Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.
Volume 31, Number 12—December 2025
Research
Silent Propagation of Classical Scrapie Prions in Homozygous K222 Transgenic Mice
Table 1
Isolates used in study of classical scrapie prions in homozygous K222 transgenic mice*
| Category | Isolate | Species | Origin | Goat PrP genotype† | Description | Supplier |
|---|---|---|---|---|---|---|
| I |
198/9 |
Sheep |
Italy |
wt; S240S |
Classical scrapie isolate from a naturally infected sheep |
ISS |
| II | S2 | Goat | Spain | wt; S240P | Classical scrapie isolate from a naturally infected goat | UNIZAR |
| CP060146 (22) | Goat | France | wt | Classical scrapie isolate from an experimentally infected goat | ENVT | |
| CP060146/K222 (22) |
Goat |
France |
K222 |
Classical scrapie isolate from an experimentally infected goat |
ENVT |
|
| II + III | UKA2 | Goat | United Kingdom | wt; S240P | Classical scrapie isolate from a naturally infected goat | APHA |
| F14 |
Goat |
France |
wt; I142M, S240P |
Classical scrapie isolate from a naturally infected goat |
INRA |
|
| IV | F10 | Goat | France | wt; S240P | Classical scrapie isolate from a naturally infected goat | INRA |
| C1 |
Goat |
Cyprus |
wt |
Classical scrapie isolate from a naturally infected goat |
VS |
|
| Negative control | Healthy goat brain | Goat | France | wt | Brain from a noninfected goat | INRA |
*Isolates were classified as previously described (31) on the basis of prion biochemical features when transmitted in transgenic mice expressing the bovine PrP (Bo-Tg110) and biologic features transmitted in mice expressing the ovine PrP (Q222-Tg501). APHA, Animal and Plant Health Agency, Surrey, United Kingdom; ENVT, École Nationale Vétérinaire Toulouse, Toulouse, France; INRA, French National Institute for Agricultural Research, Nouzilly, France; ISS, Istituto Superiore di Sanitá Animal, Rome, Italy; UNIZAR, Universidad de Zaragoza, Spain; VS, Veterinary Services, Nicosia, Cyprus; wt, wild-type. †The wt goat prion protein genotype is A136R154P240/A136R154P240. S240S, S240P and I142M refer to polymorphisms at specific codons of the PRNP gene.
References
- Prusiner SB. Molecular biology of prion diseases. Science. 1991;252:1515–22. DOIPubMedGoogle Scholar
- Marín-Moreno A, Fernández-Borges N, Espinosa JC, Andréoletti O, Torres JM. Transmission and replication of prions. Prog Mol Biol Transl Sci. 2017;150:181–201. DOIPubMedGoogle Scholar
- Baylis M, Chihota C, Stevenson E, Goldmann W, Smith A, Sivam K, et al. Risk of scrapie in British sheep of different prion protein genotype. J Gen Virol. 2004;85:2735–40. DOIPubMedGoogle Scholar
- Houston F, Goldmann W, Foster J, González L, Jeffrey M, Hunter N. Comparative susceptibility of sheep of different origins, breeds and PRNP genotypes to challenge with bovine spongiform encephalopathy and scrapie. PLoS One. 2015;10:
e0143251 . DOIPubMedGoogle Scholar - Belt PB, Muileman IH, Schreuder BE, Bos-de Ruijter J, Gielkens AL, Smits MA. Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. J Gen Virol. 1995;76:509–17. DOIPubMedGoogle Scholar
- Bossers A, Schreuder BE, Muileman IH, Belt PB, Smits MA. PrP genotype contributes to determining survival times of sheep with natural scrapie. J Gen Virol. 1996;77:2669–73. DOIPubMedGoogle Scholar
- Hunter N, Foster JD, Goldmann W, Stear MJ, Hope J, Bostock C. Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. Arch Virol. 1996;141:809–24. DOIPubMedGoogle Scholar
- Hunter N, Moore L, Hosie BD, Dingwall WS, Greig A. Association between natural scrapie and PrP genotype in a flock of Suffolk sheep in Scotland. Vet Rec. 1997;140:59–63. DOIPubMedGoogle Scholar
- Benestad SL, Arsac JN, Goldmann W, Nöremark M. Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res. 2008;39:19. DOIPubMedGoogle Scholar
- Barillet F, Mariat D, Amigues Y, Faugeras R, Caillat H, Moazami-Goudarzi K, et al. Identification of seven haplotypes of the caprine PrP gene at codons 127, 142, 154, 211, 222 and 240 in French Alpine and Saanen breeds and their association with classical scrapie. J Gen Virol. 2009;90:769–76. DOIPubMedGoogle Scholar
- González L, Martin S, Hawkins SA, Goldmann W, Jeffrey M, Sisó S. Pathogenesis of natural goat scrapie: modulation by host PRNP genotype and effect of co-existent conditions. Vet Res. 2010;41:48. DOIPubMedGoogle Scholar
- Goldmann W, Ryan K, Stewart P, Parnham D, Xicohtencatl R, Fernandez N, et al. Caprine prion gene polymorphisms are associated with decreased incidence of classical scrapie in goat herds in the United Kingdom. Vet Res. 2011;42:110. DOIPubMedGoogle Scholar
- Goldmann W, Martin T, Foster J, Hughes S, Smith G, Hughes K, et al. Novel polymorphisms in the caprine PrP gene: a codon 142 mutation associated with scrapie incubation period. J Gen Virol. 1996;77:2885–91. DOIPubMedGoogle Scholar
- Papasavva-Stylianou P, Windl O, Saunders G, Mavrikiou P, Toumazos P, Kakoyiannis C. PrP gene polymorphisms in Cyprus goats and their association with resistance or susceptibility to natural scrapie. Vet J. 2011;187:245–50. DOIPubMedGoogle Scholar
- Vaccari G, Bari MAD, Morelli L, Nonno R, Chiappini B, Antonucci G, et al. Identification of an allelic variant of the goat PrP gene associated with resistance to scrapie. J Gen Virol. 2006;87:1395–402. DOIPubMedGoogle Scholar
- Acutis PL, Bossers A, Priem J, Riina MV, Peletto S, Mazza M, et al. Identification of prion protein gene polymorphisms in goats from Italian scrapie outbreaks. J Gen Virol. 2006;87:1029–33. DOIPubMedGoogle Scholar
- Bouzalas IG, Dovas CI, Banos G, Papanastasopoulou M, Kritas S, Oevermann A, et al. Caprine PRNP polymorphisms at codons 171, 211, 222 and 240 in a Greek herd and their association with classical scrapie. J Gen Virol. 2010;91:1629–34. DOIPubMedGoogle Scholar
- Fragkiadaki EG, Vaccari G, Ekateriniadou LV, Agrimi U, Giadinis ND, Chiappini B, et al. PRNP genetic variability and molecular typing of natural goat scrapie isolates in a high number of infected flocks. Vet Res. 2011;42:104. DOIPubMedGoogle Scholar
- Eiden M, Soto EO, Mettenleiter TC, Groschup MH. Effects of polymorphisms in ovine and caprine prion protein alleles on cell-free conversion. Vet Res. 2011;42:30. DOIPubMedGoogle Scholar
- Acutis PL, Martucci F, D’Angelo A, Peletto S, Colussi S, Maurella C, et al. Resistance to classical scrapie in experimentally challenged goats carrying mutation K222 of the prion protein gene. Vet Res. 2012;43:8. DOIPubMedGoogle Scholar
- White SN, Reynolds JO, Waldron DF, Schneider DA, O’Rourke KI. Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. Gene. 2012;501:49–51. DOIPubMedGoogle Scholar
- Lacroux C, Perrin-Chauvineau C, Corbière F, Aron N, Aguilar-Calvo P, Torres JM, et al. Genetic resistance to scrapie infection in experimentally challenged goats. J Virol. 2014;88:2406–13. DOIPubMedGoogle Scholar
- Cinar MU, Schneider DA, Waldron DF, O’Rourke KI, White SN. Goats singly heterozygous for PRNP S146 or K222 orally inoculated with classical scrapie at birth show no disease at ages well beyond 6 years. Vet J. 2018;233:19–24. DOIPubMedGoogle Scholar
- Mazza M, Guglielmetti C, Pagano M, Sciuto S, Ingravalle F, Martucci F, et al. Lysine at position 222 of the goat prion protein inhibits the binding of monoclonal antibody F99/97.6.1. J Vet Diagn Invest. 2012;24:971–5. DOIPubMedGoogle Scholar
- Madsen-Bouterse SA, Stewart P, Williamson H, Schneider DA, Goldmann W. Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrPC. Genet Sel Evol. 2021;53:52. DOIPubMedGoogle Scholar
- Aguilar-Calvo P, Fast C, Tauscher K, Espinosa J-C, Groschup MH, Nadeem M, et al. Effect of Q211 and K222 PRNP polymorphic variants in the susceptibility of goats to oral infection with goat bovine spongiform encephalopathy. J Infect Dis. 2015;212:664–72. DOIPubMedGoogle Scholar
- Fast C, Goldmann W, Berthon P, Tauscher K, Andréoletti O, Lantier I, et al. Protecting effect of PrP codons M142 and K222 in goats orally challenged with bovine spongiform encephalopathy prions. Vet Res. 2017;48:52. DOIPubMedGoogle Scholar
- Colussi S, Vaccari G, Maurella C, Bona C, Lorenzetti R, Troiano P, et al. Histidine at codon 154 of the prion protein gene is a risk factor for Nor98 scrapie in goats. J Gen Virol. 2008;89:3173–6. DOIPubMedGoogle Scholar
- Aguilar-Calvo P, Espinosa JC, Pintado B, Gutiérrez-Adán A, Alamillo E, Miranda A, et al. Role of the goat K222-PrP(C) polymorphic variant in prion infection resistance. J Virol. 2014;88:2670–6. DOIPubMedGoogle Scholar
- Aguilar-Calvo P, Espinosa JC, Andréoletti O, González L, Orge L, Juste R, et al. Goat K222-PrPC polymorphic variant does not provide resistance to atypical scrapie in transgenic mice. Vet Res. 2016;47:96. DOIPubMedGoogle Scholar
- Marín-Moreno A, Aguilar-Calvo P, Espinosa JC, Zamora-Ceballos M, Pitarch JL, González L, et al. Classical scrapie in small ruminants is caused by at least four different prion strains. Vet Res. 2021;52:57. DOIPubMedGoogle Scholar
- Padilla D, Béringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, et al. Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog. 2011;7:
e1001319 . DOIPubMedGoogle Scholar - Féraudet C, Morel N, Simon S, Volland H, Frobert Y, Créminon C, et al. Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J Biol Chem. 2005;280:11247–58. DOIPubMedGoogle Scholar
- Marín-Moreno A, Huor A, Espinosa JC, Douet JY, Aguilar-Calvo P, Aron N, et al. Radical change in zoonotic abilities of atypical BSE prion strains as evidenced by crossing of sheep species barrier in transgenic mice. Emerg Infect Dis. 2020;26:1130–9. DOIPubMedGoogle Scholar
- Fraser H, Dickinson AG. The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol. 1968;78:301–11. DOIPubMedGoogle Scholar
- González L, Martin S, Houston FE, Hunter N, Reid HW, Bellworthy SJ, et al. Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep. J Gen Virol. 2005;86:827–38. DOIPubMedGoogle Scholar
- Brun A, Castilla J, Ramírez MA, Prager K, Parra B, Salguero FJ, et al. Proteinase K enhanced immunoreactivity of the prion protein-specific monoclonal antibody 2A11. Neurosci Res. 2004;48:75–83. DOIPubMedGoogle Scholar
- Andréoletti O, Berthon P, Levavasseur E, Marc D, Lantier F, Monks E, et al. Phenotyping of protein-prion (PrPsc)-accumulating cells in lymphoid and neural tissues of naturally scrapie-affected sheep by double-labeling immunohistochemistry. J Histochem Cytochem. 2002;50:1357–70. DOIPubMedGoogle Scholar
- Andréoletti O, Simon S, Lacroux C, Morel N, Tabouret G, Chabert A, et al. PrPSc accumulation in myocytes from sheep incubating natural scrapie. Nat Med. 2004;10:591–3. DOIPubMedGoogle Scholar
- Langeveld JPM, Pirisinu L, Jacobs JG, Mazza M, Lantier I, Simon S, et al. Four types of scrapie in goats differentiated from each other and bovine spongiform encephalopathy by biochemical methods. Vet Res. 2019;50:97. DOIPubMedGoogle Scholar
- Nonno R, Marin-Moreno A, Carlos Espinosa J, Fast C, Van Keulen L, Spiropoulos J, et al. Characterization of goat prions demonstrates geographical variation of scrapie strains in Europe and reveals the composite nature of prion strains. Sci Rep. 2020;10:19. DOIPubMedGoogle Scholar
- Kanata E, Humphreys-Panagiotidis C, Giadinis ND, Papaioannou N, Arsenakis M, Sklaviadis T. Perspectives of a scrapie resistance breeding scheme targeting Q211, S146 and K222 caprine PRNP alleles in Greek goats. Vet Res. 2014;45:43. DOIPubMedGoogle Scholar
- Goldmann W, Marier E, Stewart P, Konold T, Street S, Langeveld J, et al. Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds. Vet Rec. 2016;178:168. DOIPubMedGoogle Scholar
- Fediaevsky A, Tongue SC, Nöremark M, Calavas D, Ru G, Hopp P. A descriptive study of the prevalence of atypical and classical scrapie in sheep in 20 European countries. BMC Vet Res. 2008;4:19. DOIPubMedGoogle Scholar
- Bian J, Khaychuk V, Angers RC, Fernández-Borges N, Vidal E, Meyerett-Reid C, et al. Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A. 2017;114:1141–6. DOIPubMedGoogle Scholar
1These first authors contributed equally to this article.