Biology of PrP^sc accumulation in two natural scrapie-infected sheep flocks

Sheep scrapie is a prion disease that requires interaction of exogenous prions with host prion protein (PrP) supporting prion formation. Disease is associated with deposition of a host-generated conformational variant of PrP, PrP^sc, in a variety of tissues, including brain, resulting in fatal spongiform encephalopathy. Efficiency of PrP^sc formation is determined by polymorphisms in the PrP-coding sequence. This article adds to previous data of natural sheep scrapie, concentrating on the effect of host genotype and age on PrP^sc accumulation patterns during preclinical and clinical disease. Two entire scrapie-infected, predominantly Suffolk-cross, sheep flocks euthanized for regulatory purposes were genotyped and analyzed for PrP^sc deposition in various tissues using single- and dual-label immunohistochemistry. Scrapie, as defined by PrP^sc deposition, occurred in 13/80 sheep. Preclinical disease was evident in nearly 70% of infected sheep, ranging in age from 14 months to 7 years. PrP^sc accumulated systemically in the nervous tissue, various lymphoid tissues, both alimentary tract related and non-alimentary tract related, and the placenta. Clinical neurological illness was always associated with spongiform encephalopathy and PrP^sc deposition in the brain. Only 6 of 9 sheep with preclinical scrapie had PrP^sc deposition in the brain but widespread PrP^sc deposition in peripheral lymphoid tissue, supporting previous data showing peripheral PrP^sc accumulation preceding deposition in the brain. PrP^sc colocalized with a marker for follicular dendritic cells throughout the lymphoid system. PrP^sc also accumulated in the peripheral nervous system, particularly the nervous supply of the gastrointestinal tract. Abundant PrPsc was evident in trophoblast cells of placentomes but not in the endometrium, myometrium, or associated nervous plexus. PrP^sc deposits were not observed in the mammary parenchyma or bone marrow. Scrapie susceptibility was defined genetically by PrP codon 171: PrP^sc deposition was restricted to PrP genotype AA ₁₃₆RR₁₅₄QQ₁₇₁ in 12/13 cases or AV ₁₃₆RR₁₅₄QQ₁₇₁ in 1/13 cases. The earliest accumulation was observed in the single VRQ/ARQ heterozygous animal, consistent with the reported high scrapie susceptibility and brief incubation period observed in breeds with predominance of the V₁₃₆R₁₅₄Q ₁₇₁ allele. Disease occurred within, as well as independent of, mother-daughter lines, suggesting both maternal and nonmaternal transmission in the flocks.