Open AccessMarkedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP
Author(s) -
JeanLuc Vilotte,
Solange Soulier,
Rachid Essalmani,
MarieGeorges Stinnakre,
Daniel Vaiman,
Laurence Lepourry,
José Costa da Silva,
Nathalie Besnard,
Margaret Dawson,
A. Buschmann,
Martin H. Groschup,
Stéphanie Petit,
M.F. Madelaine,
Sabine Rakatobe,
Annick Le Dur,
Didier Vilette,
Hubert Laude
Publication year - 2001
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.75.13.5977-5984.2001
Subject(s) - scrapie , biology , transgene , virology , genetically modified mouse , transmissible spongiform encephalopathy , allele , incubation period , virus , bovine spongiform encephalopathy , genetically modified organism , incubation , microbiology and biotechnology , prion protein , genetics , gene , disease , medicine , biochemistry
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 PrP(VRQ)-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 PrP(VRQ) 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.