Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Abstract

Abstract. 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 PrP sc 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 136 RR 154 QQ 171 in 12/13 cases or AV 136 RR 154 QQ 171 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 V 136 R 154 Q 171 allele. Disease occurred within, as well as independent of, motherdaughter lines, suggesting both maternal and nonmaternal transmission in the flocks.

Association of N176K and L141F dimorphisms of the PRNP gene with lack of pathological prion protein deposition in placentas of naturally and experimentally scrapie-affected ARQ/ARQ sheep

“…In this work we confirm, as previously described in other sheep breeds carrying V (Andréoletti et al, 2002) or A (Tuo et al, 2002) at codon 136, that the placentas of fetus with the Q171R dimorphism do not accumulate PrP Sc (Tuo et al, 2002;Andréoletti et al, 2002;Caplazi et al, 2004;Ersdal et al, 2005;Alverson et al, 2006;Lacroux et al, 2007). Furthermore, for the first time, we have extended these results to demonstrate that besides the Q171R dimorphism, N176K is also associated with the lack of accumulation of PrP Sc in the placenta of scrapie-affected ARQ/ARQ sheep, since six ARQN 176 /ARQK 176 fetuses derived from six ARQ/ ARQ wild type sheep did not display PrP Sc accumulation in the placentas (Table 1).…”

Prion transmission

“…75,[77][78][79][80] Andréoletti and coworkers quantified the levels of PrP Sc found within the placental cotyledon and determined that these tissues contained very high levels of prion: just 47 times less than in the obex. 75 Interestingly, the accumulation of PrP Sc within placental tissues appears to be dictated by the PRNP genotype of both the ewe and fetus as well as the stage of disease progression within the ewe.…”

“…75 Where placental accumulation of PrP Sc occurs, it has been shown that this can be with ewes in the clinical and preclinical stages of disease. 75,77,80 It therefore appears that in ovine scrapie the placenta harbors very high levels of prion but in utero transmission is not occurring. However, following parturition placental tissue is a likely source of infective agent in the transmission of disease from ewes to lambs.…”

Antemortem Detection of PrPCWD in Preclinical, Ranch-Raised Rocky Mountain Elk (Cevvus Elaphus Nelsoni) by Biopsy of the Rectal Mucosa

“…Similar findings have been described in studies of the pathogenesis in sheep and mule deer. 1,4,[8][9][10][11]18,19 Prospective studies on captive and free-ranging elk using this technique are in progress. These studies will delineate the diagnostic sensitivity and specificity of RAMALT screening as a method for identification of infected elk herds as part of an integrated management program to reduce the incidence of CWD in Rocky Mountain elk.…”