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From: TSS ()
Subject: Classic Scrapie in Sheep with the ARR/ARR Prion Genotype in Germany and France
Date: July 12, 2007 at 9:55 am PST

Classic Scrapie in Sheep with the ARR/ARR Prion Genotype in Germany and France

Martin H. Groschup,*1 Caroline Lacroux,†1 Anne Buschmann,* Gesine Lühken,‡
Jacinthe Mathey,† Martin Eiden,* Séverine Lugan,† Christine Hoffmann,*
Juan Carlos Espinosa,§ Thierry Baron,¶ Juan Maria Torres,§ Georg Erhardt,‡
and Olivier Andreoletti†
*Friedrich-Loeffler-Institut, Insel Riems, Germany; †Unité de Mixte de Recherche–Institut National de la Recherche
Agronimique–Ecole National Vetérinaire de Toulouse, Toulouse, France; ‡Justus-Liebig–University Giessen,
Geissen, Germany; §Centro de Investigación en Sanidad Animal, Madrid, Spain; and ¶Unité Agents Transmissibles
Noncoventionnel, Lyon, France

1These authors contributed equally to this study.

In the past, natural scrapie and bovine spongiform encephalopathy (BSE) infections have essentially
not been diagnosed in sheep homozygous for the A136R154R171 haplotype of the prion protein. This
genotype was therefore assumed to confer resistance to BSE and classic scrapie under natural
exposure conditions. Hence, to exclude prions from the human food chain, massive breeding efforts
have been undertaken in the European Union to amplify this gene. We report the identification of 2
natural scrapie cases in ARR/ARR sheep that have biochemical and transmission characteristics
similar to cases of classic scrapie, although the abnormally folded prion protein (PrPSc) was
associated with a lower proteinase-K resistance. PrPSc was clearly distinct from BSE prions
passaged in sheep and from atypical scrapie prions. These findings strongly support the idea that
scrapie prions are a mosaic of agents, which harbor different biologic properties, rather than a
unique entity.


snip...


Discussion

Epidemiologic and genetic data collected in recent decades have indicated that sheep
carrying the PrPC-encoding ARR haplotype only are resistant to natural TSE infections, whereas
those carrying the homozygous VRQ or ARQ haplotypes are changes highly susceptible. This
assumption has been supported by genotyping data for several thousand sheep with scrapie
worldwide: only 1 homozygous ARR carrier has been found. A case of classic scrapie in
ARR/ARR sheep in Japan was reported more than a decade ago (7). However, the validity of this
diagnosis has been heavily challenged when it could not be reconfirmed independently, because
no suitable frozen or formalin-fixed material was available. Our current report shows that classic
scrapie cases can occur in homozygous ARR sheep and suggests that even the former report may
have been an imperfect first demonstration of such a case.

The apparent resistance of sheep of the ARR/ARR genotype to both natural scrapie and
experimental BSE has triggered national authorities since the late 1990s (e.g., United Kingdom,
the Netherlands, France), and since 2001 the EU, to implement a genetic selection and culling
policy in sheep to protect the human food chain from small ruminant TSEs and to eradicate TSE
from affected flocks.

This global approach, even if valuable, considered scrapie as a single entity and did not
take into account any kind of TSE agent biodiversity. Sheep TSE agents have strikingly different
abilities to replicate in hosts expressing a spectrum of PrP variants. Sheep with genotype
ARQ/ARQ in scrapie flocks are commonly affected by the disease (8). However, a historical
sheep scrapie brain pool (SSBP-1) transmits easily to VRQ homozygous or heterozygous sheep
but not to ARQ/ARQ animals (17). Similarly atypical scrapie cases (including the “Nor98” type)
are more frequently found in AHQ and AF141RQ haplotype carriers than in sheep carrying
exclusively other haplotypes. However, atypical cases have also been found in ARR/ARR
animals (18,19). Similarly, ability to of BSE to develop in ARR/ARR sheep was observed after
experimental parenteral inoculation. However, in this case, higher transmission rates and shorter
incubation periods were observed in sheep of the other genotypes, such as ARQ/ARQ, and

Page 8 of 15

AHQ/AHQ (20,21). The susceptibility of ARR/ARR sheep to an oral BSE challenge was
reported most recently (22).

Both BSE and atypical scrapie PrPSc have a characteristic molecular signature, which
allows rapid and reliable biochemical discrimination from each other and from classic scrapie
PrPSc (3,23). In both cases of scrapie in ARR/ARR sheep in France and Germany, abnormal
PrPSc harbored features (apparent molecular mass and glycotype) were very similar to those
observed in classic scrapie. However, at least in the S83 case, PrPSc seemed to have a remarkably
lower PK resistance than that observed in a panel of scrapie isolates. This observation sustains
the idea that the involved agent could belong to a particular scrapie agent group that cannot be
directly identified by using the current biochemical criteria for TSE agent discrimination.
The successful propagation of the S83 isolate in Tg338 mice that express the ovine VRQ
haplotype and the persistence of its original biochemical signature (including the low PK
resistance) allow the inference that this scrapie agent could also be present and could naturally
propagate in sheep that harbor genotypes other than ARR/ARR. The transmissibility and
contagiousness of the S83 isolate are currently under investigation in experimentally challenged
sheep. These experiments should produce a better understanding of the susceptibility of each
genotype to this agent and its capacity to spread efficiently in sheep flocks.
The discovery of these 2 cases clearly indicates that the genetic resistance of ARR/ARR
sheep to the so-called classic scrapie agent is not absolute. It also provides evidence that, rather
than being a single entity, scrapie is a mosaic of infectious agents harboring different biologic
properties in its natural host. Finally, although many thousands of cases of classic scrapie have
been reported in sheep of other PrP genotypes and hundreds of thousands of rapid tests have
been performed in Europe since the implementation of active TSE surveillance in small
ruminants began in 2001, the discovery of these 2 ARR/ARR cases supports the idea that such
infections are extremely rare.

This work was supported by the German Ministry for Food, Agriculture and Consumer Protection, by the
European Union (EU) grant QLK-CT 2001-01309 (BSE in sheep), the EU-funded Network of Excellence
“Neuroprion” (CT2004-506579), the French GIS prion strain typing group, and the EU program ACCESS (HPRT
CT 2001-00131).

Page 9 of 15

Dr Groschup is head of the Institute for Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-
Institut, Insel Riems, Germany, and extraordinary professor at the Veterinary University of Hannover, Germany. His
interests focus on prion infections, including their diagnosis, transgenic detection, and molecular determinants of
infectivity and transmission.

References

snip...full text ;


http://www.cdc.gov/eid/content/13/8/pdfs/07-0077.pdf

Recently the question has again been brought up as to whether
scrapie is transmissible to man. This has followed reports that the
disease has been transmitted to primates. One particularly lurid
speculation (Gajdusek 1977) conjectures that the agents of scrapie,
kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of
mink are varieties of a single "virus". The U.S. Department of
Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed
for human or animal food at slaughter or rendering plants" (ARC 84/77)"
The problem is emphasised by the finding that some strains of scrapie
produce lesions identical to the once which characterise the human
dementias"

Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety
of laboratory personnel requires prompt attention. Second, action
such as the "scorched meat" policy of USDA makes the solution of the
acrapie problem urgent if the sheep industry is not to suffer
grievously.

snip...

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf


J Infect Dis 1980 Aug;142(2):205-8

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to
nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep
and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were
exposed to the infectious agents only by their nonforced consumption of
known infectious tissues. The asymptomatic incubation period in the one
monkey exposed to the virus of kuru was 36 months; that in the two monkeys
exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months,
respectively; and that in the two monkeys exposed to the virus of scrapie
was 25 and 32 months, respectively. Careful physical examination of the
buccal cavities of all of the monkeys failed to reveal signs or oral
lesions. One additional monkey similarly exposed to kuru has remained
asymptomatic during the 39 months that it has been under observation.

PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract


EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE

This is provided by the statistically significant increase in the incidence
of sheep scrape from 1985, as determined from analyses of the submissions
made to VI Centres, and from individual case and flock incident studies.
........

http://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf


AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.

snip...

http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf

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


Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible
for French iatrogenic growth hormone-linked CJD taken as a control is
very different from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate;

http://www.pnas.org/cgi/content/full/041490898v1


SCRAPIE UPDATE USA AS OF MARCH 2007 NOR98 INCLUDED

http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps

TSS




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