The
prion protein gene (Prnp) plays a crucial role in the susceptibility of sheep to
scrapie in terms of attack rate and/or incubation period. However, the influence of Prnp on the pathogenesis of the disease, specifically the involvement of tissues of the lymphoreticular system (LRS), pathways of neuroinvasion and neuropathological phenotypes, remains controversial. This study reports the onset and progression of disease-associated
prion protein (
PrP(d)) accumulation in the LRS and nervous tissues of sheep of six different Prnp genotypes infected by
oral administration of the same mixed
scrapie brain homogenate. Sheep homozygous for
glutamine (Q) at
codon 171 of PrP, with either
valine (V) or
alanine (A) at
codon 136 (i.e. VRQ/VRQ, VRQ/ARQ and ARQ/ARQ), showed early and consistent
PrP(d) accumulation in LRS tissues of the pharynx and gut. In contrast, LRS involvement was minimal, inconsistent and occurred late in the incubation period in sheep heterozygous for
arginine (R) at
codon 171 (i.e. VRQ/ARR and ARQ/ARR). Despite this difference, all five groups were susceptible to
infection and developed clinical disease, albeit with significantly different incubation periods (shortest in VRQ/VRQ and longest in ARQ/ARR sheep). The remaining group of ARR/ARR homozygous sheep did not show evidence of
infection at the end of the experiment or at previous predetermined time points. As for LRS tissues, the sites of initial
PrP(d) accumulation in the brain were determined immunohistochemically. These were the same in all susceptible sheep (except for ARR/ARR sheep), regardless of their Prnp genotype which, together with an early and consistent accumulation of
PrP(d) in circumventricular organs and a late or inconsistent involvement of the enteric and autonomic nervous system and of the spinal cord, suggests neuroinvasion occurring via the blood. The neuropathological phenotype (
PrP(d) profile in the central nervous system) of clinically affected sheep was similar in the three V136 carrier groups, but showed some differences in the two A136 homozygous groups, suggesting a
codon 136-driven selection of different strains from the mixture contained in the inoculum. ARQ/ARR sheep showed an irregular distribution of brain
PrP(d), contrasting with the more widespread distribution of the other four groups. The results indicate that (1) ARQ/ARR sheep are more susceptible to oral
scrapie infection than would be predicted from incidence figures in natural disease, (2) amplification and accumulation of
PrP(d) in LRS tissues is host genotype dependent, but does not necessarily have a marked effect on the outcome of the
infection and (3) the neuropathological phenotype of
scrapie is related to the host genotype, but possibly in combination with the infecting source.