Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link

Volume 23, Number 9—September 2017

Research

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

Natalia Fernández-Borges1, Juan Carlos Espinosa1, Alba Marín-Moreno, Patricia Aguilar-Calvo, Emmanuel A. Asante, Tetsuyuki Kitamoto, Shirou Mohri, Olivier Andréoletti, and Juan María TorresComments to Author 
Author affiliations: Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (CISA-INIA); Valdeolmos, Madrid, Spain (N. Fernández-Borges, J.C. Espinosa, A. Marín-Moreno, P. Aguilar-Calvo, J.M. Torres); MRC Prion Unit, Department of Neurodegenerative Disease, University College London, Institute of Neurology, London, UK (E.A. Asante); Tohoku University Graduate School of Medicine, Sendai, Japan (T. Kitamoto, S. Mohri); UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti)

Main Article

Table 2

Transmission of cattle, porcine, sheep, and goat BSE isolates to mice in transgenic mouse lines TgMet129, TgMet/Val129, and TgVal129*

Isolates
 Mean survival time, d ±SD (no. PrPres-positive/inoculated animals) [reference]†‡
TgMet129
 TgMet/Val129
 TgVal129
First passage
 Second passage
 First passage
 Second passage
 First passage
 Second passage
Hu-sCJD MM1 219 ±17 (6/6) [40] 239 ±8 (6/6) [40] 243 ±14 (6/6) [40] 260 ±13 (6/6) [40] 327 ±19 (6/6) [40] 286 ±16 (6/6) [40]
Hu-sCJD VV2 618 ±81 (6/6) [40] 509 ±41 (6/6) [40] 588 ±74 (6/6) [40] 594 ±86 (6/6) [40] 168 ±12 (6/6) [40] 169 ±12 (6/6) [40]
Hu-TSE negative >700‡ (0/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6)
Ca-BSE0 739 (1/6) (31) 633 ±32 (6/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6)
Ca-BSE2 491–707 (0/9) [31] 572 ±37 (3/4) [31] >700‡ (0/5) ND >700‡ (0/3)§ >700‡ (0/3)§
Ca-BSE/TgPo 653 ±45 (3/5) ND ND ND >700‡ (0/6) ND
Ca-BSE/Sh(ARQ) 615 ±84 (4/6) [31] 564 ±39 (5/5) [31] >700b (0/6) >700‡ (0/6) >700‡ (0/6) >700‡ (0/6)
Ca-BSE/Go >700‡ (5/5) >700‡ (5/5) 476 (1/10) ND >700‡ (0/5)¶ ND
Go-BSE 683 ± 36 (6/6) 675 ± 36 (5/5) >700‡ (0/6) ND >700‡ (0/6) ND

*BSE, bovine spongiform encephalopathy; Ca, cattle; CJD, Creutzfeldt-Jakob disease; Go, goat; Hu, human; Met129, methionine; ND, not done; PrPres, proteinase K–resistant PrP; sCJD, sporadic CJD; Val129, valine; vCJD, variant CJD.
†Survival time is indicated for all mice that scored positive for PrPres
‡Animals without clinical signs were euthanized at 700 dpi.
§Three additional animals were culled before the end of the experiment because of intercurrent illnesses; all were negative for brain PrPres by using Western blot.
¶Positive subclinical infection tested in Bo-Tg110 mice.

Main Article

References
  1. Collinge  J, Sidle  KC, Meads  J, Ironside  J, Hill  AF. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature. 1996;383:685–90. DOIPubMedGoogle Scholar
  2. Hill  AF, Desbruslais  M, Joiner  S, Sidle  KC, Gowland  I, Collinge  J, et al. The same prion strain causes vCJD and BSE. Nature. 1997;389:448–50, 526. DOIPubMedGoogle Scholar
  3. Bruce  ME, Will  RG, Ironside  JW, McConnell  I, Drummond  D, Suttie  A, et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature. 1997;389:498–501. DOIPubMedGoogle Scholar
  4. Llewelyn  CA, Hewitt  PE, Knight  RS, Amar  K, Cousens  S, Mackenzie  J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. 2004;363:417–21. DOIPubMedGoogle Scholar
  5. Peden  AH, Head  MW, Ritchie  DL, Bell  JE, Ironside  JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 2004;364:527–9. DOIPubMedGoogle Scholar
  6. Wroe  SJ, Pal  S, Siddique  D, Hyare  H, Macfarlane  R, Joiner  S, et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet. 2006;368:2061–7. DOIPubMedGoogle Scholar
  7. Peden  A, McCardle  L, Head  MW, Love  S, Ward  HJ, Cousens  SN, et al. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia. 2010;16:296–304 . DOIPubMedGoogle Scholar
  8. Prusiner  SB, Scott  MR, DeArmond  SJ, Cohen  FE. Prion protein biology. Cell. 1998;93:337–48. DOIPubMedGoogle Scholar
  9. Prusiner  SB. Prions. Proc Natl Acad Sci U S A. 1998;95:13363–83. DOIPubMedGoogle Scholar
  10. Collinge  J. Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci. 2001;24:519–50. DOIPubMedGoogle Scholar
  11. Will  RG, Ironside  JW, Zeidler  M, Cousens  SN, Estibeiro  K, Alperovitch  A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347:921–5. DOIPubMedGoogle Scholar
  12. Parchi  P, Castellani  R, Capellari  S, Ghetti  B, Young  K, Chen  SG, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 1996;39:767–78. DOIPubMedGoogle Scholar
  13. Hill  AF, Joiner  S, Wadsworth  JD, Sidle  KC, Bell  JE, Budka  H, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain. 2003;126:1333–46. DOIPubMedGoogle Scholar
  14. Torres  JM, Espinosa  JC, Aguilar-Calvo  P, Herva  ME, Relaño-Ginés  A, Villa-Diaz  A, et al. Elements modulating the prion species barrier and its passage consequences. PLoS One. 2014;9:e89722. DOIPubMedGoogle Scholar
  15. Wadsworth  JD, Collinge  J. Update on human prion disease. Biochim Biophys Acta. 2007;1772:598–609.
  16. Palmer  MS, Dryden  AJ, Hughes  JT, Collinge  J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature. 1991;352:340–2. DOIPubMedGoogle Scholar
  17. Collinge  J, Palmer  MS, Dryden  AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. 1991;337:1441–2. DOIPubMedGoogle Scholar
  18. Mead  S, Stumpf  MP, Whitfield  J, Beck  JA, Poulter  M, Campbell  T, et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science. 2003;300:640–3. DOIPubMedGoogle Scholar
  19. Baker  HE, Poulter  M, Crow  TJ, Frith  CD, Lofthouse  R, Ridley  RM, et al. Aminoacid polymorphism in human prion protein and age at death in inherited prion disease. Lancet. 1991;337:1286. DOIPubMedGoogle Scholar
  20. Poulter  M, Baker  HF, Frith  CD, Leach  M, Lofthouse  R, Ridley  RM, et al. Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies. Brain. 1992;115:675–85. DOIPubMedGoogle Scholar
  21. Will  RG, Zeidler  M, Stewart  GE, Macleod  MA, Ironside  JW, Cousens  SN, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol. 2000;47:575–82. DOIPubMedGoogle Scholar
  22. Bishop  MT, Diack  AB, Ritchie  DL, Ironside  JW, Will  RG, Manson  JC. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease. Brain. 2013;136:1139–45. DOIPubMedGoogle Scholar
  23. Hilton  DA, Ghani  AC, Conyers  L, Edwards  P, McCardle  L, Ritchie  D, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol. 2004;203:733–9. DOIPubMedGoogle Scholar
  24. Ironside  JW, Bishop  MT, Connolly  K, Hegazy  D, Lowrie  S, Le Grice  M, et al. Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study. BMJ. 2006;332:1186–8. DOIPubMedGoogle Scholar
  25. Gill  ON, Spencer  Y, Richard-Loendt  A, Kelly  C, Dabaghian  R, Boyes  L, et al. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ. 2013;347(oct15 5):f5675. DOIPubMedGoogle Scholar
  26. Asante  EA, Linehan  JM, Desbruslais  M, Joiner  S, Gowland  I, Wood  AL, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 2002;21:6358–66. DOIPubMedGoogle Scholar
  27. Wadsworth  JD, Asante  EA, Desbruslais  M, Linehan  JM, Joiner  S, Gowland  I, et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science. 2004;306:1793–6. DOIPubMedGoogle Scholar
  28. Asante  EA, Linehan  JM, Gowland  I, Joiner  S, Fox  K, Cooper  S, et al. Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice. Proc Natl Acad Sci U S A. 2006;103:10759–64. DOIPubMedGoogle Scholar
  29. Bishop  MT, Hart  P, Aitchison  L, Baybutt  HN, Plinston  C, Thomson  V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol. 2006;5:393–8. DOIPubMedGoogle Scholar
  30. Takeuchi  A, Kobayashi  A, Ironside  JW, Mohri  S, Kitamoto  T. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes. J Biol Chem. 2013;288:21659–66. DOIPubMedGoogle Scholar
  31. 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
  32. Espinosa  JC, Herva  ME, Andréoletti  O, Padilla  D, Lacroux  C, Cassard  H, et al. Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009;15:1214–21. DOIPubMedGoogle Scholar
  33. Castilla  J, Gutiérrez Adán  A, Brun  A, Pintado  B, Ramírez  MA, Parra  B, et al. Early detection of PrPres in BSE-infected bovine PrP transgenic mice. Arch Virol. 2003;148:677–91. DOIPubMedGoogle Scholar
  34. Castilla  J, Gutiérrez-Adán  A, Brun  A, Doyle  D, Pintado  B, Ramírez  MA, et al. Subclinical bovine spongiform encephalopathy infection in transgenic mice expressing porcine prion protein. J Neurosci. 2004;24:5063–9. DOIPubMedGoogle Scholar
  35. Aguilar-Calvo  P, Fast  C, Tauscher  K, Espinosa  JC, 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
  36. Foster  JD, Hope  J, Fraser  H. Transmission of bovine spongiform encephalopathy to sheep and goats. Vet Rec. 1993;133:339–41. DOIPubMedGoogle Scholar
  37. 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
  38. Eloit  M, Adjou  K, Coulpier  M, Fontaine  JJ, Hamel  R, Lilin  T, et al. BSE agent signatures in a goat. Vet Rec. 2005;156:523–4. DOIPubMedGoogle Scholar
  39. Cooper  JK, Ladhani  K, Minor  PD. Reference materials for the evaluation of pre-mortem variant Creutzfeldt-Jakob disease diagnostic assays. Vox Sang. 2007;92:302–10.PubMedGoogle Scholar
  40. Cassard  H, Torres  JM, Lacroux  C, Douet  JY, Benestad  SL, Lantier  F, et al. Evidence for zoonotic potential of ovine scrapie prions. Nat Commun. 2014;5:5821. DOIPubMedGoogle Scholar
  41. Notari  S, Xiao  X, Espinosa  JC, Cohen  Y, Qing  L, Aguilar-Calvo  P, et al. Transmission characteristics of variably protease-sensitive prionopathy. Emerg Infect Dis. 2014;20:2006–14. DOIPubMedGoogle Scholar
  42. 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
  43. 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
  44. 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
  45. 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
  46. Wadsworth  JD, Powell  C, Beck  JA, Joiner  S, Linehan  JM, Brandner  S, et al. Molecular diagnosis of human prion disease. Methods Mol Biol. 2008;459:197–227. DOIPubMedGoogle Scholar
  47. Vidal  E, Fernández-Borges  N, Pintado  B, Ordóñez  M, Márquez  M, Fondevila  D, et al. Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features. J Neurosci. 2013;33:7778–86. DOIPubMedGoogle Scholar
  48. de Marco  MF, Linehan  J, Gill  ON, Clewley  JP, Brandner  S. Large-scale immunohistochemical examination for lymphoreticular prion protein in tonsil specimens collected in Britain. J Pathol. 2010;222:380–7. DOIPubMedGoogle Scholar
  49. Collinge  J. Medicine. Prion strain mutation and selection. Science. 2010;328:1111–2. DOIPubMedGoogle Scholar
  50. Douet  JY, Zafar  S, Perret-Liaudet  A, Lacroux  C, Lugan  S, Aron  N, et al. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease. Emerg Infect Dis. 2014;20:114–7. DOIPubMedGoogle Scholar

Main Article

1These authors contributed equally to this article.

Page created: August 14, 2017
Page updated: August 14, 2017
Page reviewed: August 14, 2017
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external