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Selection for the A R R PRNP allele is known to curb classical scrapie in sheep, and we expected it to minimize the risk for classical bovine spongiform encephalopathy (c-BSE) propagation. We orally challenged newborn ARR/ARR and ARQ/ARQ lambs with ovine-passaged c-BSE. Contrary to our expectations, prion disease developed in all ARR/ARR lambs after markedly longer incubation times (≈50 months) than ARQ/ARQ controls (≈20 months). Tissue distribution of the abnormal isoform of prion protein (PrP) in clinically affected ARR/ARR sheep largely mirrored tissue distribution seen in ARQ/ARQ animals. Bioassays in bovine- and human-PrP transgenic mice showed that passage through ARR/ARR sheep did not increase the agent's zoonotic potential. Transmission efficiency in human normal cellular isoform PrP-expressing mice remained similar to cattle c-BSE and lower than ARQ-passaged c-BSE. Our data reveal the limitations of breeding exclusively for ARR when the objective is to mitigate c-BSE risk and underscore the need to maintain specific-risk-material removal and surveillance programs.