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.