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From: TSS ()
Subject: CAN GENETIC RESEARCH SCUTTLE SCRAPIE ???
Date: January 1, 2007 at 12:55 pm PST

CAN GENETIC RESEARCH SCUTTLE SCRAPIE ???

Agricultural Research/November-December 2006

Contagious, incurable, and fatal, scrapie is a chief

disease priority for the sheep industry. It affects international

trade and domestic markets and costs U.S.

producers an estimated $20 million every year.

Now Agricultural Research Service (ARS) researchers

in Clay Center, Nebraska, have developed

more accurate genetic tests for the disease. They believe this

achievement will promote scrapie’s eventual eradication.

Like chronic wasting disease in elk or mad cow disease in

cattle, scrapie is a transmissible spongiform encephalopathy

(TSE). Its name reflects the disease’s most distinctive symptom:

an uncontrollable itching sensation that causes afflicted sheep to

compulsively scrape their bodies against nearby objects, often

tearing out their fleece in the process.

Other symptoms include hypersensitivity to noise, weight loss,

convulsive collapse, weakness, and altered gait. Most sheep die 1

to 6 months after symptoms appear, though they may be infected

for years without showing any signs.

Some sheep are more susceptible than others. Genetic predisposition

to the disease is related to variations in amino acid

sequences coded within each sheep’s DNA. Selective breeding

for resistance could reduce the genetic risk of developing scrapie

and may eventually eradicate it.

Much remains to be learned about this devastating disease,

but ARS researchers have made great progress. In Pullman,

Washington, in 1998, a team led by microbiologist Katherine I.

O’Rourke developed the first practical test for diagnosing scrapie

in live animals. Before, the only way to confirm the disease had

been to examine a dead animal’s brain for spongy pockets. The

new test takes samples from a live sheep’s third eyelid, reducing

unnecessary slaughter.

Today ARS is at the forefront of scrapie research again. Drawing

from a diverse group of hundreds of U.S. sheep, Michael P.

Heaton, a geneticist at the Roman L. Hruska U.S. Meat Animal

Research Center (USMARC) at Clay Center, and his colleagues

have resequenced the prion gene, identifying new genetic variation.

This achievement has helped save the industry money by improving

commercially available genotyping tests and enhancing

the national scrapie eradication program run by USDA’s Animal

and Plant Health Inspection Service (APHIS).

Mapping new genetic variation in sheep has allowed the scientists

to develop methods for sequencing the complete sheep

prion gene-coding region and genotyping prion “haplotypes,”

or sets of linked alleles on a chromosome.

They have also identified and stored DNA from sheep representing

15 combinations of the most common prion gene haplotypes.

This information is freely available to scientists and testing

labs to help with assay design and scrapie eradication.

In short, they’ve amassed a detailed body of knowledge allowing

them to test sheep for scrapie susceptibility with great accuracy.

With that information, breeders can select less-susceptible

sheep and eventually breed scrapie-resistant flocks.

20 Agricultural Research/November-December 2006

Better, Faster, Cheaper

“Selection for resistant sheep significantly reduces the overall

genetic risk of developing scrapie,” Heaton says.

So how does it work? Connections between genetic variations

in prions––proteins that occur naturally in all mammals––and

susceptibility to TSE in sheep are well known. In a diseased

animal, abnormally folded prion proteins cause the naturally

produced prions to fold abnormally as well. As the misfolded

proteins amass, they cause neurological problems and eventually

death.

Not every sheep that’s exposed to scrapie contracts the disease.

This is due, in part, to genetic variation. Three codons (nucleotide

trios that specifically code for one amino acid) are thought

to influence susceptibility to scrapie. Two codons are used in

APHIS’s national eradication program.

Variations in the three codons give rise to five common prion

haplotypes in U.S. flocks: ARR, ARQ, ARH, AHQ, and VRQ.

Any 2 haplotypes can combine to make 1 of 15 possible diplotypes,

which indicate varying degrees of resistance. Identifying

which of the haplotypes a sheep has makes it easier to predict

its offspring’s susceptibility to scrapie.

“Sheep with a diplotype of ARR/ARR are generally considered

the most resistant to classical scrapie. Sheep with a VRQ/VRQ

diplotype are most susceptible. Everything else falls somewhere

in between,” Heaton says.

Correctly identifying an animal’s diplotype for the prion gene

is complicated. Fortunately, Heaton and his colleagues have

identified sheep within the USMARC flock that represent each

of 15 possible diplotypes for the 5 most common haplotypes.

They collected DNA samples from these animals, determined

their prion gene coding sequences, and deposited them in a public

gene bank to improve genotyping and assay development.

APHIS veterinarian Gary Ross says the USMARC testing program

has improved the APHIS scrapie-eradication program.

“The format has enabled us to reduce our total genotyping

costs by about 40 percent. We’re doing somewhere between

40,000 and 50,000 tests a year, so that’s a significant cost reduction,”

he says. “The cost of testing three codons after using this

design was almost 80 percent lower. For the money, this would

allow us to test nearly five times more sheep at all three codons

than was previously possible. This could potentially accelerate

scrapie eradication.”

The USMARC researchers have also examined the codon sites

in great detail, enabling them to create more accurate assays,

Ross says. “For example, the work they’ve done at codon 171

has been extremely helpful in making it possible to distinguish

Q from H. There are some other haplotypes very close by, which

made it difficult to do so in the past.”

Essentially, this research is improving the speed, cost, and

quality of antiscrapie breeding methods.

“The bottom line is better, faster, cheaper,” says Heaton.

“That’s really all it is, but the impact is worth millions.”

More information on the National Accelerated Scrapie Eradication

Program, run by USDA-APHIS, is on the Web at www.aphis.

usda.gov/vs/nahps/scrapie.—By Laura McGinnis, ARS.

This research is part of Animal Health, an ARS National

Program (#103) described on the World Wide Web at www.nps.

ars.usda.gov.

Michael P. Heaton is with the USDA-ARS Roman L. Hruska

U.S. Meat Animal Research Center, Spur 18D, Clay Center,

NE 68933; phone (402) 762-4362, fax (402) 762-4375, e-mail

heaton@email.marc.usda.gov. ✸

Technician Jacky Carnahan and molecular geneticist

Michael Heaton collect blood for DNA analysis.

Technician Jacky Carnahan determines the quality and amount of

DNA used for prion gene haplotype determination.

PEGGY GREB (D641-1)

PEGGY GREB (D642-1)

21 Agricultural Research/November-December 2006

http://www.ars.usda.gov/is/AR/archive/nov06/scrapie1106.pdf


A case of scrapie in a sheep carrying the lysine-171 allele of the prion protein gene

P. L. Acutis1, F. Martucci1, M. Mazza1, S. Peletto1, B. Iulini1, C. Corona1, E. Bozzetta1, C. Casalone1 and M. Caramelli1

(1) CEA – Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, Torino, Italy

Received: 29 July 2005 Accepted: 27 February 2006 Published online: 30 March 2006

Summary. Susceptibility to scrapie in sheep depends on the host PrP genotype. No data about the linkage of the rare ARK allele to differential scrapie susceptibility are currently available. Several tissues isolated from sheep from an Italian scrapie outbreak and carrying the ARK allele were examined for the presence of the pathological prion protein. A weak positivity was detected only by Western blot in the brainstem of one ARK/ARH sheep. This result shows that the ARK allele does not confer full resistance against scrapie and that the allele needs to be studied further before it can be considered for breeding purposes.


http://www.springerlink.com/content/084l832600t50j67/

Subject: Sheep-Passaged Bovine Spongiform Encephalopathy Agent Exhibits
Altered Pathobiological Properties in Bovine-PrP Transgenic Mice
Date: December 28, 2006 at 8:41 am PST
Journal of Virology, January 2007, p. 835-843, Vol. 81, No. 2
0022-538X/07/$08.00+0 doi:10.1128/JVI.01356-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sheep-Passaged Bovine Spongiform Encephalopathy Agent Exhibits Altered
Pathobiological Properties in Bovine-PrP Transgenic Mice
Juan Carlos Espinosa,1 Olivier Andréoletti,2 Joaquín Castilla,1 María
Eugenia Herva,1 Mónica Morales,1 Elia Alamillo,1 Fayna Díaz San-Segundo,1
Caroline Lacroux,2 Séverine Lugan,2 Francisco Javier Salguero,1 Jan
Langeveld,3 and Juan María Torres1*
Centro de Investigación en Sanidad Animal, INIA, 28130 Valdeolmos, Madrid,
Spain,1 UMR INRA-ENVT 1225, Interactions Hôte Agent Pathogène, Ecole
Nationale Vétérinaire de Toulouse, Toulouse, France,2 CIDC-Lelystad, 8203 AA
Lelystad, The Netherlands3

Received 27 June 2006/ Accepted 22 October 2006

Sheep can be experimentally infected with bovine spongiform encephalopathy
(BSE), and the ensuing disease is similar to scrapie in terms of
pathogenesis and clinical signs. BSE infection in sheep is an animal and
human health concern. In this study, the transmission in BoPrP-Tg110 mice of
prions from BSE-infected sheep was examined and compared to the transmission
of original cattle BSE in cattle and sheep scrapie prions. Our results
indicate no transmission barrier for sheep BSE prions to infect BoPrP-Tg110
mice, but the course of the disease is accelerated compared to the effects
of the original BSE isolate. The shortened incubation period of sheep BSE in
the model was conserved in subsequent passage in BoPrP-Tg110 mice,
indicating that it is not related to infectious titer differences.
Biochemical signature, lesion profile, and PrPSc deposition pattern of both
cattle and sheep BSE were similar. In contrast, all three sheep scrapie
isolates tested showed an evident transmission barrier and further
adaptation in subsequent passage. Taken together, those data indicate that
BSE agent can be altered by crossing a species barrier, raising concerns
about the virulence of this new prion towards other species, including
humans. The BoPrP-Tg110 mouse bioassay should be considered as a valuable
tool for discriminating scrapie and BSE in sheep.


----------------------------------------------------------------------------
----
* Corresponding author. Mailing address: Centro de Investigación en Sanidad
Animal, INIA, 28130 Valdeolmos, Madrid, Spain. Phone: 34 91 620 23 00. Fax:
34 91 620 22 47. E-mail: jmtorres@inia.es .

Published ahead of print on 1 November 2006.


http://jvi.asm.org/cgi/content/abstract/81/2/835?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=81&issue=2&resourcetype=HWCIT


Published online before print October 20, 2005

Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102
Medical Sciences

A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes

( sheep prion | transgenic mice )

Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *, Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ||, Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude *
*Virologie Immunologie Moléculaires and ||Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway


Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)

Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.


--------------------------------------------------------------------------------

Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R., T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B. contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data; and H.L. wrote the paper.

A.L.D. and V.B. contributed equally to this work.

To whom correspondence should be addressed.

Hubert Laude, E-mail: laude@jouy.inra.fr

www.pnas.org/cgi/doi/10.1073/pnas.0502296102


http://www.pnas.org/cgi/content/abstract/0502296102v1

PrPSc accumulation in fetal cotyledons of scrapie-resistant lambs is influenced by fetus location in the uterus
Janet Alverson1,2, Katherine I. O'Rourke1,2 and Timothy V. Baszler2,3

1 USDA, ARS, Animal Disease Research Unit, 3003 ADBF, Washington State University, Pullman, WA 99164, USA
2 Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA
3 Washington Animal Disease Diagnostic Laboratory, Washington State University, Pullman, WA 99164, USA


Correspondence
Janet Alverson
janeta@vetmed.wsu.edu


ABSTRACT

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, cotyledons from fetuses of multiple births of different genotypes were examined. PrPSc was detected in fetal cotyledons of genotype ARQ/ARQ, but not in cotyledons from their dizygotic twin of genotype ARQ/ARR. This confirms earlier reports of single fetuses of these genotypes, but is the first description of such a finding in twin fetuses, one of each genotype. It is also demonstrated that cotyledons from sibling fetuses of genotypes ARQ/VRQ and ARQ/ARQ have different patterns of PrPSc accumulation depending on whether the dam is of genotype ARQ/ARQ or ARQ/VRQ. Lastly, it is shown that cotyledons from fetuses with resistant genotypes are weakly positive for PrPSc when they have shared the same pregnant uterine horn with a fetus of a susceptible genotype with cotyledons positive for the detection of PrPSc. Additionally, a PCR product for the Sry gene, a product specific to males, was found in cotyledons from female fetuses that had shared a uterine horn with a male fetus. This indicates that some sharing of fetal blood occurs between placentomes and fetuses residing in the same uterine horn, which can result in PrPSc accumulation in cotyledons with resistant genotypes.


http://vir.sgmjournals.org/cgi/content/full/87/4/1035


Subject: REPORT OF THE COMMITTEE ON SCRAPIE November 9, 2005 USAHA
Date: February 12, 2006 at 1:03 pm PST

REPORT OF THE COMMITTEE ON SCRAPIE

Chair: Dr. Jim Logan, Cheyenne, WY

Vice Chair: Dr. Joe D. Ross, Sonora, TX

Dr. Deborah L. Brennan, MS; Dr. Beth Carlson, ND; Dr. John R. Clifford, DC; Dr. Thomas F. Conner, OH; Dr. Walter E. Cook, WY; Dr. Wayne E. Cunningham, CO; Dr. Jerry W. Diemer, TX; Dr. Anita J. Edmondson, CA; Dr. Dee Ellis, TX; Dr. Lisa A. Ferguson, MD; Dr. Keith R. Forbes, NY; Dr. R. David Glauer, OH; Dr. James R. Grady, CO; Dr. William L. Hartmann, MN; Dr. Carolyn Inch, CAN; Dr. Susan J. Keller, ND; Dr. Allen M. Knowles, TN; Dr. Thomas F. Linfield, MT; Dr. Michael R. Marshall, UT; Dr. Cheryl A. Miller, In; Dr. Brian V. Noland, CO; Dr. Charles Palmer, CA; Dr. Kristine R. Petrini, MN; Mr. Stan Potratz, IA; Mr. Paul E. Rodgers, CO; Dr. Joan D. Rowe, CA; Dr. Pamela L. Smith, IA; Dr. Diane L. Sutton, MD; Dr. Lynn Anne Tesar, SD; Dr. Delwin D. Wilmot, NE; Dr. Nora E. Wineland, CO; Dr. Cindy B. Wolf, MN.

The Committee met on November 9, 2005, from 8:00am until 11:55am, Hershey Lodge and Convention Center, Hershey, Pennsylvania. The meeting was called to order by Dr. Jim Logan, chair, with vice chairman Dr. Joe D. Ross attending. There were 74 people in attendance.

The Scrapie Program Update was provided by Dr. Diane Sutton, National Scrapie Program Coordinator, United States Department of Agriculture (USDA), Animal and Plant Health Inspection Services (APHIS), Veterinary Services (VS). The complete text of the Status Report is included in these Proceedings.

Dr. Patricia Meinhardt, USDA-APHIS-VS-National Veterinary Services Laboratory (NVSL) gave the Update on Genotyping Labs and Discrepancies in Results. NVSL conducts investigations into discrepancies on genotype testing results associated with the Scrapie Eradication Program. It is the policy of the Program to conduct a second genotype test at a second laboratory on certain individual animals. Occasionally, there are discrepancies in those results. The NVSL conducts follow-up on these situations through additional testing on additional samples from the field and archive samples from the testing laboratories.

For the period of time from January 1, 2005, until October 15, 2005, there were 23 instances of discrepancies in results from 35 flocks. Of those 23 instances, 14 were caused by laboratory error (paperwork or sample mix-up), 3 results from field error, 5 were not completely resolved, and 1 originated from the use of a non-approved laboratory for the first test. As a result of inconsistencies, one laboratory’s certification was revoked by APHIS-VS.

To reduce/eliminate these problems, the Program has placed additional quality requirements on the testing laboratories: additional review of final reports, additional coding systems for testing operations, strict follow-up and reports to NVSL on corrective actions, dual data entry systems, and more frequent inspections.

The Agricultural Research Services (ARS) Scrapie Research Update was given by Janet Alverson, USDA- ARS. Dr. Alverson reported on the effect of multiple births and fetal position within the uterus on PrP-Sc accumulation in fetal cotyledons. Fetal cotyledons of fetuses with

resistant genotypes can accumulate PrP-Sc when positioned next to a fetus of susceptible genotype with cotyledons positive for PrP-Sc accumulation.

Scrapie Surveillance Evaluation Working Group Update was presented by Tracey Lynn, Epidemiologist with the National Surveillance Unit, Center for Epidemiology and Animal Health (CEAH). The presentation provided a background on evaluation, a quick review of analyses completed to date by the scrapie surveillance evaluation working group, and some of the preliminary findings. The process of surveillance system evaluation is undertaken to assist a disease control program with identifying possible improvements to their surveillance system, and includes an assessment of the overall utility of the system, identification of potential gaps in coverage, and an evaluation of the overall performance of the system. The scrapie surveillance evaluation working group reviewed the structure and processes of the scrapie surveillance program, as well as various quality and effectiveness measures.

Overall, 98-99% of surveillance samples come from the Regulatory Scrapie Surveillance System (RSSS), so the RSSS system has been the primary focus of the evaluation process. The working group developed a flow chart indicating the flow of sheep through RSSS, which identified potential gaps in surveillance coverage, including custom kill plants and sheep being exported to Mexico. Spatial analyses can assist in identifying areas with high density sheep populations with lower levels of RSSS sampling. Identification compliance is being evaluated by reviewing reports from slaughter plants on the proportion of animals with appropriate identification. Additional analyses remain, including defining the most appropriate economic analyses, and comparing the surveillance system with developing surveillance standards. The working group hopes to have a draft written report for review by the end of the year.

Giving the Update on Scrapie Diagnostics and Susceptibility was Katherine O’Roarke, Research Microbiologist, USDA-ARS. "What’s New in Scrapie" -- Biopsy sampling of the third eyelid or tonsillar lymphoid tissue is a useful live animal test for scrapie. The biopsy sample is examined for accumulation of the abnormal prion protein using immunohistochemistry. A joint project conducted by the Veterinary Laboratory Agencies and the Moredun Institute in the United Kingdom has developed an alternative technique in which tissue is collected from the narrow band of lymphoid tissue near the rectal-anal junction. The morphology of the lymphoid follicles is similar in the tonsil, retropharyngeal lymph nodes, third eyelid, and rectal-anal mucosal tissue. A report on more than 300 sheep in the United Kingdom (UK), prepared by Drs. Lorenzo Gonzalez and Jeffrey Martin, will describe the sensitivity, specificity, and optimal collection interval for this technique in a variety of breeds of British sheep. ARS has done a preliminary evaluation of the technique in US sheep. Samples of third eyelid and rectal-mucosal tissue were collected from 56 sheep. Forty-two (42) sheep had negative biopsies at both sites; most of these sheep have been necropsied and no PrP-d was found in retropharyngeal lymph node or tonsil, showing good agreement with the antemortem biopsies. Fourteen (14) sheep had positive rectal biopsy samples; of those, only 12 had positive eyelid biopsies. These sheep will be monitored for disease development. However, the protocol is identical for all samples and it is probable that these sheep represent false negative third eyelid results. Abstracts of reports on the UK studies indicate that sensitivity of the test was 70% in the UK; similar large scale testing on US sheep is necessary. The biopsy tissue is somewhat difficult to handle in the tissue processing laboratory and adaptation to an ELISA format may improve test performance.

Alexia McKnight, Assistant Professor of Radiology, University of Pennsylvania, reviewed magnetic resonance imaging (MRI) diagnostics before the committee. A synopsis containing references is attached at the end of this report. Dr. McKnight asked the question, "could MRI be a cost-effective screening test, estimated at $25-30 each with results immediately available." The committee feels that it is not practical as compared to other alternatives currently available. However, the committee expressed interest in future reference to this technology.

Dr. Diane Sutton lead the Uniform Methods and Rules (UM&R) and Regulatory Issues Discussion. Several modifications to the UM&R were discussed. Eight issues were identified and communicated to the APHIS scrapie program coordinator. The committee acknowledged that APHIS and the industry is adequately addressing the year-to-year industry concerns.

Dr. Kris Petrini representing the North Central United States Animal Health Association District presented five recommendations to the Committee. During the discussions regarding these recommendations it was evident that all five issues had been addressed during the year at this Committee meeting.

The Committee approved a recommendation that USDA-APHIS-VS continue to provide indemnity funds for animals that have been designated for testing in Flocks Under Investigation as an alternative to third eyelid testing after consultation with the designated Scrapie Epidemiologist (DSE) and the Regional Area Epidemiologist (RAE).

The 2004 Resolutions along with their responses were reviewed by the Committee.

A Resolution concerning premises registration and identification was approved by the Committee and forwarded to the Committee on Nominations and Resolutions.

Committee on Scrapie

Status Report-Fiscal Year 2005: Cooperative State-Federal Scrapie Eradication Program

Submitted by Diane Sutton, DVM and Gary Ross, DVM

National Center for Animal Health Programs, APHIS, USDA

In Fiscal Year 2005 the Scrapie Eradication Program focused on: (1) utilization of a genetic based approach to flock clean-up plans; (2) cleaning up infected and source flocks; (3) tracing and testing exposed animals and flocks; (4) expansion of regulatory slaughter surveillance (RSSS); (5) conducting considtent state reviews, (6) producer education; (7) upgrading of the Scrapie National Generic Database and ( publishing the updated Scrapie Eradication Uniform Methods and Rules (UM&R). The current Scrapie Eradication UM&R is posted at http://www.aphis.usda.gov/vs/nahps/scrapie/umr-scrapie-erad.pdf.

Consistent State Reviews

States must meet the requirements in 9 CFR 79.6 in order to move sheep and goats in interstate commerce with minimal restrictions. Twenty seven states have enacted the required identification rules, the remaining states have submitted a work plan that describes the steps that will be taken to comply and provided a timeline for completing significant milestones. USDA is conducting onsite scrapie program consistent state reviews and has completed reviews in 12 states. States must be in full compliance by the end of their current rule making cycle. States not in full compliance at that time will be removed from the consistent state list. Removal from the list would create a significant impact on the interstate movement of sheep and goats from those States.

Scrapie Flock Certification Program

As of September 30, 2005, there were 1,961 flocks participating in the Scrapie Flock Certification Program (SFCP). Of these flocks 188 were certified flocks, 1,770 were complete monitored flocks, and 3 were selective monitored flocks (figure 2). There were 209 flocks newly enrolled and 53 newly certified (13 with status dates in FY 2005 and 40 with status dates in previous years) in FY 2005 (figure 3).

Infected and Source Flocks

As of September 30, 2005, there were 105 scrapie infected and source flocks. There were a total of 165** new infected and source flocks reported for FY 2005. The total infected and source flocks that have been released in FY 2005 was 128. The ratio of infected and source flocks cleaned up or placed on clean up plans vs. new infected and source flocks discovered in FY 2005 was 1.03 : 1*. In addition 622 scrapie cases were confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2005, of which 130 were RSSS cases. Fifteen cases of scrapie in goats have been reported since 1990. The last goat case was reported in May 2005. Approximately 5,626 animals were indemnified comprised of 49% non-registered sheep, 45% registered sheep, 1.4% non-registered goats and 4.6% registered goats.

Regulatory Scrapie Slaughter Surveillance (RSSS)

RSSS was designed to utilize the findings of the Center for Epidemiology and Animal Health (CEAH) Scrapie: Ovine Slaughter Surveillance (SOSS) study. The results of SOSS can be found at http://www.aphis.usda.gov/vs/ceah/cahm/Sheep/sheep.htm . RSSS started April 1,

2003. It is a targeted slaughter surveillance program which is designed to identify infected flocks for clean-up. During FY 2005 collections increased by 32% overall and by 90% for black and mottled faced sheep improving overall program effectiveness and efficiency as demonstrated by the 26% decrease in percent positive black faced sheep compared to FY 2004. Samples have been collected from 62,864 sheep since April 1, 2003, of which results have been reported for 59,105 of which 209 were confirmed positive. During FY 2005, 33,137 samples were collected from 81 plants. There have been 130 NVSL confirmed positive cases (30 collected in FY 2004 and confirmed in FY 2005 and 100 collected and confirmed in FY 2005) in FY 2005. Face colors of these positives were 114 black, 14 mottled, 1 white and 1 unknown. The percent positive by face color is shown in the chart below.

Scrapie Testing

In FY 2005, 35,845 animals have been tested for scrapie: 30,192 RSSS; 4,742 regulatory field cases; 772 regulatory third eyelid biopsies; 10 third eyelid validations; and 129 necropsy validations (chart 9).

Animal ID

As of October 04, 2005, 103,580 sheep and goat premises have been assigned identification numbers in the Scrapie National Generic Database. Official eartags have been issued to 73,807 of these premises.

*This number based on an adjusted 12 month interval to accommodate the 60 day period for setting up flock plans.

http://www.usaha.org/committees/reports/2005/report-scr-2005.pdf

PrP genotypes of atypical scrapie cases in Great Britain

G. C. Saunders, S. Cawthraw, S. J. Mountjoy, J. Hope and O. Windl

Department of TSE Molecular Biology, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey KT15 3NB, UK

Correspondence
G. C. Saunders
g.c.saunders@vla.defra.gsi.gov.uk

Great Britain and elsewhere have detected atypical scrapie infection in sheep with PrP genotypes thought to be genetically resistant to the classical form of scrapie. DNA sequencing of the PrP gene of British atypical scrapie cases (n=69), classical scrapie cases (n=59) and scrapie-free controls (n=138) was undertaken to identify whether PrP variants, other than the three well-characterized polymorphic codons, influenced susceptibility to atypical scrapie infection. Four non-synonymous changes, M112T, M137T, L141F and P241S, were detected that are most probably associated with the A136R154Q171 haplotype. Only the PrP variant containing a phenylalanine residue at amino acid position 141 was found to be associated more commonly with the atypical scrapie cases. In addition to the single nucleotide polymorphisms associated with the ARQ allele, two out of nine atypical scrapie cases with the ARR/ARR genotype were found to contain a 24 bp insertion, leading to an additional octapeptide repeat. In terms of PrP genetics, one classification of the GB scrapie cases examined in this study would place animals carrying any homozygous or heterozygous combination of ARR, AHQ or AF141RQ alleles, or any one of these alleles when paired with ARQ, as being susceptible to atypical scrapie infection, and animals heterozygous or homozygous for VRQ or homozygous for ARQ as being susceptible to classical scrapie disease. The AHQ PrP allele was associated with the highest incidence of atypical scrapie (263 per 100 000 alleles), whilst VRQ was associated with the lowest incidence (10 per 100 000 alleles).

Published online ahead of print on 11 August 2006 as DOI 10.1099/vir.0.81779-0.

http://vir.sgmjournals.org/cgi/content/abstract/87/11/3141?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=PRION&searchid=1&FIRSTINDEX=0&volume=87&issue=11&resourcetype=HWCIT

--------------------------------------------------------------------------------
Science 17 March 2000:
Vol. 287. no. 5460, p. 1907
DOI: 10.1126/science.287.5460.1907


News Focus
Writing Scrapie's Coda, Codon by Codon?
Michael Balter
Over the past decade, geneticists have begun to unravel why some sheep are more vulnerable than others to scrapie. They have found that different variations, or polymorphisms, in the gene coding for PrP--a cellular protein that many scientists believe becomes infectious when it converts to an abnormal form called a prion--seem to confer varying degrees of susceptibility. This correlation raises the possibility that genetically susceptible sheep could be bred out of the population, leaving only scrapie-resistant animals (see main text).

Studies of sheep experimentally infected with scrapie have shown that three codons, or positions, in the PrP gene--codons 136, 154, and 171--are critical in determining whether the animal comes down with the disease. Each codon gets translated into one of the 256 amino acids of the sheep PrP protein. Individuals most vulnerable to scrapie have the amino acids valine, arginine, and glutamine at the respective positions dictated by the three codons. Using the single-letter code for amino acids, this polymorphism is referred to as VRQ. At the other extreme, sheep with the polymorphism alanine-arginine-arginine (ARR) are the most resistant. Indeed, out of hundreds of scrapie-infected sheep tested worldwide, only one, in Japan, has turned out to be ARR. Three other polymorphisms (shown at below) apparently lead to intermediate levels of vulnerability to the disease.


Muddling this neat picture, however, are some bizarre differences in the effect of polymorphisms in different sheep breeds. For example, Suffolk sheep with the genotype ARQ are susceptible to scrapie, whereas ARQ Cheviot sheep are resistant. "We really don't understand this," says Nora Hunter, a geneticist at the Institute for Animal Health's Neuropathogenesis Unit in Edinburgh. Hunter and her colleagues are currently testing several hypotheses, including the possibility that the two breeds are being infected by different prion strains, or that Suffolk sheep may produce higher levels of PrP and thus have more protein available for conversion to the prion form.
More clear, however, is why PrP polymorphisms correlate with scrapie susceptibility in the first place. Findings reported in the 17 July 1997 issue of Nature and in the 13 May 1997 Proceedings of the National Academy of Sciences show that the VRQ version of normal PrP protein is easily converted into the prion form when mixed with other prions in the test tube. (Most researchers studying prion diseases believe this mechanism is responsible for the creation of new prions in infected animals.) The ARR polymorphism, on the other hand, strongly resists this conversion, while polymorphisms corresponding to intermediate scrapie susceptibility fall in between. This biochemical confirmation of the importance of PrP polymorphisms has bolstered the view that breeding VRQ and other susceptible genotypes out of the sheep population might be the best course toward eradication. Says Hunter: "At the moment, there really isn't any good alternative."

http://www.sciencemag.org/cgi/content/full/287/5460/1907?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=scrapie+resistant&searchid=1&FIRSTINDEX=10&resourcetype=HWCIT

Scrapie

The Countess of Mar asked Her Majesty's Government:

What have been the total costs, including the set-up cost and running costs, of the National Scrapie Plan since its inception; how many full-time posts are involved; and in which tasks. [HL4601]

The Parliamentary Under-Secretary of State, Department for Environment, Food and Rural Affairs (Lord Bach): The total cost of the National Scrapie Plan (NSP) since its inception in 2001 until the end of February 2006 is approximately £97 million. This figure is inclusive of set-up and running costs.

Currently, there are 84 full-time staff engaged on NSP activities. This includes staff at the State Veterinary Service's (SVS) National Scrapie Plan Administration Centre, who are responsible for service delivery aspects, and core Defra staff responsible for the NSP policy and programme management in partnership with the GB devolved administrations. In addition, farm-based activities are carried out by SVS field staff and local veterinary inspectors alongside their other duties.

22 Mar 2006 : Column WA65


The Countess of Mar asked Her Majesty's Government:

How many cases of (a) classical, and (b) atypical scrapie have been detected in sheep in the United Kingdom since the introduction of the National Scrapie Plan; what were the genotypes of the sheep; and which strains of scrapie were found. [HL4603]

Lord Bach: In the UK there are two forms of surveillance performed for the detection of TSEs in sheep, termed passive and active surveillance. Passive surveillance is where animals are reported to the State Veterinary Service (SVS) with clinical signs of disease, and the case is investigated. In 2002 the European Union launched a Europe-wide active TSE surveillance programme to establish the prevalence of TSEs in small ruminants. This has required the testing of sheep slaughtered for human consumption and fallen sheep over 18 months of age.

Table 1 shows the number of classical cases of scrapie detected in Great Britain through the passive surveillance from the beginning of the National Scrapie Plan in July 2001 until 15 March 2006. Diagnostic methods capable of detecting atypical cases of scrapie were introduced into the passive surveillance programme in July 2004, so the data presented for atypical cases of scrapie in the table are from July 2004 to 15 March 2006.
Genotype Classical Scrapie Atypical Scrapie
Unknown 152 0
ARR/ARR 0 0
ARR/AHQ 0 1
ARR/ARQ 3 0
ARR/ARH 0 0
AHQ/AHQ 8 0
AHQ/ARH 0 0
ARQ/ARH 25 0
ARH/ARH 13 0
AHQ/ARQ 26 2
ARQ/ARQ 289 0
ARR/VRQ 59 0
AHQNRQ 2 0
ARH/VRQ 68 0
ARQIVRQ 664 0
VRQ/VRQ 203 0
Total 1,512 3

Table 2 shows the number of confirmed classical and atypical scrapie cases detected in Great Britain through active surveillance of sheep at abattoirs and fallen stock since testing began in January 2002 until 15 March 2006. The active surveillance programme is an EU requirement. From January 2002 the Veterinary Laboratories Agency has tested over 140,000 sheep samples.
Genotype Classical Scrape Atypical Scrape
Unknown 1 0
ARR/ARR 0 15
ARR/AHQ 0 29
ARR/ARQ 1 13
ARR/ARH 0 1
AHQ/AHQ 1 13
AHQ/ARH 0 2
ARQ/ARH 1 0
ARH/ARH 0 0
AHQ/ARQ 3 21
ARQ/ARQ 23 13
ARR/VRQ 32 0
AHQ/VRQ 0 0
ARH/VRQ 12 0
ARQNRQ 76 1
VRQ/VRQ 15 0
Total 165 108


22 Mar 2006 : Column WA66


Information on the strains of scrapie present in a sample is not routinely collected.
Spongiform Encephalopathy Advisory Committee

The Countess of Mar asked Her Majesty's Government:

What have been the total funds allocated by them and by the research councils for research into transmissible spongiform encephalopathies in sheep, goats and cattle since the Spongiform Encephalopathy Advisory Committee was formed; and to which individuals or organisations those funds have been allocated. [HL4605]

The Parliamentary Under-Secretary of State, Department for Environment, Food and Rural Affairs (Lord Bach): The main funders of research into transmissible spongiform encephalopathies (TSEs) in sheep, goats and cattle are MAFF/Defra, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Food Standards Agency (FSA).

MAFF/DEFRA

Since the Spongiform Encephalopathy Advisory Committee (SEAC) was formed in 1990, MAFF/Defra have funded or are currently funding 274 research projects in TSEs at a total cost of £182,600,992. The breakdown of MAFF/Defra funding per institution is as follows.

see full text;


http://www.publications.parliament.uk/pa/ld199697/ldhansrd/pdvn/lds06/text/60322w04.htm#60322w04_sbhd1


New Zealand sheep with scrapie-susceptible PrP genotypes succumb to experimental challenge with a sheep-passaged scrapie isolate (SSBP/1)
E. F. Houston1, S. I. Halliday1, M. Jeffrey3, W. Goldmann2 and N. Hunter2

Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, UK1
BBSRC/MRC Neuropathogenesis Unit, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK2
VLA Lasswade, Pentlands Science Park, Bush Loan, Penicuik, Midlothian EH26 0PZ, UK3


Author for correspondence: Fiona Houston. Fax +44 1635 577263. e-mail fiona.houston@bbsrc.ac.uk


Abstract

Scrapie does not occur in New Zealand (NZ), although PrP gene alleles associated with susceptibility to the disease are found at relatively high frequencies in NZ sheep. The hypothesis that scrapie is a genetic disease of sheep is thus unlikely to be true. To confirm that NZ sheep are actually susceptible to scrapie infection, NZ sheep of various PrP genotypes were challenged by subcutaneous inoculation with a sheep-passaged scrapie isolate (SSBP/1). Showing similar PrP genetics to that seen in UK sheep, all NZ sheep carrying the VRQ PrP allele developed clinical signs typical of scrapie, with characteristic neurodegenerative changes and PrPSc evident on histopathological examination of their brains and lymphoid tissues. The incubation periods recorded in NZ sheep were generally shorter than those found in UK sheep. The results confirm that New Zealand sheep are as susceptible as their UK counterparts to experimental scrapie infection by subcutaneous inoculation.

http://vir.sgmjournals.org/cgi/content/full/83/5/1247

355 Emerging traits of interest to the livestock industries: scrapie resistance

in sheep. R. M. Lewis*1 and B. Villanueva2, 1Virginia Polytechnic

Institute and State University, Blackburg, 2Scottish Agricultural College,

Edinburgh, UK.

Many loci with major effects on performance, including fitness, have been identified

in livestock. Where genotype tests characterizing polymorphisms at such

loci are available, breeders have opportunity to use such information to increase

the frequency of beneficial alleles. A clear example is the Prion Protein

(PrP) locus in sheep, which is associated with resistance to the fatal transmissible

spongiform (TSE) scrapie. Five main haplotypes have been identified for

this locus resulting from polymorphisms at codons 136, 154 and 171. Animals

homozygous for the ARR haplotype are considered resistant while animals carrying

the VRQ haplotype are considered highly susceptible. Genetic strategies

based on PrP genotyping have thus been adopted to eradicate scrapie in infected

flocks while increasing the resistance of national flocks. The voluntary

National Scrapie Plan (NSP) in Great Britain is one of the earliest PrP genotyping

programs. It began in 2001 by genotyping rams registered with breed societies

favoring rams with beneficial genotypes for breeding. Since other TSE diseases

may be present in sheep, another aim of NSP is to remove the theoretical risk of

bovine spongiform encephalopathy naturally affecting sheep. Although increasing

genetic resistance to TSEs is clearly important, the path to achieving resistance

requires care. For instance, limited evidence suggests ARR homozygosity

may not unequivocally result in scrapie resistance, perhaps reflecting variable

strains of scrapie. Semen banks designed to preserve alleles currently disfavored

are needed to ensure flexibility to manage future TSEs. Furthermore, if

favored alleles are antagonistic to other economically important traits or are

sufficiently rare that selection increases inbreeding and reduces genetic variability,

a focus on scrapie alone may prove risky. The careful integration of

scrapie resistance into the overall breeding goal is thus central.

http://www.fass.org/2005/abstracts/05abs230.pdf

7. The new research reports the experimental transmission of BSE

to ARR/ARR sheep following intracerebral challenge with 0.5ml

10% BSE-infected bovine brain homogenate. The incubation

period of disease is approximately twice the average incubation

period of 556 days reported in BSE susceptible genotypes

(ARQ/ARQ sheep) challenged by intracerebral inoculation with

BSE in the same study. Apart from a single unconfirmed report of

1 on inclusion of ruminant derived MBM in concentrate foodstuffs for ruminants (the feed ban).

© SEAC 2003

naturally occurring scrapie in Japan, this is the first record of a

TSE infection in ARR/ARR sheep.

http://www.seac.gov.uk/statements/sheep_final_statement.pdf


TSS



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