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From: TSS ()
Date: April 18, 2007 at 6:22 pm PST

In Reply to: Re: NOR98-LIKE STRAIN OF SCRAPIE FOUND IN WYOMING update posted by TSS on April 18, 2007 at 3:18 pm:

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

Annick Le Dur*†, Vincent Be´ ringue*†, Olivier Andre´ oletti‡, Fabienne Reine*, Thanh Lan Laý¨*, Thierry Baron§,
Bjørn Bratberg¶, Jean-Luc Vilotte, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*††
*Virologie Immunologie Mole´ culaires and Ge´ne´ tique Biochimique et Cytoge´ne´ tique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas,
France; ‡Unite´ Mixte de Recherche, Institut National de la Recherche Agronomique–Ecole Nationale Ve´ te´ rinaire de Toulouse, Interactions Hoˆ te Agent
Pathoge` ne, 31066 Toulouse, France; §Agence Franc¸aise de Se´ curite´ Sanitaire des Aliments, Unite´ 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.


Atypical Scrapie and Discordant Cases in Small Ruminants Involve a
Truly Infectious Agent. Whether a transmissible agent is actually
involved in the so-called ‘‘atypical’’ or ‘‘unclassified’’ scrapie
cases recurrently detected in sheep, notably in individuals with
resistant PrP genotypes, has become a growing concern during
the last few years. Here we show that inoculation to transgenic
mice of 12 isolates of such types consistently led to a distinctive
fatal TSE disease. These isolates originated from two Nor98
clinically affected sheep and from nine sheep and one goat that
produced a discordant response upon rapid test screening. This
result demonstrates that PrPSc deposition in the brain of such
animals, hardly evidenced through conventional scrapie diagnosis
techniques, is associated with the multiplication of a bona fide
infectious agent. Hence, such atypical scrapie forms or cases
must now be considered as true TSE, involving a prion rather
than simply arising from a PrP protein disorder, whatever their
origin might be, acquired or spontaneous.


Our study demonstrates that an authentic TSE infectious agent
is responsible in sheep and goats of sporadic atypical infections
that remained unnoticed until recently. This raises important
issues with regard to control of scrapie infection in small
ruminants. Of major concern, ARRARR sheep can no longer
be regarded as free of natural TSE infection. This finding
challenges, at least to some extent, the foundation of the selective
breeding programs engaged in several European Union member
states (47, 48) and may call for a reappraisal of possible
consequences of this strategy in the long term. Finally, more
information about this newly discovered type of TSE agent, its
prevalence in countries free of scrapie or BSE disease, and its
potential to across-species transmission would be needed for a
comprehensive evaluation of its implications in terms of public
We thank S. Hawke (Imperial College School of Medicine, London), and
J. Grassi (Commissariat a` l’Energie Atomique, Saclay, France) for kindly
providing antibodies ICSM18 and 12F10, respectively; the staff of
the Animalerier Rongeurs (Institut National de la Recherche
Agronomique) for mouse care; our colleagues of the French scrapie
strain-typing network (chaired by M. Eloit) for discussions; and Anne-
Lise Haenni for carefully reading the manuscript. This study was
supported by national grants from the Ministries of Research (Groupement
d’Inte´reˆt Scientifique Infections a` Prion) and Agriculture (Direction
Ge´ne´rale de l’Alimentation).
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16036  www.pnas.orgcgidoi10.1073pnas.0502296102 Le Dur et al.tss

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