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Journal of Virology, July 2001, p. 5977-5984, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5977-5984.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Markedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP

Jean-Luc Vilotte,1 Solange Soulier,1 Rachid Essalmani,1 Marie-George Stinnakre,1 Daniel Vaiman,1 Laurence Lepourry,1 Jose Costa Da Silva,1 Nathalie Besnard,1 Mike Dawson,2 Anne Buschmann,3 Martin Groschup,3 Stephanie Petit,4 Marie-Francoise Madelaine,4 Sabine Rakatobe,4 Annick Le Dur,4 Didier Vilette,4 and Hubert Laude4,*

Génétique Biochimique et Cytogénétique1 and Virologie Immunologie Moléculaires,4 Institut National de la Recherche Agronomique, Jouy-en-Josas, France; Central Veterinary Laboratory, Addelstone, United Kingdom2; and Federal Centre for Virus Diseases of Animals, Tübingen, Germany3

Received 12 December 2000/Accepted 3 April 2001

The susceptibility of sheep to scrapie is known to involve, as a major determinant, the nature of the prion protein (PrP) allele, with the VRQ allele conferring the highest susceptibility to the disease. Transgenic mice expressing in their brains three different ovine PrPVRQ-encoding transgenes under an endogenous PrP-deficient genetic background were established. Nine transgenic (tgOv) lines were selected and challenged with two scrapie field isolates derived from VRQ-homozygous affected sheep. All inoculated mice developed neurological signs associated with a transmissible spongiform encephalopathy (TSE) disease and accumulated a protease-resistant form of PrP (PrPres) in their brains. The incubation duration appeared to be inversely related to the PrP steady-state level in the brain, irrespective of the transgene construct. The survival time for animals from the line expressing the highest level of PrP was reduced by at least 1 year compared to those of two groups of conventional mice. With one isolate, the duration of incubation was as short as 2 months, which is comparable to that observed for the rodent TSE models with the briefest survival times. No survival time reduction was observed upon subpassaging of either isolate, suggesting no need for adaptation of the agent to its new host. Overexpression of the transgene was found not to be required for transmission to be accelerated compared to that observed with wild-type mice. Conversely, transgenic mice overexpressing murine PrP were found to be less susceptible than tgOv lines expressing ovine PrP at physiological levels. These data argue that ovine PrPVRQ provided a better substrate for sheep prion replication than did mouse PrP. Altogether, these tgOv mice could be an improved model for experimental studies on natural sheep scrapie.

* Corresponding author. Mailing address: Virologie Immunologie Moléculaires, INRA, 78352 Jouy-en-Josas cedex, France. Phone: 331 3465 2600. Fax: 331 3465 2621. E-mail: laude{at}biotec.jouy.inra.fr.

Journal of Virology, July 2001, p. 5977-5984, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5977-5984.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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