Susceptibility to scrapie and disease phenotype in sheep: cross-PRNP genotype experimental transmissions with natural sources

Lorenzo González,Paula Stewart,Scott Hamilton,Hugh W Reid,Jeanie Finlayson,Martin Jeffrey,Francesca Chianini,Philip Steele,Yvonne Pang,Wilfred Goldmann,Samantha L Eaton,Stuart Martin,Sílvia Sisó,Mark P Dagleish

doi:10.1186/1297-9716-43-55

Abstract

It has long been established that the sheep Prnp genotype influences the susceptibility to scrapie, and some studies suggest that it can also determine several aspects of the disease phenotype. Other studies, however, indicate that the source of infection may also play a role in such phenotype. To address this question an experiment was set up in which either of two different natural scrapie sources, AAS from AA136 Suffolk and VVC from VV136 Cheviot sheep, were inoculated into AA136, VA136 and VV136 sheep recipients (n = 52). The immunohistochemical (IHC) profile of disease-associated PrP (PrPd) accumulation in the brain of recipient sheep was highly consistent upon codon 136 homologous and semi-homologous transmission, but could be either similar to or different from those of the inoculum donors. In contrast, the IHC profiles were highly variable upon heterologous transmission (VVC to AA136 and AAS to VV136). Furthermore, sheep of the same Prnp genotype could exhibit different survival times and PrPd profiles depending on the source of infection, and a correlation was observed between IHC and Western blot profiles. It was found that additional polymorphisms at codons 112 or 141 of AA136 recipients resulted in a delayed appearance of clinical disease or even in protection from infection. The results of this study strongly suggest that the scrapie phenotype in sheep results from a complex interaction between source, donor and recipient factors, and that the Prnp genotype of the recipient sheep does not explain the variability observed upon codon 136 heterologous transmissions, arguing for other genetic factors to be involved.

Highlights

Classical scrapie is a transmissible spongiform encephalopathy (TSE) that occurs as a natural infectious and contagious disease of sheep and goats
None of them showed any evidence of PrPd or PrPres accumulation in any of the tissues examined by IHC and Western blotting (WB), respectively
When measuring the efficiency of transmission in terms of attack rate and survival time, the results of this experiment showed that the degree of genotypic homology between donors and recipients is a key factor in the development of scrapie

Summary

Introduction

Classical scrapie is a transmissible spongiform encephalopathy (TSE) that occurs as a natural infectious and contagious disease of sheep and goats. It can be transmitted experimentally by a variety of routes, to its natural host species and to other mammals, notably laboratory rodents. The aetiological agent of scrapie is thought by many to be a prion, which is defined as an abnormal and infectious isoform of a cellular prion protein, PrPc [1], encoded by the host Prnp gene [2]. “In vitro” assays have led some researchers to postulate that such relative susceptibility or resistance may result from the efficiency by which different polymorphic variants of PrPc can convert to PrPres [7]

Methods

Results

Conclusion