Abstract
The prion protein gene (Prnp) is highly influential in determining risk and susceptibility of sheep exposed to classical scrapie. Sheep homozygous for alanine at codon 136 and arginine at codons 154 and 171 (ARR/ARR) of the Prnp gene are historically considered to be highly resistant to classical scrapie, although they form a significant fraction of cases of atypical scrapie. To date, experimental transmission of prions to ARR/ARR sheep has only been achieved with the BSE agent and mostly by the intracerebral route. We summarise here the results of six separate studies, in which 95 sheep of the ARR/ARR genotype were naturally exposed to (n = 18) or experimentally challenged with (n = 77) natural or experimental sources of classical scrapie by the oral, intra-intestinal, subcutaneous or intracerebral routes and allowed to survive for periods of up to 94 months post-infection. Only the intracerebral route resulted in disease and/or amplification of disease associated PrP (PrPd), and only in two of 19 sheep that survived for longer than 36 months. Discriminatory immunohistochemistry and Western blot confirmed the scrapie, non-BSE signature of PrPd in those two sheep. However, the neuropathological phenotype was different from any other scrapie (classical or atypical) or BSE source previously reported in sheep of any Prnp genotype. These studies confirm the widely held view that ARR/ARR sheep are highly resistant to classical scrapie infection, at least within their commercial lifespan. Moreover, within the constraints of the present studies (only two infected sheep), these results do not support the suggestion that atypical scrapie or BSE are generated by adaptation or mutation of classical scrapie in sheep of resistant ARR/ARR genotype.
Highlights
The transmissible spongiform encephalopathies (TSEs) are characterised by the accumulation of abnormal forms of a hostcoded, cell membrane sialoglycoprotein called prion protein (PrP)
Of the 14 sheep challenged by the intracerebral route only two, one Cheviot and one Suffolk sheep, showed PrPd accumulation, as described below
In agreement with previously published studies, the above experiments show that ARR/ARR sheep are extremely resistant to classical scrapie when naturally exposed to a highly contaminated environment or when infected by experimental protocols that approximate natural exposure
Summary
The transmissible spongiform encephalopathies (TSEs) are characterised by the accumulation of abnormal forms of a hostcoded, cell membrane sialoglycoprotein called prion protein (PrP). A novel, apparently noncontagious or sporadic form of sheep TSE, originally called Nor 98 [1] and more commonly referred to as atypical scrapie, has been recognised in Europe and elsewhere. The prion protein gene (Prnp) controls susceptibility to both atypical and classical scrapie [2]. Sheep bearing alanine (A) or valine (V) at codon 136 and glutamine (Q) at codon 171 of PrP are susceptible to classical scrapie. Classical scrapie is rarely reported in sheep homo- or hetero-zygous for the allele that bears A at codon 136 and arginine (R) at codons 154 and 171. Other epidemiological studies show that scrapie is very rare in ARQ/ARR sheep and absent from ARR/ARR sheep in the UK [7]. Single cases of natural scrapie infection in ARR/ARR sheep have been reported from Germany, France [8] and possibly Japan [9]
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