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From: TSS ()
Subject: Experimental transmission of atypical scrapie to sheep
Date: April 9, 2008 at 2:41 pm PST

Research article

Experimental transmission of atypical scrapie to sheep

Marion M Simmons*1, Timm Konold1, Hugh A Simmons3,
Yvonne I Spencer1, Richard Lockey1, John Spiropoulos1, Sharon Everitt2 and
Derek Clifford3

Address: 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, UK and 3Animal Services Unit, Veterinary Laboratories
Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey
KT15 3NB, UK

Email: Marion M Simmons* -; Timm Konold -;
Hugh A Simmons -; Yvonne I Spencer -;
Richard Lockey -; John Spiropoulos -;
Sharon Everitt -; Derek Clifford -
* Corresponding author


Background: 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

Results: 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.
Conclusion: 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 repre-
sents 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 [17,18].
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.

WHY not the potential for some of the cases of atypical scrapie being a
result of a food born exposure as
evidence pointed out for the typical scrapie ???


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.

typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;





To minimise the risk of farmers' claims for compensation from feed

To minimise the potential damage to compound feed markets through adverse

To maximise freedom of action for feed compounders, notably by
maintaining the availability of meat and bone meal as a raw
material in animal feeds, and ensuring time is available to make any
changes which may be required.




MAFF remains under pressure in Brussels and is not skilled at
handling potentially explosive issues.

5. Tests _may_ show that ruminant feeds have been sold which
contain illegal traces of ruminant protein. More likely, a few positive
test results will turn up but proof that a particular feed mill knowingly
supplied it to a particular farm will be difficult if not impossible.

6. The threat remains real and it will be some years before feed
compounders are free of it. The longer we can avoid any direct
linkage between feed milling _practices_ and actual BSE cases,
the more likely it is that serious damage can be avoided. ...

SEE full text ;


Aspects of the Cerebellar Neuropathology in Nor98

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1
1National Veterinary Insitute, Sweden; 2National Veterinary Institute,

Nor98 is a prion disease of old sheep and goats. This atypical form of
scrapie was first
described in Norway in 1998. Several features of Nor98 were shown to be
from classical scrapie including the distribution of disease associated
prion protein
(PrPd) accumulation in the brain. The cerebellum is generally the most
affected brain
area in Nor98. The study here presented aimed at adding information on the
neuropathology in the cerebellum of Nor98 naturally affected sheep of
genotypes in Sweden and Norway. A panel of histochemical and
(IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic
amyloid, and cell markers for phagocytic cells were conducted. The type of
lesions and tissue reactions were evaluated. The types of PrPd deposition
characterized. The cerebellar cortex was regularly affected, even though
there was a
variation in the severity of the lesions from case to case. Neuropil
vacuolation was
more marked in the molecular layer, but affected also the granular cell
layer. There was
a loss of granule cells. Punctate deposition of PrPd was characteristic. It
morphologically and in distribution identical with that of synaptophysin,
that PrPd accumulates in the synaptic structures. PrPd was also observed in
granule cell layer and in the white matter. ***The pathology features of
Nor98 in the
cerebellum of the affected sheep showed similarities with those of sporadic
Creutzfeldt-Jakob disease in humans.

full text ;



The flocks of origin are WY, CO, CA, IN, and MN.

personal communication USDA et al. ...TSS


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