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Title:   Author  item
                                            Greenlee, Justinitem
                                            Kunkle, Robertitem
                                            Richt, Juergenitem
                                            Nicholson, Ericitem
                                            Hamir, Amirali
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/26/2014
                                    Publication  Date: 9/18/2014
                                    Citation: Greenlee, J.J., Kunkle, R.A., Richt, J.A., Nicholson, E.M., Hamir, A.N. 2014. Lack of prion accumulation in lymphoid tissues of PRNP ARQ/ARR sheep intracranially inoculated with the agent of scrapie. PLoS One. 9(9):e108029.Interpretive Summary: Sheep scrapie is the archetype transmissible spongiform encephalopathy. This invariably fatal neurologic disease can be transmitted horizontally through the shedding of infectious scrapie prions. Genetics greatly influence the susceptibility of prion-exposed sheep to scrapie. Definitive diagnosis is established by immunoassay detection of disease-associated prions (PrPsc) in tissues of scrapie-affected sheep. This study recorded the clinical course and PrPsc distribution in tissues of sheep after intra-cerebral inoculation with scrapie infectious brain tissue. The study included sheep with high resistance and high susceptibility genotypes. All of the sheep succumbed to scrapie and had accumulated PrPsc in central nervous tissue. Sheep with the high and moderate susceptibility genotype had abundant and moderate PrPsc in lymphoid tissues. Sheep with the high resistant genotype had no detectable PrPsc in lymphoid tissues. Our data suggest that genetic resistance to scrapie is associated with failure of a disease initiating event, that of PrPsc to accumulate in lymphoid tissue, and not due to non-permissiveness of CNS tissue to PrPsc amplification.
                                Technical Abstract: Sheep scrapie is a transmissible spongiform encephalopathy that can be transmitted horizontally. The prion protein gene (PRNP) profoundly influences the susceptibility of sheep to the scrapie agent and the tissue levels and distribution of PrPSc in affected sheep. The purpose of this study was to compare the survival time and PrPSc tissue distribution in sheep with highly resistant and highly susceptibile PRNP genotypes after intracranial inoculation of the agent of scrapie. Five sheep each of genotype VRQ/VRQ, VRQ/ARR or ARQ/ARR were inoculated. Sheep were euthanized when clinical signs of scrapie became severe. Clinical signs, microscopic lesions, and western blot profiles were uniform across genotypes and consistent with manifestations of classical scrapie. Mean survival time differences were associated with the 171 polymorphic site with VRQ/VRQ sheep surviving 18 months, and VRQ/ARR and ARQ/ARR survived 60 and 56 months, respectively. Labeling of PrPSc by immunohistochemistry revealed similar accumulations in central nervous system tissues regardless of host genotype. Immunoreactivity for PrPSc in lymphoid tissue was consistently abundant in VRQ/VRQ, present but confined to tonsil or retropharyngeal lymph node in 4/5 VRQ/ARR, and totally absent in ARQ/ARR sheep. The results of this study demonstrate the susceptibility of sheep with the ARQ/ARR genotype to scrapie by the intracranial inoculation route with PrPSc accumulation in CNS tissues, but prolonged incubation times and lack of PrPSc in lymphoid tissue.


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