions of regions sequenced using each primer.
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids including white-tailed (Odocoileus virginianus) and mule deer (Odocoileus hemionus), Rocky Mountain elk (Cervus elaphus nelsoni), and moose (Alces alces). A leucine variant at position 132 (132L) in prion protein of Rocky Mountain elk confers a long incubati...
This report describes the genetics of the prion protein gene (PRNP) at codons 136, 154, and 171 for sheep diagnosed with naturally acquired classical scrapie in Canada between 1998 and 2008. Genotyping analysis was performed on 249 sheep with confirmed classical scrapie infection representing 98 flocks from 6 provinces. A further case-control analy...
Scrapie, a transmissible spongiform encephalopathy of sheep and goats, exists in most small ruminant-producing countries of the world. A novel form of this disease was recently recognized and is known by various names, including Nor98, Nor98-like, and atypical scrapie. Differing from classic scrapie in epidemiology, histopathology, and biochemical...
Eyes and nuclei of the visual pathways in the brain were examined in 30 Rocky Mountain elk (Cervus elaphus nelsoni) representing 3 genotypes of the prion protein gene PRNP (codon 132: MM, ML, or LL). Tissues were examined for the presence of the abnormal isoform of the prion protein associated with chronic wasting disease (PrP(CWD)). Nuclei and axo...
Molecular genetic data provide powerful tools for genealogy reconstruction to reveal mechanisms underlying disease ecology. White-tailed deer (Odocoileus virginianus) congregate in matriarchal groups; kin-related close social spacing may be a factor in the spread of infectious diseases. Spread of chronic wasting disease (CWD), a prion disorder of d...
Chronic wasting disease (CWD), an important emerging prion disease of cervids, is readily transmitted by intracerebral or oral inoculation from deer-to-deer and elk-to-elk, suggesting the latter is a natural route of exposure. Studies of host range susceptibility to oral infection, particularly of those species found in habitats where CWD currently...
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of Rocky Mountain elk in North America. Recent studies suggest that tissue and blood mineral levels may be valuable in assessing TSE infection in sheep and cattle. The objectives of this study were to examine baseline levels of copper, manganese, magnesium, zinc, selen...
A distinct strain of scrapie identified in sheep of Norway in 1998 has since been identified in numerous countries throughout Europe. The disease is known as Nor98 or Nor98-like scrapie, among other names. Distinctions between classic scrapie and Nor98 scrapie are made based on histopathology and immunodiagnostic results. There are also differences...
Chronic wasting disease (CWD) is a contagious, fatal prion disease of deer and elk that continues to emerge in new locations. To explore the means by which prions are transmitted with high efficiency among cervids, we examined prion infectivity in the apical skin layer covering the growing antler (antler velvet) by using CWD-susceptible transgenic...
Classical scrapie disease is a transmissible spongiform encephalopathy of sheep that is enzootic in the United States. Susceptibility of sheep to classical scrapie is linked to single nucleotide polymorphisms in the prion protein gene (PRNP), forming the basis for genetic testing strategies used by national efforts to eradicate scrapie. Such effort...
The examination of rectoanal mucosa-associated lymphoid tissue (RAMALT) biopsy specimens for the diagnosis of transmissible spongiform encephalopathies has been described in sheep, elk, and small numbers of mule and white-tailed deer. Previous sample numbers have been too small to validate examination of this type of tissue as a viable antemortem d...
Antemortem biopsy of the rectal mucosa was evaluated as a method for the preclinical diagnosis of chronic wasting disease (CWD) in a herd of ranch-raised Rocky Mountain elk (Cervus elaphus nelsoni) quarantined because of exposure to CWD. Biopsy samples were obtained from 41 elk during the winter of 2005-2006 and from 26 elk from that herd still ali...
Selective breeding of sheep for arginine (R) at prion gene (PRNP) codon 171 confers resistance to classical scrapie. However, other effects of 171R selection are uncertain. Ovine progressive pneumonia/Maedi-Visna virus (OPPV) may infect up to 66% of a flock thus any affect of 171R selection on OPPV susceptibility or disease progression could have m...
In September 2002, chronic wasting disease (CWD), a prion disorder of captive and wild cervids, was diagnosed in a white-tailed deer (Odocoileus virginianus) from a captive farm in Wisconsin. The facility was subsequently quarantined, and in January 2006 the remaining 76 deer were depopulated. Sixty animals (79%) were found to be positive by immuno...
Variation in the ovine prion protein amino acid sequence influences scrapie progression, with sheep homozygous for A136R154Q171 considered susceptible. This study examined the association of survival time of scrapie-exposed ARQ sheep with variation
elsewhere in the ovine prion gene. Four single nucleotide polymorphism alleles were associated with p...
Sheep scrapie is the prototypical transmissible spongiform encephalopathy (prion disease), which has a fundamental pathogenesis
involving conversion of normal cellular prion protein (PrPC [C superscript stands for cellular]) to disease-associated prion protein (PrPSc [Sc superscript stands for sheep scrapie]). Sheep microglial cell cultures, derive...
Scrapie eradication efforts cost 18 million dollars annually in the United States and rely heavily upon PRNP genotyping of sheep. Genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so PRNP coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at...
Collaboration was established in 2001 to evaluate a commercially available immunohistochemistry assay kit for the detection of bovine spongiform encephalopathy (BSE) disease-associated prion protein in formic acid-treated formalin-fixed samples of bovine brain. The kit protocol was evaluated at the National Centre for Foreign Animal Diseases (Winni...
Neuroinvasion of the enteric nervous system by prions is an important step in dissemination to the brain, yet very little is known about the basic process of enteric neuroinvasion. Using an alimentary model of neonatal disease transmission, neuroinvasion by scrapie prions in the ileum of lambs was detected by immunohistochemical staining for the di...
To compare clinical and pathologic findings of chronic wasting disease (CWD) in a natural host, 3 groups (n = 5) of white-tailed deer (WTD) fawns were intracerebrally inoculated with a CWD prion of WTD, mule deer, or elk origin. Three other uninoculated fawns served as controls. Approximately 10 months postinoculation (MPI), 1 deer from each of the...
For placental transmission of scrapie to occur, the normal cellular prion protein (PrPC) must be converted to an abnormal infectious form known as PrPSc. PrPC genotype influences susceptibility to contracting scrapie, but we still do not understand whether genotype or expression levels of PrPC are important in transmission of scrapie. Some evidence...
Transmissible mink encephalopathy (TME) occurs as sporadic outbreaks associated with ingestion of feed presumably contaminated with some type of prion disease. Mink lack a species barrier to primary oral challenge with bovine spongiform encephalopathy, whereas they have a barrier to such challenge with scrapie. We investigated whether mink have a s...
Scrapie eradication efforts cost 18 million dollars annually in the United States and rely heavily upon PRNP genotyping of sheep. Genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so PRNP coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at...
The transmissible spongiform encephalopathies (TSEs) invariably result in fatal neurodegeneration and accumulation of PrP, an abnormal form of the host prion protein PrP, encoded by the PRNP gene. A naturally occurring polymorphism (methionine/valine) at PRNP codon 129 is associated with variation in relative disease susceptibility, incubation time...
To determine whether selection for the homozygous A136 R171 genotype that confers resistance to classic scrapie infection negatively affects production traits in sheep.
996 commercial lambs obtained from 2 flocks at separate locations across 3 consecutive years. Procedures-Genotyping at codon 136 and 171 was performed by use of commercially availab...
Scrapie is a neurodegenerative disease in domestic sheep and goats. Scrapie has a long incubation period that can vary from two to five years. The etiology is an extremely stable isoform (PrP8c) of the normal cellular prion protein (PrPc). The accumulation of this protein in the brain is thought to result in the spongiform encephalopathy that chara...
The objective of this study was to develop a reliable Taqman 5' Nuclease Assay for genotyping sheep for scrapie susceptibility. The sheep prion gene contains 2 single nucleotide polymorphisms (SNPs) that may mediate resistance to classical scrapie, one at codon 136, alanine (A) or valine (V), and another at codon 171, arginine (R) or glutamine (Q)....
Placentae from scrapie-infected ewes have been shown to accumulate PrPSc when the genotype of the fetus is of a susceptible genotype (VRQ/VRQ, ARQ/VRQ or ARQ/ARQ). Cotyledons from fetuses of genotypes ARR/ARR, ARQ/ARR and ARQ/VRR have previously been shown to be resistant to PrPSc accumulation. By using ewes from a naturally infected scrapie flock,...
Two commercially available automated immunohistochemistry platforms, Ventana NexES and DakoCytomation Autostainer Universal Staining System, were compared for diagnosing sheep scrapie and cervid chronic wasting disease. Both automated platforms used the same antiprion protein monoclonal primary antibodies, but different platform-specific linker and...
Numerous sheep with the prion gene (PRNP) that encodes for 171QQ develop scrapie, a neurodegenerative prion disease of sheep. Relatively few cases of scrapie-affected sheep with PRNP genetics that encode for 171RR, however, have been found. Using flow cytometric analysis, statistically fewer PrPc-positive microglia and monocytes were observed from...
Chronic wasting disease (CWD), a transmissible prion disease that affects elk and deer, poses new challenges to animal and human health. Although the transmission of CWD to humans has not been proven, it remains a possibility. If this were to occur, it is important to know whether the "acquired" human prion disease would show a phenotype including...
To compare the genetic susceptibility of elk (Cervus elaphus nelsoni) with various alleles of the PRNP gene, which encodes the normal cellular prion protein, to chronic wasting disease (CWD), eight 8-month-old elk calves of 3 genotypes (2 132MM, 2 132LM, and 4 132LL) were orally dosed with CWD-infected brain material from elk. During postinoculatio...