• 1. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216:136144.

  • 2. Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998;95:1336313383.

  • 3. Jeffrey M, Gonzalez L. Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease. Neuropathol Appl Neurobiol 2007;33:373394.

    • Search Google Scholar
    • Export Citation
  • 4. Hadlow WJ. Scrapie and kuru. Lancet 1959;274:289290.

  • 5. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977;197:943960.

  • 6. Gibbs CJ Jr, Gajdusek DC, Asher DM, et al. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 1968;161:388389.

    • Search Google Scholar
    • Export Citation
  • 7. Wells GA, Scott AC, Johnson CT, et al. A novel progressive spongiform encephalopathy in cattle. Vet Rec 1987;121:419420.

  • 8. Hope J, Reekie LJD, Hunter N, et al. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature 1988;336:390392.

    • Search Google Scholar
    • Export Citation
  • 9. Williams ES, Young S. Spongiform encephalopathy of Rocky Mountain elk. J Wildl Dis 1982;18:465471.

  • 10. Williams ES, Young S. Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J Wildl Dis 1980;16:8998.

  • 11. Wyatt JM, Pearson GR, Smerdon TN, et al. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Vet Rec 1991;129:233236.

    • Search Google Scholar
    • Export Citation
  • 12. Hartsough GR, Burger D. Encephalopathy of mink: I. Epizootiologic and clinical observations. J Infect Dis 1965;115:387392.

  • 13. Burger D, Hartsough GR. Encephalopathy of mink: II. Experimental and natural transmission. J Infect Dis 1965;115:393399.

  • 14. Babelhadj B, Di Bari MA, Pirisinu L, et al. Prion disease in dromedary camels, Algeria. J Emerg Infect Dis 2018;24:10291036.

  • 15. Brown P, Bradley R. 1755 and all that: a historical primer of transmissible spongiform encephalopathy. BMJ 1998;317:16881692.

  • 16. Journal of the House of Commons 1775;27.

  • 17. Leopold JGL. Nützliche und auf die Erfahrung gegründete Einleitung zu der Landwirthschaft. Berlin: Christian Friedrich Günthern, 1759.

    • Search Google Scholar
    • Export Citation
  • 18. Besnoit CMC. Note sur les lesions nerveuses de la tremblante du mouton. Rev Vet 1898;23:307343.

  • 19. Cuillé J, Chelle PL. La maladie dite “tremblante” du mouton; est-elle inoculable? Compte Rend Acad Sci 1936;203:15521554.

  • 20. Alper T, Cramp WA, Haig DA, et al. Does the agent of scrapie replicate without nucleic acid? Nature 1967;214:764766.

  • 21. Hunter GD, Millson GC. Studies on the heat stability and chromatographic behaviour of the scrapie agent. J Gen Microbiol 1964;37:251258.

    • Search Google Scholar
    • Export Citation
  • 22. Pattison IH. Resistance of the scrapie agent to formalin. J Comp Pathol 1965;75:159164.

  • 23. Griffith JS. Nature of the scrapie agent: self-replication and scrapie. Nature 1967;215:10431044.

  • 24. Dickinson AG, Meikle VM, Fraser H. Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. J Comp Pathol 1968;78:293299.

    • Search Google Scholar
    • Export Citation
  • 25. Bolton DC, McKinley MP, Prusiner SB. Identification of a protein that purifies with the scrapie prion. Science 1982;218:13091311.

  • 26. Sajnani G, Requena JR. Prions, proteinase K and infectivity. Prion 2012;6:430432.

  • 27. Chesebro B, Race R, Wehrly K, et al. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature 1985;315:331333.

    • Search Google Scholar
    • Export Citation
  • 28. Oesch B, Westaway D, Walchli M, et al. A cellular gene encodes scrapie PrP 27–30 protein. Cell 1985;40:735746.

  • 29. Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1993;73:13391347.

  • 30. Zhang Z, Zhang Y, Wang F, et al. De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J 2013;27:47684775.

    • Search Google Scholar
    • Export Citation
  • 31. Wang F, Wang X, Yuan CG, et al. Generating a prion with bacterially expressed recombinant prion protein. Science 2010;327:11321135.

  • 32. Donne DG, Viles JH, Groth D, et al. Structure of the recombinant full-length hamster prion protein PrP(29–231): the N terminus is highly flexible. Proc Natl Acad Sci U S A 1997;94:1345213457.

    • Search Google Scholar
    • Export Citation
  • 33. Stahl N, Borchelt DR, Hsiao K, et al. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 1987;51:229240.

  • 34. Brown DR, Qin K, Herms JW, et al. The cellular prion protein binds copper in vivo. Nature 1997;390:684687.

  • 35. Wang C, Wu R, Li FD, et al. Expression patterns of prion protein gene in differential genotypes sheep: quantification using molecular beacon real-time RT-PCR. Virus Genes 2011;42:457462.

    • Search Google Scholar
    • Export Citation
  • 36. Büeler H, Fischer M, Lang Y, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992;356:577582.

    • Search Google Scholar
    • Export Citation
  • 37. Benestad SL, Austbø L, Tranulis MA, et al. Healthy goats naturally devoid of prion protein. Vet Res 2012;43:87.

  • 38. Criado JR, Sanchez-Alavez M, Conti B, et al. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis 2005;19:255265.

    • Search Google Scholar
    • Export Citation
  • 39. Collinge J. Prion protein is necessary for normal synaptic function. Nature 1994;370:295297.

  • 40. Ding NZ, Wang XM, Jiao XW, et al. Cellular prion protein is involved in decidualization of mouse uterus. Biol Reprod 2018;99:319325.

  • 41. Tobler I, Gaus SE, Deboer T, et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 1996;380:639642.

    • Search Google Scholar
    • Export Citation
  • 42. Watarai M, Kim S, Erdenebaatar J, et al. Cellular prion protein promotes Brucella infection into macrophages. J Exp Med 2003;198:517.

    • Search Google Scholar
    • Export Citation
  • 43. Thackray AM, Bujdoso R. PrPc expression influences the establishment of herpes simplex virus type 1 latency. J Virol 2002;76:24982509.

    • Search Google Scholar
    • Export Citation
  • 44. Thackray AM, Bujdoso R. Elevated PrPC expression predisposes to increased HSV-1 pathogenicity. Antivir Chem Chemother 2006;17:4152.

    • Search Google Scholar
    • Export Citation
  • 45. Ballerini C, Gourdain P, Bachy V, et al. Functional implication of cellular prion protein in antigen-driven interactions between T cells and dendritic cells. J Immunol 2006;176:72547262.

    • Search Google Scholar
    • Export Citation
  • 46. de Almeida CJ, Chiarini LB, da Silva JP, et al. The cellular prion protein modulates phagocytosis and inflammatory response. J Leukoc Biol 2005;77:238246.

    • Search Google Scholar
    • Export Citation
  • 47. Brown DR, Schulz-Schaeffer WJ, Schmidt B, et al. Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD-1 activity. Exp Neurol 1997;146:104112.

    • Search Google Scholar
    • Export Citation
  • 48. Del Río JA, Ferrer I, Gavín R. Role of cellular prion protein in interneuronal amyloid transmission. Prog Neurobiol 2018;165–167:87102.

    • Search Google Scholar
    • Export Citation
  • 49. Fluharty BR, Biasini E, Stravalaci M, et al. An N-terminal fragment of the prion protein binds to amyloid-beta oligomers and inhibits their neurotoxicity in vivo. J Biol Chem 2013;288:78577866.

    • Search Google Scholar
    • Export Citation
  • 50. Wong BS, Pan T, Liu T, et al. Differential contribution of superoxide dismutase activity by prion protein in vivo. Biochem Biophys Res Commun 2000;273:136139.

    • Search Google Scholar
    • Export Citation
  • 51. Wong BS, Liu T, Li R, et al. Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein. J Neurochem 2001;76:565572.

    • Search Google Scholar
    • Export Citation
  • 52. Klamt F, Dal-Pizzol F, Conte da Frota ML Jr, et al. Imbalance of antioxidant defense in mice lacking cellular prion protein. Free Radic Biol Med 2001;30:11371144.

    • Search Google Scholar
    • Export Citation
  • 53. Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 1993;90:1096210966.

    • Search Google Scholar
    • Export Citation
  • 54. Wille H, Michelitsch MD, Guénebaut V, et al. Structural studies of the scrapie prion protein by electron crystallography. Proc Natl Acad Sci U S A 2002;99:35633568.

    • Search Google Scholar
    • Export Citation
  • 55. Vázquez-Fernández E, Vos MR, Afanasyev P, et al. The structural architecture of an infectious mammalian prion using electron cryomicroscopy. PLoS Pathog 2016;12:e1005835.

    • Search Google Scholar
    • Export Citation
  • 56. Govaerts C, Wille H, Prusiner SB, et al. Evidence for assembly of prions with left-handed β-helices into trimers. Proc Natl Acad Sci U S A 2004;101:83428347.

    • Search Google Scholar
    • Export Citation
  • 57. Aguzzi A, Montrasio F, Kaeser PS. Prions: health scare and biological challenge. Nat Rev Mol Cell Biol 2001;2:118126.

  • 58. Terry C, Wadsworth JDF. Recent advances in understanding mammalian prion structure: a mini review. Front Mol Neurosci 2019;12:169.

  • 59. Mallucci G, Dickinson A, Linehan J, et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 2003;302:871874.

    • Search Google Scholar
    • Export Citation
  • 60. Brandner S, Isenmann S, Raeber A, et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 1996;379:339343.

    • Search Google Scholar
    • Export Citation
  • 61. Chesebro B, Trifilo M, Race R, et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 2005;308:14351439.

    • Search Google Scholar
    • Export Citation
  • 62. Mallucci GR, White MD, Farmer M, et al. Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron 2007;53:325335.

    • Search Google Scholar
    • Export Citation
  • 63. Moreno JA, Radford H, Peretti D, et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 2012;485:507.

    • Search Google Scholar
    • Export Citation
  • 64. Sandberg MK, Al-Doujaily H, Sharps B, et al. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 2011;470:540542.

    • Search Google Scholar
    • Export Citation
  • 65. Ryder SJ, Dexter GE, Heasman L, et al. Accumulation and dissemination of prion protein in experimental sheep scrapie in the natural host. BMC Vet Res 2009;5:9.

    • Search Google Scholar
    • Export Citation
  • 66. Westaway D, Zuliani V, Cooper CM, et al. Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie. Genes Dev 1994;8:959969.

    • Search Google Scholar
    • Export Citation
  • 67. Bossers A, Belt P, Raymond GJ, et al. Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms. Proc Natl Acad Sci U S A 1997;94:49314936.

    • Search Google Scholar
    • Export Citation
  • 68. Bossers A, Schreuder BE, Muileman IH, et al. PrP genotype contributes to determining survival times of sheep with natural scrapie. J Gen Virol 1996;77:26692673.

    • Search Google Scholar
    • Export Citation
  • 69. Goldmann W, Hunter N, Foster JD, et al. Two alleles of a neural protein gene linked to scrapie in sheep. Proc Natl Acad Sci U S A 1990;87:24762480.

    • Search Google Scholar
    • Export Citation
  • 70. Goldmann W, Hunter N, Smith G, et al. PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. J Gen Virol 1994;75:989995.

    • Search Google Scholar
    • Export Citation
  • 71. Belt PB, Muileman IH, Schreuder BE, et al. Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. J Gen Virol 1995;76:509517.

    • Search Google Scholar
    • Export Citation
  • 72. Hunter N, Goldmann W, Foster JD, et al. Natural scrapie and PrP genotype: case-control studies in British sheep. Vet Rec 1997;141:137140.

    • Search Google Scholar
    • Export Citation
  • 73. Hunter N, Moore L, Hosie BD, et al. Association between natural scrapie and PrP genotype in a flock of Suffolk sheep in Scotland. Vet Rec 1997;140:5963.

    • Search Google Scholar
    • Export Citation
  • 74. Greenlee JJ, Smith JD, Hamir AN. Oral inoculation of neonatal Suffolk sheep with the agent of classical scrapie results in PrPSc accumulation in sheep with the PRNP ARQ/ARQ but not the ARQ/ARR genotype. Res Vet Sci 2016;105:188191.

    • Search Google Scholar
    • Export Citation
  • 75. Hunter N, Foster JD, Goldmann W, et al. Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. Arch Virol 1996;141:809824.

    • Search Google Scholar
    • Export Citation
  • 76. Tongue SC, Pfeiffer DU, Warner R, et al. Estimation of the relative risk of developing clinical scrapie: the role of prion protein (PrP) genotype and selection bias. Vet Rec 2006;158:43.

    • Search Google Scholar
    • Export Citation
  • 77. Groschup MH, Lacroux C, Buschmann A, et al. Classic scrapie in sheep with the ARR/ARR prion genotype in Germany and France. Emerg Infect Dis 2007;13:12011207.

    • Search Google Scholar
    • Export Citation
  • 78. Ikeda T, Horiuchi M, Ishiguro N, et al. Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan. J Gen Virol 1995;76:25772581.

    • Search Google Scholar
    • Export Citation
  • 79. Acutis PL, Sbaiz L, Verburg F, et al. Low frequency of the scrapie resistance-associated allele and presence of lysine-171 allele of the prion protein gene in Italian Biellese ovine breed. J Gen Virol 2004;85:31653172.

    • Search Google Scholar
    • Export Citation
  • 80. Boukouvala E, Gelasakis AI, Kanata E, et al. The association between 171 K polymorphism and resistance against scrapie affection in Greek dairy sheep. Small Rumin Res 2018;161:5156.

    • Search Google Scholar
    • Export Citation
  • 81. Guo X, Kupfer DM, Fitch GQ, et al. Identification of a novel lysine-171 allele in the ovine prion protein (PRNP) gene. Anim Genet 2003;34:303305.

    • Search Google Scholar
    • Export Citation
  • 82. Greenlee JJ, Zhang X, Nicholson EM, et al. Prolonged incubation time in sheep with prion protein containing lysine at position 171. J Vet Diagn Invest 2012;24:554558.

    • Search Google Scholar
    • Export Citation
  • 83. Cassmann ED, Moore SJ, Smith JD, et al. Sheep with homozygous lysine-171 prion protein genotype are resistant to classical scrapie after experimental oronasal inoculation. Vet Pathol 2019;56:409417.

    • Search Google Scholar
    • Export Citation
  • 84. Díaz C, Vitezica ZG, Rupp R, et al. Polygenic variation and transmission factors involved in the resistance/susceptibility to scrapie in a Romanov flock. J Gen Virol 2005;86:849857.

    • Search Google Scholar
    • Export Citation
  • 85. Hamir AN, Kunkle RA, Greenlee JJ, et al. Experimental oral transmission of United States origin scrapie to neonatal sheep. J Vet Diagn Invest 2009;21:6468.

    • Search Google Scholar
    • Export Citation
  • 86. Hamir AN, Kunkle RA, Richt JA, et al. Experimental transmission of sheep scrapie by intracerebral and oral routes to genetically susceptible Suffolk sheep in the United States. J Vet Diagn Invest 2005;17:39.

    • Search Google Scholar
    • Export Citation
  • 87. Prinz M, Huber G, Macpherson AJ, et al. Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes. Am J Pathol 2003;162:11031111.

    • Search Google Scholar
    • Export Citation
  • 88. St Rose SG, Hunter N, Foster JD, et al. Quantification of Peyer's patches in Cheviot sheep for future scrapie pathogenesis studies. Vet Immunol Immunopathol 2007;116:163171.

    • Search Google Scholar
    • Export Citation
  • 89. Marruchella G, Ligios C, Di Guardo G. Age, scrapie status, PrP genotype and follicular dendritic cells in ovine ileal Peyer's patches. Res Vet Sci 2012;93:853856.

    • Search Google Scholar
    • Export Citation
  • 90. Jacobs JG, Sauer M, van Keulen LJ, et al. Differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and CH1641 scrapie. J Gen Virol 2011;92:222232.

    • Search Google Scholar
    • Export Citation
  • 91. Buschmann A, Biacabe AG, Ziegler U, et al. Atypical scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. J Virol Methods 2004;117:2736.

    • Search Google Scholar
    • Export Citation
  • 92. González L, Siso S, Monleon E, et al. Variability in disease phenotypes within a single PRNP genotype suggests the existence of multiple natural sheep scrapie strains within Europe. J Gen Virol 2010;91:26302641.

    • Search Google Scholar
    • Export Citation
  • 93. Moore SJ, Smith JD, Greenlee MHW, et al. Comparison of two US sheep scrapie isolates supports identification as separate strains. Vet Pathol 2016;53:11871196.

    • Search Google Scholar
    • Export Citation
  • 94. Bruce ME. TSE strain variation. Br Med Bull 2003;66:99108.

  • 95. Fraser H, Dickinson AG. The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 1968;78:301311.

    • Search Google Scholar
    • Export Citation
  • 96. Bruce ME, Boyle A, Cousens S, et al. Strain characterization of natural sheep scrapie and comparison with BSE. J Gen Virol 2002;83:695704.

    • Search Google Scholar
    • Export Citation
  • 97. Sisó S, Jeffrey M, Martin S, et al. Characterization of strains of ovine transmissible spongiform encephalopathy with a short PrPd profiling method. J Comp Pathol 2010;142:300310.

    • Search Google Scholar
    • Export Citation
  • 98. González L, Martin S, Begara-McGorum I, et al. Effects of agent strain and host genotype on PrP accumulation in the brain of sheep naturally and experimentally affected with scrapie. J Comp Pathol 2002;126:1729.

    • Search Google Scholar
    • Export Citation
  • 99. Gough KC, Rees HC, Ives SE, et al. Methods for differentiating prion types in food-producing animals. Biology (Basel) 2015;4:785813.

  • 100. Hope J, Wood SC, Birkett CR, et al. Molecular analysis of ovine prion protein identifies similarities between BSE and an experimental isolate of natural scrapie, CH1641. J Gen Virol 1999;80:14.

    • Search Google Scholar
    • Export Citation
  • 101. Stack MJ, Chaplin MJ, Clark J. Differentiation of prion protein glycoforms from naturally occurring sheep scrapie, sheeppassaged scrapie strains (CH1641 and SSBP1), bovine spongiform encephalopathy (BSE) cases and Romney and Cheviot breed sheep experimentally inoculated with BSE using two monoclonal antibodies. Acta Neuropathol 2002;104:279286.

    • Search Google Scholar
    • Export Citation
  • 102. Pirisinu L, Migliore S, Di Bari MA, et al. Molecular discrimination of sheep bovine spongiform encephalopathy from scrapie. Emerg Infect Dis 2011;17:695698.

    • Search Google Scholar
    • Export Citation
  • 103. Vulin J, Beck KE, Bencsik A, et al. Selection of distinct strain phenotypes in mice infected by ovine natural scrapie isolates similar to CH1641 experimental scrapie. J Neuropathol Exp Neurol 2012;71:140147.

    • Search Google Scholar
    • Export Citation
  • 104. Baron T, Bencsik A, Vulin J, et al. A C-terminal protease-resistant prion fragment distinguishes ovine “CH1641-like” scrapie from bovine classical and L-type BSE in ovine transgenic mice. PLoS Pathog 2008;4:e1000137.

    • Search Google Scholar
    • Export Citation
  • 105. Makarava N, Baskakov IV. The evolution of transmissible prions: the role of deformed templating. PLoS Pathog 2013;9:e1003759.

  • 106. Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science 2007;318:930936.

  • 107. Collinge J. Prion strain mutation and selection. Science 2010;328:11111112.

  • 108. Baron T, Bencsik A, Morignat E. Prions of ruminants show distinct splenotropisms in an ovine transgenic mouse model. PLoS One 2010;5:e10310.

    • Search Google Scholar
    • Export Citation
  • 109. Thackray AM, Hopkins L, Lockey R, et al. Emergence of multiple prion strains from single isolates of ovine scrapie. J Gen Virol 2011;92:14821491.

    • Search Google Scholar
    • Export Citation
  • 110. Shmakov AN, Ghosh S. Prion proteins and the gut: une liaison dangereuse? Gut 2001;48:443447.

  • 111. Heggebø R, Press CM, Gunnes G, et al. Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. J Gen Virol 2000;81:23272337.

    • Search Google Scholar
    • Export Citation
  • 112. Hadlow WJ, Kennedy RC, Race RE. Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982;146:657664.

  • 113. Gough KC, Maddison BC. Prion transmission: prion excretion and occurrence in the environment. Prion 2010;4:275282.

  • 114. Spiropoulos J, Hawkins SA, Simmons MM, et al. Evidence of in utero transmission of classical scrapie in sheep. J Virol 2014;88:45914594.

    • Search Google Scholar
    • Export Citation
  • 115. Foster JD, Goldmann W, Hunter N. Evidence in sheep for prenatal transmission of scrapie to lambs from infected mothers. PLoS One 2013;8:e79433.

    • Search Google Scholar
    • Export Citation
  • 116. Pattison IH, Watson WA, Hoare MN, et al. Spread of scrapie to sheep and goats by oral dosing with fetal membranes from scrapie-affected sheep. Vet Rec 1972;90:465.

    • Search Google Scholar
    • Export Citation
  • 117. Tuo W, Zhuang D, Knowles DP, et al. PrP-C and PrP-Sc at the fetal-maternal interface. J Biol Chem 2001;276:1822918234.

  • 118. Konold T, Moore SJ, Bellworthy SJ, et al. Evidence of scrapie transmission via milk. BMC Vet Res 2008;4:14.

  • 119. Konold T, Moore SJ, Bellworthy SJ, et al. Evidence of effective scrapie transmission via colostrum and milk in sheep. BMC Vet Res 2013;9:99.

    • Search Google Scholar
    • Export Citation
  • 120. Konold T, Hawkins SA, Thurston LC, et al. Objects in contact with classical scrapie sheep act as a reservoir for scrapie transmission. Front Vet Sci 2015;2:32.

    • Search Google Scholar
    • Export Citation
  • 121. Gough KC, Baker CA, Rees HC, et al. The oral secretion of infectious scrapie prions occurs in preclinical sheep with a range of PRNP genotypes. J Virol 2012;86:566571.

    • Search Google Scholar
    • Export Citation
  • 122. Tamgüney G, Richt JA, Hamir AN, et al. Salivary prions in sheep and deer. Prion 2012;6:5261.

  • 123. Andrievskaia O, Algire J, Balachandran A, et al. Prion protein in sheep urine. J Vet Diagn Invest 2008;20:141146.

  • 124. Rubenstein R, Chang BG, Gray P, et al. Prion disease detection, PMCA kinetics, and IgG in urine from sheep naturally/experimentally infected with scrapie and deer with preclinical/clinical chronic wasting disease. J Virol 2011;85:90319038.

    • Search Google Scholar
    • Export Citation
  • 125. Terry LA, Howells L, Bishop K, et al. Detection of prions in the faeces of sheep naturally infected with classical scrapie. Vet Res 2011;42:65.

    • Search Google Scholar
    • Export Citation
  • 126. Ersdal C, Ulvund MJ, Benestad SL, et al. Accumulation of pathogenic prion protein (PrPSc) in nervous and lymphoid tissues of sheep with subclinical scrapie. Vet Pathol 2003;40:164174.

    • Search Google Scholar
    • Export Citation
  • 127. van Keulen LJ, Vromans ME, van Zijderveld FG. Early and late pathogenesis of natural scrapie infection in sheep. APMIS 2002;110:2332.

    • Search Google Scholar
    • Export Citation
  • 128. Andréoletti O, Berthon P, Marc D, et al. Early accumulation of PrP(Sc) in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie. J Gen Virol 2000;81:31153126.

    • Search Google Scholar
    • Export Citation
  • 129. Donaldson DS, Kobayashi A, Ohno H, et al. M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol 2012;5:216225.

  • 130. Bradford BM, Reizis B, Mabbott NA. Oral prion disease pathogenesis is impeded in the specific absence of CXCR5-expressing dendritic cells. J Virol 2017;91:e00124e17.

    • Search Google Scholar
    • Export Citation
  • 131. McCulloch L, Brown KL, Bradford BM, et al. Follicular dendritic cell-specific prion protein (PrPc) expression alone is sufficient to sustain prion infection in the spleen. PLoS Pathog 2011;7:e1002402.

    • Search Google Scholar
    • Export Citation
  • 132. Mabbott NA, Bruce ME. Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies. Semin Immunol 2002;14:285293.

    • Search Google Scholar
    • Export Citation
  • 133. Mabbott NA, Young J, McConnell I, et al. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 2003;77:68456854.

    • Search Google Scholar
    • Export Citation
  • 134. Mohan J, Brown KL, Farquhar CF, et al. Scrapie transmission following exposure through the skin is dependent on follicular dendritic cells in lymphoid tissues. J Dermatol Sci 2004;35:101111.

    • Search Google Scholar
    • Export Citation
  • 135. Sisó S, Jeffrey M, González L. Neuroinvasion in sheep transmissible spongiform encephalopathies: the role of the haematogenous route. Neuropathol Appl Neurobiol 2009;35:232246.

    • Search Google Scholar
    • Export Citation
  • 136. Terry LA, Howells L, Hawthorn J, et al. Detection of PrPsc in blood from sheep infected with the scrapie and bovine spongiform encephalopathy agents. J Virol 2009;83:1255212558.

    • Search Google Scholar
    • Export Citation
  • 137. Houston F, McCutcheon S, Goldmann W, et al. Prion diseases are efficiently transmitted by blood transfusion in sheep. Blood 2008;112:47394745.

    • Search Google Scholar
    • Export Citation
  • 138. Schmerr MJ, Jenny AL, Bulgin MS, et al. Use of capillary electrophoresis and fluorescent labeled peptides to detect the abnormal prion protein in the blood of animals that are infected with a transmissible spongiform encephalopathy. J Chromatogr A 1999;853:207214.

    • Search Google Scholar
    • Export Citation
  • 139. Bannach O, Birkmann E, Reinartz E, et al. Detection of prion protein particles in blood plasma of scrapie infected sheep. PLoS One 2012;7:e36620.

    • Search Google Scholar
    • Export Citation
  • 140. Jeffrey M, Gonzalez L, Espenes A, et al. Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep. J Pathol 2006;209:414.

    • Search Google Scholar
    • Export Citation
  • 141. van Keulen LJ, Bossers A, van Zijderveld F. TSE pathogenesis in cattle and sheep. Vet Res 2008;39:24.

  • 142. Beekes M, McBride PA. Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 2000;278:181184.

    • Search Google Scholar
    • Export Citation
  • 143. Grégoire S, Bergot AS, Féraudet C, et al. The murine B cell repertoire is severely selected against endogenous cellular prion protein. J Immunol 2005;175:64436449.

    • Search Google Scholar
    • Export Citation
  • 144. Zabel MD, Avery AC. Prions–not your immunologist's pathogen. PLoS Pathog 2015;11:e1004624.

  • 145. Lv Y, Chen C, Zhang BY, et al. Remarkable activation of the complement system and aberrant neuronal localization of the membrane attack complex in the brain tissues of scrapie-infected rodents. Mol Neurobiol 2015;52:11651179.

    • Search Google Scholar
    • Export Citation
  • 146. Blanquet-Grossard F, Thielens NM, Vendrely C, et al. Complement protein C1q recognizes a conformationally modified form of the prion protein. Biochemistry 2005;44:43494356.

    • Search Google Scholar
    • Export Citation
  • 147. Mabbott NA, Bruce ME, Botto M, et al. Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 2001;7:485487.

    • Search Google Scholar
    • Export Citation
  • 148. Klein MA, Kaeser PS, Schwarz P, et al. Complement facilitates early prion pathogenesis. Nat Med 2001;7:488492.

  • 149. Greenlee JJ, Kunkle RA, Richt JA, et al. Lack of prion accumulation in lymphoid tissues of PRNP ARQ/ARR sheep intracranially inoculated with the agent of scrapie. PLoS One 2014;9:e108029.

    • Search Google Scholar
    • Export Citation
  • 150. Ersdal C, Ulvund MJ, Espenes A, et al. Mapping PrPSc propagation in experimental and natural scrapie in sheep with different PrP genotypes. Vet Pathol 2005;42:258274.

    • Search Google Scholar
    • Export Citation
  • 151. Benestad SL, Sarradin P, Thu B, et al. Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet Rec 2003;153:202208.

    • Search Google Scholar
    • Export Citation
  • 152. Loiacono CM, Thomsen BV, Hall SM, et al. Nor98 scrapie identified in the United States. J Vet Diagn Invest 2009;21:454463.

  • 153. Benestad SL, Arsac JN, Goldmann W, et al. Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res 2008;39:19.

    • Search Google Scholar
    • Export Citation
  • 154. Cook RW, Bingham J, Besier AS, et al. Atypical scrapie in Australia. Aust Vet J 2016;94:452455.

  • 155. Kittelberger R, Chaplin MJ, Simmons MM, et al. Atypical scrapie/Nor98 in a sheep from New Zealand. J Vet Diagn Invest 2010;22:863875.

    • Search Google Scholar
    • Export Citation
  • 156. Moore SJ, Simmons M, Chaplin M, et al. Neuroanatomical distribution of abnormal prion protein in naturally occurring atypical scrapie cases in Great Britain. Acta Neuropathol 2008;116:547559.

    • Search Google Scholar
    • Export Citation
  • 157. Greenlee JJ. Review: update on classical and atypical scrapie in sheep and goats. Vet Pathol 2019;56:616.

  • 158. Andréoletti O, Orge L, Benestad SL, et al. Atypical/Nor98 scrapie infectivity in sheep peripheral tissues. PLoS Pathog 2011;7:e1001285.

    • Search Google Scholar
    • Export Citation
  • 159. Simmons MM, Konold T, Simmons HA, et al. Experimental transmission of atypical scrapie to sheep. BMC Vet Res 2007;3:20.

  • 160. Simmons MM, Moore SJ, Konold T, et al. Experimental oral transmission of atypical scrapie to sheep. Emerg Infect Dis 2011;17:848854.

    • Search Google Scholar
    • Export Citation
  • 161. Fediaevsky A, Tongue SC, Noremark M, et al. A descriptive study of the prevalence of atypical and classical scrapie in sheep in 20 European countries. BMC Vet Res 2008;4:19.

    • Search Google Scholar
    • Export Citation
  • 162. Fediaevsky A, Gasqui P, Calavas D, et al. Discrepant epidemiological patterns between classical and atypical scrapie in sheep flocks under French TSE control measures. Vet J 2010;185:338340.

    • Search Google Scholar
    • Export Citation
  • 163. Korth C, Stierli B, Streit P, et al. Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 1997;390:7477.

  • 164. van Keulen LJ, Schreuder BE, Meloen RH, et al. Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. J Clin Microbiol 1996;34:12281231.

    • Search Google Scholar
    • Export Citation
  • 165. Schreuder BE, van Keulen LJ, Vromans ME, et al. Tonsillar biopsy and PrPSc detection in the preclinical diagnosis of scrapie. Vet Rec 1998;142:564568.

    • Search Google Scholar
    • Export Citation
  • 166. O'Rourke KI, Baszler TV, Besser TE, et al. Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue. J Clin Microbiol 2000;38:32543259.

    • Search Google Scholar
    • Export Citation
  • 167. González L, Dagleish MP, Martin S, et al. Diagnosis of preclinical scrapie in live sheep by the immunohistochemical examination of rectal biopsies. Vet Rec 2008;162:397403.

    • Search Google Scholar
    • Export Citation
  • 168. O'Rourke KI, Duncan JV, Logan JR, et al. Active surveillance for scrapie by third eyelid biopsy and genetic susceptibility testing of flocks of sheep in Wyoming. Clin Diagn Lab Immunol 2002;9:966971.

    • Search Google Scholar
    • Export Citation
  • 169. González L, Horton R, Ramsay D, et al. Adaptation and evaluation of a rapid test for the diagnosis of sheep scrapie in samples of rectal mucosa. J Vet Diagn Invest 2008;20:203208.

    • Search Google Scholar
    • Export Citation
  • 170. Laude H, Vilette D, Le Dur A, et al. New in vivo and ex vivo models for the experimental study of sheep scrapie: development and perspectives. C R Biol 2002;325:4957.

    • Search Google Scholar
    • Export Citation
  • 171. Vilotte JL, Soulier S, Essalmani R, et al. Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine prp. J Virol 2001;75:59775984.

    • Search Google Scholar
    • Export Citation
  • 172. Thackray AM, Hopkins L, Spiropoulos J, et al. Molecular and transmission characteristics of primary-passaged ovine scrapie isolates in conventional and ovine PrP transgenic mice. J Virol 2008;82:1119711207.

    • Search Google Scholar
    • Export Citation
  • 173. Saborio GP, Permanne B, Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 2001;411:810813.

    • Search Google Scholar
    • Export Citation
  • 174. Atarashi R, Moore RA, Sim VL, et al. Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein. Nat Methods 2007;4:645650.

    • Search Google Scholar
    • Export Citation
  • 175. Thorne L, Holder T, Ramsay A, et al. In vitro amplification of ovine prions from scrapie-infected sheep from Great Britain reveals distinct patterns of propagation. BMC Vet Res 2012; 8:223.

    • Search Google Scholar
    • Export Citation
  • 176. Atarashi R, Wilham JM, Christensen L, et al. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat Methods 2008;5:211212.

    • Search Google Scholar
    • Export Citation
  • 177. Atarashi R, Sano K, Satoh K, et al. Real-time quaking-induced conversion: a highly sensitive assay for prion detection. Prion 2011;5:150153.

    • Search Google Scholar
    • Export Citation
  • 178. Atarashi R, Satoh K, Sano K, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 2011;17:175178.

    • Search Google Scholar
    • Export Citation
  • 179. Shi S, Mitteregger-Kretzschmar G, Giese A, et al. Establishing quantitative real-time quaking-induced conversion (qRT-QuIC) for highly sensitive detection and quantification of PrPSc in prion-infected tissues. Acta Neuropathol Commun 2013;1:44.

    • Search Google Scholar
    • Export Citation
  • 180. Cheng K, Vendramelli R, Sloan A, et al. Endpoint quaking-induced conversion: a sensitive, specific, and high-throughput method for antemortem diagnosis of Creutzfeldt-Jacob disease. J Clin Microbiol 2016;54:17511754.

    • Search Google Scholar
    • Export Citation
  • 181. Vendramelli R, Sloan A, Simon SLR, et al. ThermoMixer-aided endpoint quaking-induced conversion (EP-QuIC) permits faster sporadic Creutzfeldt-Jakob disease (sCJD) identification than real-time quaking-induced conversion (RT-QuIC). J Clin Microbiol 2018;56:e00423e18.

    • Search Google Scholar
    • Export Citation
  • 182. Hwang S, Greenlee JJ, Nicholson EM. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy. PLoS One 2017;12:e0172391.

    • Search Google Scholar
    • Export Citation
  • 183. Moore SJ, Vrentas CE, Hwang S, et al. Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent. BMC Vet Res 2018;14:80.

    • Search Google Scholar
    • Export Citation
  • 184. Peretz D, Scott MR, Groth D, et al. Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 2001;10:854863.

    • Search Google Scholar
    • Export Citation
  • 185. Vrentas CE, Greenlee JJ, Baron T, et al. Stability properties of PrP(Sc) from cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay. BMC Vet Res 2013;9:167.

    • Search Google Scholar
    • Export Citation
  • 186. Moore SJ, West Greenlee MH, Smith JD, et al. A comparison of classical and H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism in wild-type and EK211 cattle following intracranial inoculation. Front Vet Sci 2016;3:78.

    • Search Google Scholar
    • Export Citation
  • 187. Vrentas CE, Greenlee JJ, Tatum TL, et al. Relationships between PrPSc stability and incubation time for United States scrapie isolates in a natural host system. PLoS One 2012;7:e43060.

    • Search Google Scholar
    • Export Citation
  • 188. Fernández-Borges N, Parra B, Vidal E, et al. Unraveling the key to the resistance of canids to prion diseases. PLoS Pathog 2017;13:e1006716.

    • Search Google Scholar
    • Export Citation
  • 189. Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJD and BSE. Nature 1997;389:448450, 526.

  • 190. Collinge J. Variant Creutzfeldt-Jakob disease. Lancet 1999;354:317323.

  • 191. Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 1997;389:498501.

    • Search Google Scholar
    • Export Citation
  • 192. Eloit M, Adjou K, Coulpier M, et al. BSE agent signatures in a goat. Vet Rec 2005;156:523524.

  • 193. Baron T, Bencsik A, Biacabe AG, et al. Phenotypic similarity of transmissible mink encephalopathy in cattle and L-type bovine spongiform encephalopathy in a mouse model. Emerg Infect Dis 2007;13:18871894.

    • Search Google Scholar
    • Export Citation
  • 194. Marsh RF, Bessen RA, Lehmann S, et al. Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. J Gen Virol 1991;72:589594.

    • Search Google Scholar
    • Export Citation
  • 195. Cutlip RC, Miller JM, Hamir AN, et al. Resistance of cattle to scrapie by the oral route. Can J Vet Res 2001;65:131132.

  • 196. Konold T, Spiropoulos J, Chaplin MJ, et al. Unsuccessful oral transmission of scrapie from British sheep to cattle. Vet Rec 2013;173:118.

    • Search Google Scholar
    • Export Citation
  • 197. Cutlip RC, Miller JM, Lehmkuhl HD. Second passage of a US scrapie agent in cattle. J Comp Pathol 1997;117:271275.

  • 198. Cutlip RC, Miller JM, Race RE, et al. Intracerebral transmission of scrapie to cattle. J Infect Dis 1994;169:814820.

  • 199. Konold T, Lee YH, Stack MJ, et al. Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain. BMC Vet Res 2006;2:31.

    • Search Google Scholar
    • Export Citation
  • 200. Konold T, Nonno R, Spiropoulos J, et al. Further characterisation of transmissible spongiform encephalopathy phenotypes after inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain. BMC Res Notes 2015;8:312.

    • Search Google Scholar
    • Export Citation
  • 201. Greenlee JJ, Smith JD, Kunkle RA. White-tailed deer are susceptible to the agent of sheep scrapie by intracerebral inoculation. Vet Res 2011;42:107.

    • Search Google Scholar
    • Export Citation
  • 202. Greenlee J, Moore S, Smith J, et al. Scrapie transmits to white-tailed deer by the oral route and has a molecular profile similar to chronic wasting disease and distinct from the scrapie inoculum. Prion 2015;9:S62.

    • Search Google Scholar
    • Export Citation
  • 203. Hamir AN, Miller JM, Cutlip RC, et al. Preliminary observations on the experimental transmission of scrapie to elk (Cervus elaphus nelson) by intracerebral inoculation. Vet Pathol 2003;40:8185.

    • Search Google Scholar
    • Export Citation
  • 204. Hamir AN, Kunkle RA, Miller JM, et al. Second passage of sheep scrapie and transmissible mink encephalopathy (TME) agents in raccoons (Procyon lotor). Vet Pathol 2005;42:844851.

    • Search Google Scholar
    • Export Citation
  • 205. Moore SJ, Smith JD, Richt JA, et al. Raccoons accumulate PrPSc after intracranial inoculation of the agents of chronic wasting disease or transmissible mink encephalopathy but not atypical scrapie. J Vet Diagn Invest 2019;31:200209.

    • Search Google Scholar
    • Export Citation
  • 206. Greenlee JJ, Kunkle RA, Smith JD, et al. Scrapie in swine: a diagnostic challenge. Food Saf (Tokyo) 2016;4:110114.

  • 207. Will RG. Epidemiology of Creutzfeldt-Jakob disease. Br Med Bull 1993;49:960970.

  • 208. Greenlee JJ, Greenlee MH. The transmissible spongiform encephalopathies of livestock. ILAR J 2015;56:725.

  • 209. Cassard H, Torres JM, Lacroux C, et al. Evidence for zoonotic potential of ovine scrapie prions. Nat Commun 2014;5:5821.

  • 210. Comoy EE, Mikol J, Luccantoni-Freire S, et al. Transmission of scrapie prions to primate after an extended silent incubation period. Sci Rep 2015;5:11573.

    • Search Google Scholar
    • Export Citation
  • 211. Gibbs CJ, Gajdusek DC. Experimental subacute spongiform virus encephalopathies in primates and other laboratory animals. Science 1973;182:6768.

    • Search Google Scholar
    • Export Citation
  • 212. Foster JD, Hope J, Fraser H. Transmission of bovine spongiform encephalopathy to sheep and goats. Vet Rec 1993;133:339341.

  • 213. Bellworthy SJ, Hawkins SA, Green RB, et al. Tissue distribution of bovine spongiform encephalopathy infectivity in Romney sheep up to the onset of clinical disease after oral challenge. Vet Rec 2005;156:197202.

    • Search Google Scholar
    • Export Citation
  • 214. Foster JD, Bruce M, McConnell I, et al. Detection of BSE infectivity in brain and spleen of experimentally infected sheep. Vet Rec 1996;138:546548.

    • Search Google Scholar
    • Export Citation
  • 215. Houston F, Goldmann W, Foster J, et al. Comparative susceptibility of sheep of different origins, breeds and PRNP genotypes to challenge with bovine spongiform encephalopathy and scrapie. PLoS One 2015;10:e0143251.

    • Search Google Scholar
    • Export Citation
  • 216. Hunter N, Houston F, Foster J, et al. Susceptibility of young sheep to oral infection with bovine spongiform encephalopathy decreases significantly after weaning. J Virol 2012;86:1185611862.

    • Search Google Scholar
    • Export Citation
  • 217. Bellworthy SJ, Dexter G, Stack M, et al. Natural transmission of BSE between sheep within an experimental flock. Vet Rec 2005;157:206.

  • 218. Stack M, Jeffrey M, Gubbins S, et al. Monitoring for bovine spongiform encephalopathy in sheep in Great Britain, 1998–2004. J Gen Virol 2006;87:20992107.

    • Search Google Scholar
    • Export Citation
  • 219. Simmons MM, Chaplin MJ, Konold T, et al. L-BSE experimentally transmitted to sheep presents as a unique disease phenotype. Vet Res 2016;47:112.

    • Search Google Scholar
    • Export Citation
  • 220. Hamir AN, Kunkle RA, Cutlip RC, et al. Transmission of chronic wasting disease of mule deer to Suffolk sheep following intracerebral inoculation. J Vet Diagn Invest 2006;18:558565.

    • Search Google Scholar
    • Export Citation
  • 221. USDA APHIS Veterinary Services. National Scrapie Surveillance Plan, 2019. Available at: www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/national_scrapie_surv_plan.pdf. Accessed Feb 11, 2020.

    • Search Google Scholar
    • Export Citation
  • 222. OIE. Terrestrial Animal Health Code. Scrapie. Available at: www.oie.int/index.php?id=169&L=0&htmfile=chapitre_scrapie.htm. Accessed Feb 11, 2020.

    • Search Google Scholar
    • Export Citation
  • 223. USDA APHIS. National Scrapie Eradication Program. Available at: www.aphis.usda.gov/aphis/ourfocus/animalhealth/animal-disease-information/sheep-and-goat-health/national-scrapie-eradication-program. Accessed Feb 11, 2020.

    • Search Google Scholar
    • Export Citation
  • 224. USDA APHIS Veterinary Services. Scrapie program standards volume 2: scrapie free flock certification program (SFCP). Available at: www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/standards_current.pdf. Accessed Feb 11, 2020.

    • Search Google Scholar
    • Export Citation
  • 225. USDA APHIS Veterinary Services. National Scrapie Eradication Program fiscal year 2019 report, Jan 10, 2020. Available at: www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/annual_report.pdf. Accessed Feb 13, 2020.

    • Search Google Scholar
    • Export Citation
  • 226. USDA APHIS Veterinary Services. Scrapie in sheep and goats: final rule. Fed Regist 2019;84:1117011196.

  • 227. USDA APHIS Scrapie program standards volume 1: National Scrapie Eradication Program. Available at: www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/nsep-program-standards-final-rule.pdf. Accessed Feb 11, 2020.

    • Search Google Scholar
    • Export Citation

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Pathogenesis, detection, and control of scrapie in sheep

Eric D. Cassmann DVM, PhD1,2 and Justin J. Greenlee DVM, PhD1
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  • 1 1Virus and Prion Research Unit, National Animal Disease Center, Agricultural Research Service, USDA, Ames, IA 50010.
  • | 2 2Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830.

Abstract

In sheep, scrapie is a fatal neurologic disease that is caused by a misfolded protein called a prion (designated PrPSc). The normal cellular prion protein (PrPC) is encoded by an endogenous gene, PRNP, that is present in high concentrations within the CNS. Although a broad range of functions has been described for PrPC, its entire range of functions has yet to be fully elucidated. Accumulation of PrPSc results in neurodegeneration. The PRNP gene has several naturally occurring polymorphisms, and there is a strong correlation between scrapie susceptibility and PRNP genotype. The cornerstone of scrapie eradication programs is the selection of scrapie-resistant genotypes to eliminate classical scrapie. Transmission of classical scrapie in sheep occurs during the prenatal and periparturient periods when lambs are highly susceptible. Initially, the scrapie agent is disseminated throughout the lymphoid system and into the CNS. Shedding of the scrapie agent occurs before the onset of clinical signs. In contrast to classical scrapie, atypical scrapie is believed to be a spontaneous disease that occurs in isolated instances in older animals within a flock. The agent that causes atypical scrapie is not considered to be naturally transmissible. Transmission of the scrapie agent to species other than sheep, including deer, has been experimentally demonstrated as has the transmission of nonscrapie prion agents to sheep. The purpose of this review is to outline the current methods for diagnosing scrapie in sheep and the techniques used for studying the pathogenesis and host range of the scrapie agent. Also discussed is the US scrapie eradication program including recent updates.

Abstract

In sheep, scrapie is a fatal neurologic disease that is caused by a misfolded protein called a prion (designated PrPSc). The normal cellular prion protein (PrPC) is encoded by an endogenous gene, PRNP, that is present in high concentrations within the CNS. Although a broad range of functions has been described for PrPC, its entire range of functions has yet to be fully elucidated. Accumulation of PrPSc results in neurodegeneration. The PRNP gene has several naturally occurring polymorphisms, and there is a strong correlation between scrapie susceptibility and PRNP genotype. The cornerstone of scrapie eradication programs is the selection of scrapie-resistant genotypes to eliminate classical scrapie. Transmission of classical scrapie in sheep occurs during the prenatal and periparturient periods when lambs are highly susceptible. Initially, the scrapie agent is disseminated throughout the lymphoid system and into the CNS. Shedding of the scrapie agent occurs before the onset of clinical signs. In contrast to classical scrapie, atypical scrapie is believed to be a spontaneous disease that occurs in isolated instances in older animals within a flock. The agent that causes atypical scrapie is not considered to be naturally transmissible. Transmission of the scrapie agent to species other than sheep, including deer, has been experimentally demonstrated as has the transmission of nonscrapie prion agents to sheep. The purpose of this review is to outline the current methods for diagnosing scrapie in sheep and the techniques used for studying the pathogenesis and host range of the scrapie agent. Also discussed is the US scrapie eradication program including recent updates.

Contributor Notes

Address correspondence to Dr. Greenlee (justin.greenlee@usda.gov).