Sheep With the Homozygous Lysine-171 Prion Protein Genotype Are Resistant to Classical Scrapie After Experimental Oronasal Inoculation

Abstract

<p>Scrapie is a fatal neurodegenerative disease of sheep resulting from the accumulation of a misfolded form of the prion protein (PrP^Sc). Polymorphisms in the host prion protein gene (<em>PRNP</em>) can affect susceptibility to the scrapie agent. Lysine (K) at codon 171 of <em>PRNP</em> is an inadequately characterized, naturally occurring polymorphism in sheep. We inoculated Barbado sheep with <em>PRNP</em> genotypes QQ171, QK171, or KK171 by either the intracranial (IC, <em>n</em> = 2–7 per genotype) or oronasal (ON, <em>n</em> = 5 per genotype) routes with a scrapie isolate to investigate the effect of lysine at codon 171 on susceptibility. When neurologic signs were observed or at the end of the experiment (70 months postinoculation [MPI]), sheep were necropsied and tissue collected for histopathologic, immunohistochemical, enzyme immunoassay and Western blot examination for PrP^Sc. All genotypes of sheep developed scrapie after IC inoculation. After ON inoculation, sheep with the QK171 genotype had prolonged incubation periods compared to the QQ genotype. During the experiment, 2 of 5 of the ON-inoculated QK genotype sheep developed neurologic signs and had PrP^Sc in the brain. The other 3 of 5 sheep were asymptomatic at 70 MPI but had detectable PrP^Sc in peripheral tissues. None of the ON-inoculated sheep of the KK171 genotype developed signs or had detectable PrP^Sc. Our experiments demonstrate that sheep with the KK171 genotype are resistant to scrapie via oronasal exposure and that sheep with the QK171 genotype have prolonged incubation relative to QQ171 sheep. The K171 prion protein allele may be useful to enhance scrapie resistance in certain breeds of sheep.</p>