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From: TSS ()
Date: November 20, 2007 at 12:07 pm PST

In Reply to: NEW MYSTERIES SPONTANEOUS MAD COW STRAIN IN USA $$$ posted by TSS on November 19, 2007 at 6:30 pm:

Subject: Re: Polymorphisms of the prion gene promoter region that influence classical bovine spongiform encephalopathy susceptibility are not applicable to other transmissible spongiform encephalopathies in cattle
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
Date: Tue, 20 Nov 2007 19:58:21 +0000
Content-Type: text/plain

Research article
Experimental transmission of atypical scrapie to sheep
Marion M Simmons1 , Timm Konold1 , Hugh A Simmons3 , Yvonne I Spencer1 ,
Richard Lockey1 , John Spiropoulos1 , Sharon Everitt2 and Derek Clifford3

1Department of Pathology, Veterinary Laboratories Agency – Weybridge,
Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK
2Department of Molecular Pathogenesis and Genetics, Veterinary Laboratories
Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB,
3Animal Services Unit, Veterinary Laboratories Agency – Weybridge, Woodham
Lane, New Haw, Addlestone, Surrey KT15 3NB, UK

author email corresponding author email

BMC Veterinary Research 2007, 3:20doi:10.1186/1746-6148-3-20

The electronic version of this article is the complete one and can be found
online at:

Received: 26 March 2007
Accepted: 28 August 2007
Published: 28 August 2007

© 2007 Crown copyright; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (,
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

Active surveillance for transmissible spongiform encephalopathies in small
ruminants has been an EU regulatory requirement since 2002. A number of
European countries have subsequently reported cases of atypical scrapie,
similar to previously published cases from Norway, which have pathological and
molecular features distinct from classical scrapie. Most cases have occurred
singly in flocks, associated with genotypes considered to be more resistant to
classical disease. Experimental transmissibility of such isolates has been
reported in certain ovinised transgenic mice, but has not previously been
reported in the natural host. Information on the transmissibility of this agent is
vital to ensuring that disease control measures are effective and proportionate.

This report presents the successful experimental transmission, in 378 days, of
atypical scrapie to a recipient sheep of homologous genotype with
preservation of the pathological and molecular characteristics of the donor.
This isolate also transmitted to ovinised transgenic mice (Tg338) with a murine
phenotype indistinguishable from that of Nor 98.

This result strengthens the opinion that these cases result from a distinct
strain of scrapie agent, which is potentially transmissible in the natural host
under field conditions.



To our knowledge this is the first report of the successful experimental
transmission of atypical scrapie within the natural host. The retention of the
molecular and pathological characteristics of the scrapie agent following this
experimental transmission supports the hypothesis that disease in the donor
animal was caused by a stable strain of the TSE agent which has phenotypic
characteristics distinct from those associated with classical scrapie. Although
clinical signs were not recorded from the donor animal because it presented
dead (fallen stock), the signs seen in the challenged animal were consistent
with those reported for the small number of passive surveillance cases so far
identified in the UK [14,15] and elsewhere [6,16], which were characterised by
gait abnormalities, abnormal behaviour and a relative lack of pruritic signs.

The transmission characteristics of atypical scrapie from different countries in
Tg338 mice [12] and emerging data from similar transmissions of the isolate in
this report indicate that at least one strain of atypical scrapie compatible
with/indistinguishable from Nor98 is widespread across Europe, despite its
relatively recent identification.

Although it has now been demonstrated to be experimentally transmissible
within and between species via the intracerebral route, there is little
epidemiological evidence for ease of transmission of this strain under field
conditions, where scrapie is most likely transmitted via the oral route. This
raises the question of how it came to be so geographically widespread. One
hypothesis is that this represents a spontaneous genetic disease in sheep
similar to the familial forms of TSE in man (e.g. GSS, familial CJD and FFI etc.),
in which the resultant disease can subsequently be transmitted experimentally

Horizontal transmission of classical scrapie has been shown to occur in adult
sheep exposed to an affected flock [19] and even in animals which have had
contact only with a contaminated environment (GI Dexter and SJ Bellworthy,
personal communication). The environmental persistence of the classical
scrapie agent is also supported by epidemiological evidence from Icelandic
repopulation studies [20,21]. However, the low molecular mass (<14 kD) band
of PrPSc seen in Western blots of atypical isolates is associated with a
reduction in PK resistance of this disease-associated protein. It is possible
that this relative protease susceptibility may make the agent less robust in
field conditions and thereby reduce the extent to which it is transmissible by
natural routes, and so limit the number of cases. It could be argued that this
in turn supports the hypothesis that the natural disease may arise
spontaneously. However, although genetic studies have indicated a PrP
genotype host range for atypical scrapie which, for the majority of cases, is
almost fully distinct from that of the classical forms of disease, they have not
identified a single genetic feature (such as the point mutations in some human
forms [22]) which might account for this.

This relative PrPSc fragility [23] compared to the PrPSc in classical scrapie,
may also account for the total absence of intracellular PrPSc immunolabelling.
The different PK cleavage sites in PrP associated with different strains of TSE
infecting small ruminants can be used to differentiate them, both in blots and
by immunohistochemistry. Intracellular immunostaining is significantly reduced
in sheep infected with BSE compared to classical scrapie, when the
appropriate monoclonal antibodies are applied, and it has been speculated that
this demonstrates a partial digestion of the PrPSc molecule by the endogenous
proteases within the cells [24]. If the PrPSc is more protease sensitive, then
this loss of intracellular immunolabelling even with an antibody to the core of
the protein (such as MAb 2G11) might indicate that cells can more effectively
catabolise this abnormal form of the protein than more 'classical' forms, and
therefore succumb to clinical disease much later, if at all. This may also
account for the apparent absence of disease-related PrPSc in lymphoid
tissues. It is interesting to note that in familial CJD (E200K mutation) also, PrP
labelling was seen as a uniformly fine deposit throughout all cortical layers [25].

This study confirms that 'atypical scrapie' is transmissible within the natural
host species, via the intracerebral route, without alteration of the pathological
and molecular characteristics. This is the first report from a larger study which
will explore more widely the effect of the PrP gene on the experimental
susceptibility and resultant phenotype following intracerebral or oral challenge
with this type of scrapie isolate.

At present the significance of this result, in terms of the transmissibility or
pathogenicity under 'field conditions' of this agent strain in any species
remains speculative, but it supports the need for appropriate control measures
protecting both the animal and the human food chain to encompass atypical
scrapie cases specifically.


Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA,
10.1073/pnas.0502296102Medical 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
etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-
en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche
Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent
Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire
des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon,
France; **Pathologie Infectieuse et Immunologie, InstitutNational 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 amisfolded 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 tothe 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 goatflocks and
may have important implications in terms of scrapie control andpublic 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,


OF COURSE, the USDA et al once was concerned for human health from typical
scrapie, and rightly so, typical scrapie transmits to primates by there NON-


ALSO, 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.


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