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Journal of Virology, June 2001, p. 5328-5334, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5328-5334.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Efficient Transmission of Two Different Sheep Scrapie Isolates in Transgenic Mice Expressing the Ovine PrP Gene

Carole Crozet,1,* Frederic Flamant,2 Anna Bencsik,1 Denise Aubert,2 Jacques Samarut,2 and Thierry Baron1

Unité de Virologie---ATNC, Agence Française de Sécurité Sanitaire des Aliments (AFSSA),1 and Laboratoire de Biologie Moléculaire et Cellulaire, Ecole Normale Supérieure de Lyon,2 Lyon, France

Received 19 September 2000/Accepted 2 March 2001

We produced transgenic mice expressing the sheep prion protein to obtain a sensitive model for sheep spongiform encephalopathies (scrapie). The complete open reading frame, with alanine, arginine, and glutamine at susceptibility codons 136, 154, and 171, respectively, was inserted downstream from the neuron-specific enolase promoter. A mouse line, Tg(OvPrP4), devoid of the murine PrP gene, was obtained by crossing with PrP knockout mice. Tg(OvPrP4) mice were shown to selectively express sheep PrP in their brains, as demonstrated in mRNA and protein analysis. We showed that these mice were susceptible to infection by sheep scrapie following intracerebral inoculation with two natural sheep scrapie isolates, as demonstrated not only by the occurrence of neurological signs but also by the presence of the spongiform changes and abnormal prion protein accumulation in their brains. Mean times to death of 238 and 290 days were observed with these isolates, but the clinical course of the disease was strikingly different in the two cases. One isolate led to a very early onset of neurological signs which could last for prolonged periods before death. Independently of the incubation periods, some of the mice inoculated with this isolate showed low or undetectable levels of PrPsc, as detected by both Western blotting and immunohistochemistry. The development of experimental scrapie in these mice following inoculation of the scrapie infectious agent further confirms that neuronal expression of the PrP open reading frame alone is sufficient to mediate susceptibility to spongiform encephalopathies. More importantly, these mice provide a new and promising tool for studying the infectious agents in sheep spongiform encephalopathies.

* Corresponding author. Mailing address: Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Unité de Virologie---ATNC, 31 avenue Tony Garnier, 69364 Lyon, France. Phone: 33 (0) 4 78 72 65 43. Fax: 33 (0) 4 78 61 91 45. E-mail: c.crozet{at}lyon.afssa.fr.

Journal of Virology, June 2001, p. 5328-5334, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5328-5334.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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