Location: Virus and Prion ResearchTitle: Sheep with the homozygous lysine-171 prion protein genotype are resistant to classical scrapie after experimental oronasal inoculation
|CASSMANN, E - Iowa State University|
|MOORE, S - Orise Fellow|
|SMITH, J - Iowa State University|
Submitted to: Veterinary Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/8/2018
Publication Date: 12/17/2018
Citation: Cassmann, E.D., Moore, S.J., Smith, J.D., Greenlee, J.J. 2018. Sheep with the homozygous lysine-171 prion protein genotype are resistant to classical scrapie after experimental oronasal inoculation. Veterinary Pathology. 56(3):409-417. https://doi.org/10.1177/0300985818817066.
Interpretive Summary: Scrapie is a fatal disease of sheep and goats that causes damaging changes in the brain. The infectious agent is an abnormal protein called a prion that has misfolded from its normal state. Whether or not a sheep will get scrapie is determined by its genetics. A change in the DNA that codes for the amino acid sequence of the host prion protein can cause the animal to be either resistant or susceptible to the disease. A specific location on this gene, codon 171, seems to play the biggest role in determining disease susceptibility. Sheep with the amino acid arginine (R) at 171 are resistant to scrapie while those with glutamine (Q) at that position are not. It has been suggested that lysine (K) at 171 may behave similarly to R because the two amino acids have a similar structure. This study tested whether sheep with one K allele at codon 171 (QK171) or two K alleles at codon 171 (KK171) had a different response to the disease than sheep that were QQ171. The study determined that while QK171 were not resistant to the disease after oronasal exposure, they took longer to develop scrapie than QQ171 sheep. While KK171 sheep were susceptible to the scrapie agent after intracranial inoculation, they were resistant to infection by the oronasal route. This work suggests that selective breeding for the K171 allele in sheep breeds where this allele is represented may help prevent the development of scrapie after natural exposure. This information is useful to sheep farmers and breeders that are selectively breeding animals with genotypes resistant to scrapie. Further, this result is important to regulators with roles in designing programs to enhance genetic resistance to scrapie.
Technical Abstract: Scrapie is a fatal neurodegenerative disease of sheep resulting from the accumulation of a misfolded form of the prion protein (PrPSc). Polymorphisms in the host prion protein gene (PRNP) can affect susceptibility to the scrapie agent. Lysine (K) at codon 171 of PRNP is an inadequately characterized, naturally occurring polymorphism in sheep. We inoculated Barbado sheep with PRNP genotypes QQ171, QK171 or KK171 by either the intracranial (IC) or oronasal (ON) 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 post-inoculation (MPI)), sheep were necropsied and tissues were collected for histopathologic, immunohistochemical, enzyme immunoassay, and immunoblot examination for PrPSc. 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, 2/5 (40%) of the ON inoculated QK genotype sheep developed neurologic signs and had PrPSc in the brain. The other 3/5 (60%) sheep were asymptomatic at 70 MPI, but had detectable PrPSc in peripheral tissues. None of the ON inoculated sheep of the KK171 genotype developed signs or had detectable PrPSc. 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 enhancing scrapie resistance in certain breeds of sheep.