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All major prion types recognised by a multiplex immunofluorometric assay for disease screening and confirmation in sheep
Tang, Y. ; gielbert, A. ; Jacobs, J.G. ; Baron, T. ; Andreoletti, O. ; Langeveld, J.P.M. ; Sauer, M.J. - \ 2012
Journal of Immunological Methods 380 (2012)1-2. - ISSN 0022-1759 - p. 30 - 39.
bovine spongiform encephalopathy - atypical scrapie - natural scrapie - monoclonal-antibodies - molecular analysis - protein - bse - ch1641 - strains - isolate
Prion diseases or transmissible spongiform encephalopathies (TSEs) in small ruminants are presented in many forms: classical scrapie, Nor98/atypical scrapie, CH1641 scrapie and bovine spongiform encephalopathy (BSE). We previously described a multiplex immunofluorometric assay (mIFMA), based on a bead array flow cytometry technology, which provided, in a single assay, discrimination between BSE (in cattle and sheep) and classical scrapie (Tang et al., 2010). In this study, we extended the mlFMA to differentiate classical scrapie, atypical scrapie, BSE (experimentally infected sheep and naturally infected cattle) and CH1641 (both experimental and natural CH1641-like infections in sheep). Three capture antibodies were used, two distinct PrP N-terminus specific antibodies 12B2 and 9A2, and a PrP core specific antibody 94B4. All three antibodies were shown to bind classical scrapie PrPres strongly, whereas in Nor98/atypical scrapie PrPres only 12B2 and 9A2 binding was observed. PrPres binding of 12B2 was low for both BSE and CH1641, as expected. Furthermore, analysis of serially diluted samples indicated that the assay provided a similar level of sensitivity for atypical scrapie as that found using a well established commercial test. Unexpectedly, 9A2 binding to CH1641 PrPres was reduced by 2.1 fold both for experimental CH1641 and CH1641-like scrapie when compared with BSE, suggesting that major cleavage of the N-terminus occurs further towards the C-terminus in CH1641 than in BSE. The ratios of 12B2/94B4 and 9A2/94B4 were similar between experimental CH1641 and CH1641-like cases, although two CH1641-like subjects displayed slightly elevated ratios of both 12B2/94B4 and 9A2/94B4. To verify this finding for PrPres, mass spectrometry based quantification was used to determine the absolute abundance of the peptides associated with all three antibody binding regions. There was a 2.2 fold reduction of peptides containing the 9A2 epitope for experimental CH1641 PrPres in comparison to BSE PrPres. Observation of reduced PrPres may serve as a new marker for CH1641. This mIFMA may thus provide the basis for simplified TSE diagnosis with capability for simultaneous screening and differential diagnosis
|Active surveillance for scrapie in the Netherlands: effect of a breeding programme on the prevalence of scrapie in sheep (2002-2010)? = Acht jaar actieve scrapie-surveillance in Nederland: het effect van het fokprogramma op de prevalentie van schrapie bij het schaap (2002-2010)
Melchior, M.B. ; Hagenaars, T.H.J. ; Davidse, A. ; Keulen, L.J.M. van; Bossers, A. ; Zijderveld, F.G. van - \ 2011
Tijdschrift voor Diergeneeskunde 136 (2011)2. - ISSN 0040-7453 - p. 84 - 93.
bovine spongiform encephalopathy - in-vitro conversion - natural scrapie - prion protein - immunohistochemical detection - experimental flock - bse - transmission - prp - susceptibility
The susceptibility of sheep to scrapie is modulated by the prion protein (PrP) genotype of the animal. An ambitious voluntary scrapie control programme was started in the Netherlands in 1998, based on selection of rams with theARR/ARR genotype for breeding. This programme was followed by an obligatory programme in 2004; the programme has been voluntary since 2007. We monitored the prevalence of PrP genotype frequencies and the prevalence of scrapie in the Dutch sheep population between 2002 and June 2010. Results showed that selection for scrapie-resistant sheep resulted in an increase in the ARR allele frequency in the Dutch national flock from 37.5% in 2005 to 61.4% in 2009. Moreover, surveillance data showed that there was a significant decrease in the prevalence of scrapie a few years after the start of the obligatory breeding programme, from more than 0.2% in 2004 to 0.015% in 2009. This decrease is a consequence of the increased number of scrapie-resistant sheep in the Dutch sheep population. To date, the results and the models based on the data show that the selective breeding programme should be continued for several years in order to successfully eradicate scrapie. It will be important to monitor the PrP frequency and scrapie prevalence in the Dutch sheep population in the coming years.
Differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and CH1641 scrapie
Jacobs, J.G. ; Sauer, M. ; Keulen, L.J.M. van; Tang, Y. ; Bossers, A. ; Langeveld, J.P.M. - \ 2011
Journal of General Virology 92 (2011)1. - ISSN 0022-1317 - p. 222 - 232.
creutzfeldt-jakob-disease - abnormal prion protein - natural sheep scrapie - monoclonal-antibodies - molecular analysis - atypical scrapie - prp(d) accumulation - transgenic mice - infected sheep - bse
With increased awareness of the diversity of transmissible spongiform encephalopathy (TSE) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. Exposure to bovine spongiform encephalopathy (BSE) has been associated with the human TSE, variant Creutzfeldt–Jakob disease, emphasizing the necessity in distinguishing low-risk TSE types from BSE. TSE type discrimination in ruminants such as cattle, sheep, goats and deer, requires the application of several prion protein (PrP)-specific antibodies in parallel immunochemical tests on brain homogenates or tissue sections from infected animals. This study uses in a single incubation step, three PrP-specific antibodies and fluorescent Alexa dye-labelled anti-mouse Fabs on a Western blot. The usual amount of brain tissue needed is 0.5 mg. This multiplex application of antibodies directed towards three different PrP epitopes enabled differential diagnosis of all established main features of classical scrapie, BSE and Nor98-like scrapie in sheep and goats, as well as the currently known BSE types C, H and L in cattle. Moreover, due to an antibody-dependent dual PrP-banding pattern, for the first time CH1641 scrapie of sheep can be reliably discriminated from the other TSE isolate types in sheep.
Breeding with resistant rams leads to rapid control of classical scrapie in affected sheep flocks
Nodelijk, G. ; Roermund, H.J.W. van; Keulen, L.J.M. van; Engel, B. ; Vellema, P. ; Hagenaars, T.H.J. - \ 2011
Veterinary Research 42 (2011)1. - ISSN 0928-4249 - 11 p.
natural scrapie - prion protein - prp genotype - british sheep - immunohistochemical detection - clinical signs - transmission - bse - dynamics - gene
Susceptibility to scrapie, a transmissible spongiform encephalopathy in sheep, is modulated by the genetic make-up of the sheep. Scrapie control policies, based on selecting animals of resistant genotype for breeding, have recently been adopted by the Netherlands and other European countries. Here we assess the effectiveness of a breeding programme based on selecting rams of resistant genotype to obtain outbreak control in classical scrapie-affected sheep flocks under field conditions. In six commercially-run flocks following this breeding strategy, we used genotyping to monitor the genotype distribution, and tonsil biopsies and post-mortem analyses to monitor the occurrence of scrapie infection. The farmers were not informed about the monitoring results until the end of the study period of six years. We used a mathematical model of scrapie transmission to analyze the monitoring data and found that where the breeding scheme was consistently applied, outbreak control was obtained after at most four years. Our results also show that classical scrapie control can be obtained before the frequency of non-resistant animals is reduced to zero in the flock. This suggests that control at the national scale can be obtained without a loss of genetic polymorphisms from any of the sheep breeds
Variability in disease phenotypes within a single PRNP genotype suggests the existence of multiple natural sheep scarpie strains within Europe
González, L. ; Sisó, S. ; Monleón, E. ; Casalone, C. ; Keulen, L.J.M. van; Balkema-Buschmann, A. ; Ortiz-Peláez, A. ; Lulini, B. ; Langeveld, J.P.M. ; Hoffmann, C. ; Badiola, J.J. ; Jeffrey, M. ; Acín, C. - \ 2010
Journal of General Virology 91 (2010). - ISSN 0022-1317 - p. 2630 - 2641.
bovine spongiform encephalopathy - prion protein gene - prp accumulation - immunohistochemical detection - molecular analysis - infected sheep - bse - brain - immunoreactivity - patterns
Variability of pathological phenotypes within classical sheep scrapie cases has been reported for some time, but in many instances it has been attributed to differences in the PRNP genotype of the host. To address this issue we have examined by immunohistochemistry (IHC) and Western blotting (WB) for the disease-associated form of the prion protein (PrPd), the brains of 23 sheep from five European countries, all of which were of the same ARQ/ARQ genotype. As a result of IHC examinations, sheep were distributed into five groups with different phenotypes and the groups were the same regardless of the scoring method used, ‘long’ or ‘short’ PrPd profiling. The groups made did not respond to the geographical origin of the cases and did not correlate with the vacuolar lesion profiles, which showed a high individual variability. Discriminatory IHC and WB methods coincided to detect a ‘CH1641-like’ case but otherwise correlated poorly in the classification of disease phenotypes. No other polymorphisms of the PRNP gene were found that could account for the pathological differences, except perhaps for a sheep from Spain with a mutation at codon 103 and a unique pathological phenotype. Preliminary evidence indicates that those different IHC phenotypes correlate with distinct biological properties on bioassay, suggesting that they are indicative of strain diversity. We therefore conclude that natural scrapie strains exist and that they can be revealed by detailed pathological examinations, which can be harmonized between laboratories to produce comparable results.
Scrapie prevalence in sheep of susceptible genotype is declining in a population subject to breeding for resistance
Hagenaars, T.H.J. ; Melchior, M.B. ; Bossers, A. ; Davidse, A. ; Engel, B. ; Zijderveld, F.G. van - \ 2010
BMC Veterinary Research 6 (2010). - ISSN 1746-6148
great-britain - british sheep - classical scrapie - active surveillance - prp genotype - flock - program - risk - bse - epidemiology
Background - Susceptibility of sheep to scrapie infection is known to be modulated by the PrP genotype of the animal. In the Netherlands an ambitious scrapie control programme was started in 1998, based on genetic selection of animals for breeding. From 2002 onwards EU regulations required intensive active scrapie surveillance as well as certain control measures in affected flocks. Here we analyze the data on genotype frequencies and scrapie prevalence in the Dutch sheep population obtained from both surveillance and affected flocks, to identify temporal trends. We also estimate the genotype-specific relative risks to become a detected scrapie case. Results - We find that the breeding programme has produced a steady increase in the level of genetic scrapie resistance in the Dutch sheep population. We also find that a significant decline in the prevalence of scrapie in tested animals has occurred a number of years after the start of the breeding programme. Most importantly, the estimated scrapie prevalence level per head of susceptible genotype is also declining significantly, indicating that selective breeding causes a population effect. Conclusions - The Dutch scrapie control programme has produced a steady rise in genetic resistance levels in recent years. A recent decline in the scrapie prevalence per tested sheep of susceptible prion protein genotype indicates that selective breeding causes the desired population effect.
Bovine spongiform encephalopathy in Sweden: an H-type variant
Gavier-Widen, D. ; Noremark, M. ; Langeveld, J.P.M. ; Stack, M. ; Biacabe, A.G. ; Vulin, J. ; Chaplin, M. ; Richt, J.A. ; Jacobs, J.G. ; Acin, C. ; Monleón, E. ; Renström, A. ; Klingeborn, B. ; Baron, T.G.M. - \ 2008
Journal of Veterinary Diagnostic Investigation 20 (2008)1. - ISSN 1040-6387 - p. 2 - 10.
creutzfeldt-jakob-disease - prion protein glycoforms - monoclonal-antibodies - strain variation - lesion profile - great-britain - bse - scrapie - sheep - mice
Bovine spongiform encephalopathy (BSE) had never been detected in Sweden until 2006, when the active surveillance identified a case in a 12-year-old cow. The case was an unusual form, because several molecular features of the protease-resistant prion protein (PrPres) were different from classical BSE. The differences included higher susceptibility for proteinase K, higher molecular weight of the PrPres bands, affinity to the N-terminus¿specific antibodies 12B2 and P4, and peculiar banding pattern with antibody SAF84 showing an additional band at the 14 kDa position. The molecular characteristics were in accordance to previous descriptions of H-type BSE. This report shows that a range of Western blot techniques and antibodies can be applied to confirm H-type BSE and further describes that the ratio of the amounts of PrPres#1 and PrPres#2, after deglycosylation, depends on the antibody used during processing. Immunohistochemistry on sections of medulla at the level of the obex applying antibodies with epitopes covering a broad range of the PrP sequence showed accumulation of disease-specific PrP (PrPd) in the gray matter. Fine punctate deposition in the neuropil was the most predominant type and was more severe in BSE target nuclei. The types of PrPd deposition are described in comparison with classical BSE. PrP-gene sequencing showed 6 copy octarepeat alleles and no abnormalities. It is postulated that the disease had a spontaneous origin, rather than having had been acquired in the BSE epidemic.
Atypical status of bovine spongiform encephalopathy in Poland: a molecular typing study
Polak, M.P. ; Zmudzinski, J.F. ; Jacobs, J.G. ; Langeveld, J.P.M. - \ 2008
Archives of Virology 153 (2008)1. - ISSN 0304-8608 - p. 69 - 79.
creutzfeldt-jakob-disease - natural sheep scrapie - prion protein - strain variation - bse - identification - agent - mice - discrimination - transmission
The aim of this study was to analyze molecular features of protease-resistant prion protein (PrPres) in Western blots of BSE cases diagnosed in Poland with respect to a possible atypical status. Confirmed cases were analyzed by Western blotting with several monoclonal antibodies directed at N-terminal and core epitopes of prion protein (PrP). Most cases showed the classical glycoprofile characterized by the dominance of the di- over the monoglycosylated PrPres band, yielding di-/mono- ratios well above 2 and by reactivity with antibodies having their epitopes in bovine PrP region 110-242 (C-type cases). Surprisingly, seven cases of BSE were atypical. Six were classified as L-type based on a slightly lower molecular mass (M-r) of the non- glycosylated band with respect to C-types and a conspicuously low di-/mono- ratio of glycosylated PrPres bands approaching unity. One case was classified as H-type because of a higher M-r of PrPres bands on the blot when compared with C-type cases. A characteristic epitope of H-type PrPres occurred in the 101-110 region of PrP for which only antibody 12B2 had a sufficient affinity. The occurrence of atypical cases only in animals 9 years of age and older raises questions about the mechanisms of prion diseases and the origin of BSE.
H-type bovine spongiform encephalopathy-complex molecular featrues and similarities with some human prion diseases
Biacabe, A.G. ; Jacobs, J.G. ; Bencsik, A. ; Langeveld, J.P.M. ; Baron, T.G.M. - \ 2007
Prion 1 (2007)1. - ISSN 1933-6896 - p. 61 - 68.
straussler-scheinker-disease - creutzfeldt-jakob-disease - monoclonal-antibodies - atypical scrapie - strain variation - sheep scrapie - protein - mice - prp - bse
We previously reported that some cattle affected by bovine spongiform encephalopathy (BSE) showed distinct molecular features of the protease-resistant prion protein (PrPres) in Western blot, with a 1-2 kDa higher apparent molecular mass of the unglycosylated PrPres associated with labelling by antibodies against the 86-107 region of the bovine PrP protein (H-type BSE). By Western blot analyses of PrPres, we now showed that the essential features initially described in cattle were observed with a panel of different antibodies and were maintained after transmission of the disease in C57Bl/6 mice. In addition, antibodies against the C-terminal region of PrP revealed a second, more C-terminally cleaved, form of PrPres (PrPres #2), which, in unglycosylated form, migrated as a approximate to 14 kDa fragment. Furthermore, a PrPres fragment of approximate to 7 kDa, which was not labelled by C-terminus-specific antibodies and was thus presumed to be a product of cleavage at both N- and C-terminal sides of PrP protein, was also detected. Both PrPres #2 and approximate to 7 kDa PrPres were detected in cattle and in C57Bl/6 infected mice. These complex molecular features are reminiscent of findings reported in human prion diseases. This raises questions regarding the respective origins and pathogenic mechanisms in prion diseases of animals and humans.
Quantitative risk assessment for Bovine Spongiform Encephalopathy in low or zero prevalence countries: the example of Norway
Hogasen, H.R. ; Koeijer, A.A. de - \ 2007
Risk Analysis 27 (2007)5. - ISSN 0272-4332 - p. 1105 - 1117.
great-britain - bse - cattle - infection - surveillance - epidemic - dairy
A predictive case-cohort model is applied to Norwegian data to analyze the interaction between challenge and stability factors for bovine spongiform encephalopathy (BSE) during the period 1980¿2010. For each year, the BSE risk in cattle is estimated as the expected number of cases. The age distribution of expected cases as well as the relative impact of different challenges is estimated. The model consists of a simple, transparent, and practical deterministic spreadsheet calculation model, in which the following country-specific inputs are entered: (i) annual imports of live cattle and meat and bone meal, (ii) age distribution of native cattle, and (iii) estimated annual basic reproduction ratio (R0) for BSE. Results for Norway indicate that the highest risk of BSE cases was in 1989, when a total BSE risk of 0.13 cases per year was expected. After that date, the year-to-year decrease in risk ranged between 3% and 47%, except for a secondary peak in 1994 at 0.06 cases per year. The primary peak was almost entirely (99%) attributable to the importation of 11 cattle from the United Kingdom between 1982 and 1986. The secondary peak, in 1994, originated mainly from the recycling of the U.K. imported cattle (92%). In 2006, the remaining risk was 0.0003 cases per year, or 0.001 per million cows per year, with a maximal age-specific incidence of 0.03 cases per million per year in 10-year-old cattle. Only 15% of the cases were expected in imported cattle. The probability of having zero cases in Norway in 2006 was estimated to be 99.97%. The model and results are compared to previous risk assessments of Norway by the EU.
Immunological characterization of abnormal prion protein from atypical scrapie cases in sheep using a panel of monoclonal antibodies
Gretzschel, A. ; Buschmann, A. ; Langeveld, J.P.M. ; Groschup, M.H. - \ 2006
Journal of General Virology 87 (2006). - ISSN 0022-1317 - p. 3715 - 3722.
bovine spongiform encephalopathy - creutzfeldt-jakob-disease - amyloid protein - nor98 - bse - prp - variant - tissue - accumulation - replication
After the implementation of an active surveillance programme for scrapie in sheep in the EU, the number of diagnosed classical scrapie cases rose sharply and a novel kind of so-called atypical scrapie case was discovered. These atypical scrapie cases display unusual features concerning the distribution of the abnormal prion protein (PrPSc) in the brain, a distinct electrophoretic profile of PrPSc and an inconsistent reaction pattern in the currently used rapid tests. In this report, PrPSc of two German atypical sheep scrapie cases was characterized by epitope mapping using a panel of 18 monoclonal antibodies that were directed against epitopes located throughout the prion protein. This analysis suggests that PrPSc derived from atypical scrapie cases and treated with proteinase K is largely composed of an 11 kDa fragment (previously referred to as the 12 kDa band) and of polymeric fragments thereof. The 11 kDa band corresponds to a prion protein fragment spanning approximately aa 90¿153 and may therefore represent a novel PrPSc type
Transmission of new bovine prion to mice
Baron, T.G.M. ; Biacabe, A.G. ; Bencsik, A. ; Langeveld, J.P.M. - \ 2006
Emerging Infectious Diseases 12 (2006)7. - ISSN 1080-6040 - p. 1125 - 1128.
creutzfeldt-jakob-disease - spongiform encephalopathy - molecular analysis - scrapie - protein - agent - bse
We previously reported that cattle were affected by a prion disorder that differed from bovine spongiform encephalopathy (BSE) by showing distinct molecular features of disease-associated protease-resistant prion protein (PrPres). We show that intracerebral injection of such isolates into C57BL/6 mice produces a disease with preservation of PrPres molecular features distinct from BSE.
Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease
Yull, H.M. ; Ritchie, D.L. ; Langeveld, J.P.M. ; Zijderveld, F.G. van; Bruce, M.E. ; Ironside, J.W. ; Head, M.W. - \ 2006
American Journal of Pathology 168 (2006)1. - ISSN 0002-9440 - p. 151 - 157.
bovine spongiform encephalopathy - molecular classification - sheep scrapie - bse - cjd - prpsc - mice - transmissions - heterogeneity - phenotype
Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform encephalopathy). Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt-Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain
Epidemiological analysis of data for scrapie in Great Britain
Hagenaars, T.H.J. ; Donnelly, C. ; Ferguson, N.M. - \ 2006
Epidemiology and Infection 134 (2006)2. - ISSN 0950-2688 - p. 359 - 367.
bovine spongiform encephalopathy - sheep flock - british sheep - transmission - bse - infection - program
In recent years, the control or eradication of scrapie and any other transmissible spongiform encephalopathies (TSEs) possibly circulating in the sheep population has become a priority in Britain and elsewhere in Europe. A better understanding of the epidemiology of scrapie would greatly aid the development and evaluation of control and eradication strategies. Here we bound the range of key epidemiological parameters using a combination of relatively detailed pathogenesis and demography data, more limited data on susceptibility and incubation times, and recent survey data on scrapie incidence in Great Britain. These data are simultaneously analysed using mathematical models describing scrapie transmission between sheep and between flocks. Our analysis suggests that occurrence of scrapie in a flock typically provokes changes in flock management that promote termination of the outbreak, such as the adoption of selective breeding, and that a large fraction of cases (possibly over 80%) goes undetected. We show that the data analysed are consistent with the within-flock reproduction number of scrapie lying in the range 1·5¿6, consistent with previous epidemiological studies
Immunohistochemical studies of scrapie archival material from Irish ARQ/ARQ sheep for evidence of bovine spongiform encephalopathy-derived disease
Sharpe, A. ; McElroy, M. ; Langeveld, J.P.M. ; Bassett, H. ; O'Donoghue, A.M. ; Sweeney, T. - \ 2005
Research in Veterinary Science 79 (2005)1. - ISSN 0034-5288 - p. 29 - 35.
prion protein prp - natural scrapie - monoclonal-antibodies - lymphoid-tissues - clinical signs - bse - transmission - variants - ireland - goats
Since scrapie and bovine spongiform encephalopathy (BSE) in sheep are clinicopathologically indistinguishable, BSE in sheep may have been misdiagnosed as scrapie. Disease-specific prion protein (PrPd) patterns in archival tissues of 38 Irish ARQ/ARQ sheep diagnosed as scrapie-affected were compared to those in four Dutch BSE-challenged sheep. When medulla oblongata was immunolabelled with an antibody directed against amino acids 93-99 of ovine prion protein (ovPrP), intraneuronal PrPd was apparent in all 38 Irish sheep but was absent in BSE-challenged sheep. When lymphoid follicles were immunolabelled with antibodies directed against amino acids 93-106 of ovPrP, granule clusters of PrPd were seen in 34 of the 38 Irish sheep. Follicles of the remaining four archive sheep contained either no PrPd or single PrPd granules, similar to follicles from BSE-challenged sheep. Based on the medulla results, none of the archival cases had BSE-derived disease. The identification of some scrapie sheep with little or no intrafollicular PrPd suggests that this technique may be limited in discriminating between the two diseases.
Immunohistochemical distinction between preclinical bovine spongiform encephalopathy and scrapie infection in sheep
Thuring, C.M.A. ; Keulen, L.J.M. van; Langeveld, J.P.M. ; Vromans, M.E.W. ; Zijderveld, F.G. van; Sweeney, T. - \ 2005
Journal of Comparative Pathology 132 (2005)1. - ISSN 0021-9975 - p. 59 - 69.
prion protein - monoclonal-antibodies - natural scrapie - lymphoid-tissue - clinical signs - bse - brain - diagnosis - biopsy - mice
Sheep are susceptible experimentally to bovine spongiform encephalopathy (BSE), the clinical signs being indistinguishable from those of scrapie. Because of the possibility of natural ovine BSE infection, laboratory tests are needed to distinguish between scrapie and BSE infection. The objectives of this study were to determine whether (1) PrPSc accumulates in biopsy samples of the tonsil or third eyelid, or both, of BSE-infected sheep before the appearance of clinical disease, and (2) such samples from BSE- and scrapie-infected sheep differ in respect of PrPSc accumulations. Homozygous ARQ sheep (n=10) were dosed orally at 4-5 months of age with a brain homogenate from BSE-infected cattle. Third eyelid and tonsillar biopsy samples were taken at ¿6 monthly intervals post-infection and examined immunohistochemically for PrPSc. Third eyelid protuberances were difficult to identify, resulting in many unsuitable samples; however, third eyelid samples shown to contain lymphoid follicles were invariably negative for PrPSc. In contrast, tonsillar biopsy samples became positive for PrPSc from 11 to 20 months post-infection. Consistent differences in the morphology of PrPSc granules in tingible body macrophages (TBMs) between BSE- and scrapie-infected sheep were detected with anti-peptide antibodies directed towards amino acids 93-106 of the ovine prion protein: thus, PrPSc appeared as single granules in TBMs of tonsillar sections from BSE-infected sheep, whereas clusters of PrPSc granules were observed within TBMs in the tonsils of scrapie-infected sheep. In contrast, antibodies against epitopes situated N- and C-terminally from the 93-106 region of the ovine prion protein revealed no differences between BSE- and scrapie-infected sheep in terms of PrPSc granules in TBMs.
Discrimination between scrapie and bovine spongiform encephalopathy in sheep by molecular size, immunoreactivity, and glycoprofile of prion protein
Thuring, C.M.A. ; Erkens, J.H.F. ; Jacobs, J.G. ; Bossers, A. ; Keulen, L.J.M. van; Garssen, G.J. ; Zijderveld, F.G. van; Ryder, S.J. ; Groschup, M.H. ; Sweeney, T. ; Langeveld, J.P.M. - \ 2004
Journal of Clinical Microbiology 42 (2004)3. - ISSN 0095-1137 - p. 972 - 980.
natural scrapie - immunohistochemical detection - monoclonal-antibodies - strain variation - prpsc detection - variant cjd - bse - brain - diagnosis - agent
A procedure for discrimination between scrapie and bovine spongiform encephalopathy (BSE) in sheep is of importance for establishing whether BSE has entered the sheep population. Since BSE has not yet been found in sheep at the farm level, such discrimination procedures can be developed only with experimental sheep BSE. Two distinctive molecular features of the prion protein (PrP)-molecular size and glycosylation profile-in proteinase K digests of brain stem tissue from sheep were used here; upon Western blotting, these features led to an unequivocal discrimination among natural scrapie, experimental scrapie, and experimental BSE. The higher electrophoretic mobility of PrP in sheep BSE could be best observed after deglycosylation treatment with N-glycosidase F. A simpler method for confirmation of this size difference involved comparison of the ratios for the binding of two monoclonal antibodies: P4 and 66.94b4. Based on epitope mapping studies with P4 and peptides, it appeared that N-terminal amino acid sequence WGQGGSH was intact only in sheep scrapie digests. Another feature typical for PrP in sheep BSE was the large fraction of diglycosylated PrP (70% or more). These data were obtained for a large group of positive sheep, consisting of 7 sheep with experimental BSE infection (genotypes: six ARQ/ARQ and one AHQ/AHQ), 48 sheep naturally infected with scrapie (six different genotypes), and 3 sheep with primary experimental scrapie infection. Routine tests of slaughter material serve well for the initial detection of both BSE and scrapie. With Western blotting as a rapid follow-up test, a 66.94b4/P4 antibody binding ratio above 1.5 is a practical indicator for serious suspicion of BSE infection in sheep.
Effects on inbreeding of different strategies aimed at eliminating scrapie sensitivity alleles in rare sheep breeds in the Netherlands
Windig, J.J. ; Eding, J.H. ; Moll, L. ; Lansbergen, L.M.T.E. - \ 2004
Animal Science 79 (2004)1. - ISSN 1357-7298 - p. 11 - 20.
schapen - schapenrassen - genen - allelen - scrapie - ziektebestrijding - bestrijdingsprogramma's - dierveredeling - genetica - genetische diversiteit - inteelt - nederland - sheep - sheep breeds - genes - alleles - disease control - control programmes - animal breeding - genetics - genetic diversity - inbreeding - netherlands - prp genotype frequencies - natural scrapie - gene - association - selection - codon-136 - survival - program - bse
The Dutch scrapie eradication programme aims at the exclusive use of homozygous ARR/ARR breeding rams by the end of 2004. As a consequence, breeds with a small population size and a low frequency of the ARR allele may suffer unacceptable losses of genetic diversity and high inbreeding levels. We simulated three breeding strategies to assess their efficacy in eliminating scrapie sensitive alleles and their effect on inbreeding levels. Under mild selection, both homozygous and heterozygous ARR rams were used indiscriminately. Under moderate selection, homozygous ARR rams were used preferably but they were supplemented with heterozygous rams when necessary. Under severe selection, only homozygous rams were used. Severe selection mimics then the proposed eradication programme. Simulations were carried out with allelic frequencies and population parameters of existent rare breeds in The Netherlands. With severe selection all simulated breeds showed unacceptably high inbreeding rates (>0.5% per year). For some breeds, moderate selection resulted in acceptable inbreeding rates, while for other breeds only mild selection resulted in acceptable rates. The frequency of the ARR allele after 5 years of selection was only slightly lower with moderate selection than with severe selection (0.8% lower on average), but it was clearly lower with mild selection. Based on these simulations, we propose a selection programme where with low frequencies of the ARR allele, mild selection is used initially. Once the ARR frequencies rise to a particular value, the switch can be made to moderate selection. The population size (e.g. below 750, 750 to 3750 and above 3750 ewes) determines the frequency of the ARR allele at which the switch can be made (33%, 25% and 10%, respectively). With even higher ARR frequencies (above 70%, 50% and 33%, respectively) the regime can be changed to severe selection
The Dutch scrapie eradication programme aims at the exclusive use of homozygous ARR/ARR breeding rams by the end of 2004. As a consequence, breeds with a small population size and a low frequency of the ARR allele may suffer unacceptable losses of genetic diversity and high inbreeding levels. We simulated three breeding strategies to assess their efficacy in eliminating scrapie sensitive alleles and their effect on inbreeding levels. Under mild selection, both homozygous and heterozygous ARR rams were used indiscriminately. Under moderate selection, homozygous ARR rams were used preferably but they were supplemented with heterozygous rams when necessary. Under severe selection, only homozygous rams were used. Severe selection mimics then the proposed eradication programme. Simulations were carried out with allelic frequencies and population parameters of existent rare breeds in The Netherlands. With severe selection all simulated breeds showed unacceptably high inbreeding rates (> 0.5% per year). For some breeds, moderate selection resulted in acceptable inbreeding rates, while for other breeds only mild selection resulted in acceptable rates. The frequency of the ARR allele after 5 years of selection was only slightly lower with moderate selection than with severe selection (0.8% lower on average), but it was clearly lower with mild selection. Based on these simulations, we propose a selection programme where with low frequencies of the ARR allele, mild selection is used initially. Once the ARR frequencies rise to a particular value, the switch can be made to moderate selection. The population size ( e. g. below 750, 750 to 3750 and above 3750 ewes) determines the frequency of the ARR allele at which the switch can be made (33%, 25% and 10%, respectively). With even higher ARR frequencies (above 70%, 50% and 33%, respectively) the regime can be changed to severe selection.
Association between PrP genotypes and littersize and 135 dags weight in Texel sheep
Brandsma, J.H. ; Janss, L.L.G. ; Visscher, A.H. - \ 2004
Livestock Production Science 85 (2004). - ISSN 0301-6226 - p. 59 - 64.
growth-performance - natural scrapie - pigs - frequencies - traits - breed - bse
Susceptibility to scrapie is associated with polymorphisms in the ovine prion protein (PrP) gene. The polymorphisms at codons 136 (A to V), 154 (R to H) and 171 (Q to R, H) occur most frequently, where each letter represents the amino acid coded at the indicated codon. The VRQ allele is significantly associated with a high susceptibility to scrapie, while the ARR allelic variant is significantly associated with resistance to scrapie. The Dutch scrapie eradication strategy is based on selection for the genetically less susceptible variant ARR/ARR. The program indicates to use only ARR/ARR rams in the 2004 breeding season. In this study the association of PrP gene with performance traits was investigated. The data included 8919 genotyped Texel rams born from 1996 to 2000. The associations of PrP gene were evaluated with their estimated breeding value for littersize and 135 days weight. The results from this study indicated that selection for ARR/ARR genotype had a small positive effect on littersize, and a small negative effect on 135 days weight. The susceptible VRQ allele probably remained in the population due to positive association with littersize and 135 days weight. It is speculated that the wild type may have been favoured by selection due to associations with other performance traits, such as certain type traits. (C) 2003 Elsevier B.V. All rights reserved.
Enzymatic degradation of prion protein in brain stem from infected cattle and sheep
Langeveld, J.P.M. ; Wang, J.J. ; Wiel, D.F.M. van de; Shih, G.C. ; Garssen, G.J. ; Bossers, A. ; Shih, J.C.H. - \ 2003
The Journal of Infectious Diseases 188 (2003)11. - ISSN 0022-1899 - p. 1782 - 1789.
bovine spongiform encephalopathy - scrapie prion - rendering procedures - prp 27-30 - agent - inactivation - bse - infectivity - transmission - keratinase
Prions¿infectious agents involved in transmissible spongiform encephalopathies¿normally survive proteolytic and mild protein-destructive processes. Using bacterial keratinase produced by Bacillus licheniformis strain PWD-1, we tested conditions to accomplish the full degradation of prion protein (PrP) in brain-stem tissue from animals with bovine spongiform encephalopathy and scrapie. The detection of PrPSc, the disease-associated isoform of PrP, in homogenates was done by Western blotting and various antibodies. The results indicated that only in the presence of detergents did heat pretreatment at >100°C allow the extensive enzymatic breakdown of PrPSc to a state where it is immunochemically undetectable. Proteinase K and 2 other subtilisin proteases, but not trypsin and pepsin, were also effective. This enzymatic process could lead to the development of a method for the decontamination of medical and laboratory equipment. The ultimate effectiveness of this method of prion inactivation has to be tested in mouse bioassays.