lunes, 27 de julio de 2009

BSE and Scrapie in Porcine-PrP Transgenic Mice | CDC EID


Volume 15, Number 8–August 2009
Research
Transgenic Mice Expressing Porcine Prion Protein Resistant to Classical Scrapie but Susceptible to Sheep Bovine Spongiform Encephalopathy and Atypical Scrapie


Juan-Carlos Espinosa,1 María-Eugenia Herva,1 Olivier Andréoletti, Danielle Padilla, Caroline Lacroux, Hervé Cassard, Isabelle Lantier, Joaquin Castilla, and Juan-María Torres
Author affiliations: Centro de Investigación en Sanidad Animal, Madrid, Spain (J.-C. Espinosa, M.-E. Herva, D. Padilla, J. Castilla, J.-M. Torres); École Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti, C. Lacroux, H. Cassard); and Centre Institut National de la Recherche Agronomique de Tours, Nouzilly, France (I. Lantier)

Suggested citation for this article

Abstract
How susceptible pigs are to infection with sheep prions is unknown. We show, through transmission experiments in transgenic mice expressing porcine prion protein (PrP), that the susceptibility of this mouse model to bovine spongiform encephalopathy (BSE) can be enhanced after its passage in ARQ sheep, indicating that the pathogenicity of the BSE agent is modified after passage in sheep. Transgenic mice expressing porcine PrP were, nevertheless, completely resistant to infection with a broad panel of classical scrapie isolates from different sheep PrP genotypes and with different biochemical characteristics. The atypical (Nor98 like) isolate (SC-PS152) was the only scrapie isolate capable of transmission in these mice, although with a marked transmission barrier. Unexpectedly, the atypical scrapie agent appeared to undergo a strain phenotype shift upon transmission to porcine-PrP transgenic mice and acquired new strain properties, suggesting that atypical scrapie agent may exhibit different phenotypes depending on the host cellular PrP or other genetic factors.

Transmissible spongiform encephalopathies (TSEs) are infectious diseases that affect humans and several livestock species, causing fatal neurodegeneration. TSEs are linked to the conversion of cellular prion protein (PrPC) to the aberrant form associated with the disease (PrPSC). Sheep scrapie, the most widely known TSE (1), has been documented in Europe for >2 centuries and is thought to have spread to other countries worldwide throughout the 1900s (2). Classical scrapie is caused by a variety of prion strains that can be distinguished by their biological and biochemical features (3), although several so-called atypical scrapie strains that have remarkably different biochemical and transmission characteristics have been recently described (4,5). Other TSEs include bovine spongiform encephalopathy (BSE), which reached epidemic proportions in Europe at the end of the past century due to the use of animal feed containing BSE-contaminated feedstuffs (6). A human variant of BSE, called variant Creutzfeldt-Jacob disease (vCJD) (7), was discovered in 1994 and reported in 1996 as linked to the BSE epidemic in the United Kingdom and elsewhere.

No reports exist of naturally occurring TSEs in pigs. However, the experimental inoculation of pigs and transgenic mice overexpressing porcine PrP has indicated that swine are susceptible to BSE infection by the parenteral route, although with a considerable transmission barrier (8,9). The oral transmission of BSE in pigs has not been demonstrated to date.

The potential spread of BSE to animals in the human food chain such as sheep, goats, and pigs needs assessing because a risk for human infection by animals other than BSE-infected cattle cannot be excluded. Moreover, the use of pigs as graft donors could cause concern, given a recent report of vCJD in the recipient of a porcine dura mater graft (10).

The transmission barrier limits TSE infection between different species. Sheep can be experimentally infected with BSE that is not easily distinguished from some scrapie strains showing a 19-kDa atypical proteinase K–resistant PrP (PrPres) unglycosylated band (11–13). Susceptibility and resistance to TSE infection in sheep is determined by polymorphisms at PrP amino acid positions 136, 154, and 171; sheep have the VRQ and ARQ alleles that are most susceptible to scrapie infection (14). Although ARQ is considered to show the highest susceptibility to BSE infection (15), the ARR allele was until recently thought to confer full resistance to BSE and scrapie (16,17). However, the successful transmission of BSE prions to ARR/ARR sheep (18) and the detection of natural cases of classical scrapie in sheep with the ARR/ARR genotype (19) have shown that this resistance is penetrable. Moreover, the identification of previously unrecognized atypical scrapie strains in sheep with various genotypes, including ARR/ARR, further supports this statement (20,21).

Although only 1 case of BSE in a goat has been confirmed, several putative field cases of BSE infection affecting goats and sheep have been detected in Europe, and the infectious properties of the resulting TSEs are not well known (22,23). In addition, a rise in scrapie outbreaks among flocks in Europe has been described; it is possible that some cases of alleged sheep scrapie could be ovine BSE. In a previous report, we demonstrated that BSE experimentally passaged in homozygous ARQ sheep showed enhanced infectivity (compared with cattle BSE) as determined in transgenic mice expressing bovine PrP protein (24).

Previous experiments showed that transgenic mice expressing porcine PrP (PoPrP-Tg001) can be infected with cattle BSE, but that infection is limited by a strong barrier (8): only some BSE inocula were able to infect PoPrP-Tg001 mice in primary transmission experiments, and when transmission occurred only a reduced percentage of the inoculated mice were affected. In the present study, we used the PoPrP-Tg001 mouse model to compare the porcine PrP transmission barrier to BSE infection before and after passage in sheep. In parallel, we also analyzed the susceptibility of PoPrP-Tg001 mice to a broad panel of scrapie isolates from different ovine PrP genotypes and with different biochemical characteristics.


abrir aquí para acceder al documento CDC completo (muy extenso):
BSE and Scrapie in Porcine-PrP Transgenic Mice | CDC EID

No hay comentarios: