1887

Abstract

Prion strains are defined by their biological properties after transmission to wild-type mice, specifically by their incubation periods and patterns of vacuolar pathology (‘lesion profiles’). Preliminary results from transmissions of variant Creutzfeldt–Jakob disease (vCJD) to wild-type mice provided the first compelling evidence for the close similarity of the vCJD agent to the agent causing bovine spongiform encephalopathy (BSE). Complete results from this investigation, including the transmission characteristics of vCJD from brain and peripheral tissues of 10 cases (after primary transmission and subsequent mouse-to-mouse passage), have now been analysed. All 10 vCJD sources resulted in consistent incubation periods and lesion profiles, suggesting that all 10 patients were infected with the same strain of agent. Incubation periods suggested that infectious titres may be subject to regional variation within the brain. Comparison of incubation periods and lesion profiles from transmission of brain and peripheral tissues showed no evidence of tissue-specific modification in the biological properties of the agent. Analysis of the protease-resistant prion protein (PrP) by Western blotting from primary and subsequent passages in mice showed a glycosylation pattern closely resembling that of vCJD in humans, the so-called BSE ‘glycoform signature’. Minor variations in PrP fragment size were evident between mouse strains carrying different alleles of the gene encoding PrP both in primary transmissions and on further passages of vCJD brain. Overall, the results closely resembled those of previously reported transmissions of BSE in the same mouse strains, consistent with BSE being the origin of all of these vCJD cases.

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2009-12-01
2019-11-20
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References

  1. Asante, E. A., Linehan, J. M., Desbruslais, M., Joiner, S., Gowland, I., Wood, A. L., Welch, J., Hill, A. F., Lloyd, S. E. & other authors ( 2002; ). BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 21, 6358–6366.[CrossRef]
    [Google Scholar]
  2. Beringue, V., Le Dur, A., Tixador, P., Reine, F., Lepourry, L., Perret-Liaudet, A., Haik, S., Vilotte, J. L., Fontes, M. & Laude, H. ( 2008; ). Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS One 3, e1419 [CrossRef]
    [Google Scholar]
  3. Bishop, M. T., Hart, P., Aitchison, L., Baybutt, H. N., Plinston, C., Thomson, V., Tuzi, N. L., Head, M. W., Ironside, J. W. & other authors ( 2006; ). Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol 5, 393–398.[CrossRef]
    [Google Scholar]
  4. Bruce, M. E., McConnell, I., Fraser, H. & Dickinson, A. G. ( 1991; ). The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J Gen Virol 72, 595–603.[CrossRef]
    [Google Scholar]
  5. Bruce, M. E., Will, R. G., Ironside, J. W., McConnell, I., Drummond, D., Suttie, A., McCardle, L., Chree, A., Hope, J. & other authors ( 1997; ). Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389, 498–501.[CrossRef]
    [Google Scholar]
  6. Bruce, M. E., McConnell, I., Will, R. G. & Ironside, J. W. ( 2001; ). Detection of variant Creutzfeldt–Jakob disease infectivity in extraneural tissues. Lancet 358, 208–209.[CrossRef]
    [Google Scholar]
  7. Bruce, M. E., Boyle, A., Cousens, S., McConnell, I., Foster, J., Goldmann, W. & Fraser, H. ( 2002; ). Strain characterization of natural sheep scrapie and comparison with BSE. J Gen Virol 83, 695–704.
    [Google Scholar]
  8. Caughey, B., Raymond, G. J. & Bessen, R. A. ( 1998; ). Strain-dependent differences in β-sheet conformations of abnormal prion protein. J Biol Chem 273, 32230–32235.[CrossRef]
    [Google Scholar]
  9. Collinge, J., Sidle, K. C., Meads, J., Ironside, J. & Hill, A. F. ( 1996; ). Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383, 685–690.[CrossRef]
    [Google Scholar]
  10. Dickinson, A. G. & Meikle, V. M. ( 1971; ). Host-genotype and agent effects in scrapie incubation: change in allelic interaction with different strains of agent. Mol Gen Genet 112, 73–79.[CrossRef]
    [Google Scholar]
  11. Farquhar, C. F., Somerville, R. A. & Bruce, M. E. ( 1998; ). Straining the prion hypothesis. Nature 391, 345–346.[CrossRef]
    [Google Scholar]
  12. Fraser, H. & Dickinson, A. G. ( 1968; ). The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78, 301–311.[CrossRef]
    [Google Scholar]
  13. Head, M. W., Ritchie, D., Smith, N., McLoughlin, V., Nailon, W., Masson, S., Bishop, M., McCardle, L. & Ironside, J. W. ( 2004; ). Peripheral tissue involvement in sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease. An immunohistochemical, quantitative, and biochemical study. Am J Pathol 164, 143–153.[CrossRef]
    [Google Scholar]
  14. Hill, A. F., Desbruslais, M., Joiner, S., Sidle, K. C., Gowland, I., Collinge, J., Doey, L. J. & Lantos, P. ( 1997; ). The same prion strain causes vCJD and BSE. Nature 389, 448–450. –526.[CrossRef]
    [Google Scholar]
  15. Hilton, D. A., Ghani, A. C., Conyers, L., Edwards, P., McCardle, L., Ritchie, D., Penney, M., Hegazy, D. & Ironside, J. W. ( 2004a; ). Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 203, 733–739.[CrossRef]
    [Google Scholar]
  16. Hilton, D. A., Sutak, J., Smith, M. E., Penney, M., Conyers, L., Edwards, P., McCardle, L., Ritchie, D., Head, M. W. & other authors ( 2004b; ). Specificity of lymphoreticular accumulation of prion protein for variant Creutzfeldt-Jakob disease. J Clin Pathol 57, 300–302.[CrossRef]
    [Google Scholar]
  17. Ironside, J. W., Head, M. W., Bell, J. E., McCardle, L. & Will, R. G. ( 2000; ). Laboratory diagnosis of variant Creutzfeldt–Jakob disease. Histopathology 37, 1–9.[CrossRef]
    [Google Scholar]
  18. Ironside, J. W., Bishop, M. T., Connolly, K., Hegazy, D., Lowrie, S., Le Grice, M., Ritchie, D. L., McCardle, L. M. & Hilton, D. A. ( 2006; ). Variant Creutzfeldt–Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study. BMJ 332, 1186–1188.[CrossRef]
    [Google Scholar]
  19. Lasmezas, C. I., Deslys, J. P., Demaimay, R., Adjou, K. T., Lamoury, F., Dormont, D., Robain, O., Ironside, J. & Hauw, J. J. ( 1996; ). BSE transmission to macaques. Nature 381, 743–744.[CrossRef]
    [Google Scholar]
  20. Lloyd, S. E., Thompson, S. R., Beck, J. A., Linehan, J. M., Wadsworth, J. D., Brandner, S., Collinge, J. & Fisher, E. M. ( 2004; ). Identification and characterization of a novel mouse prion gene allele. Mamm Genome 15, 383–389.[CrossRef]
    [Google Scholar]
  21. Parchi, P., Castellani, R., Capellari, S., Ghetti, B., Young, K., Chen, S. G., Farlow, M., Dickson, D. W., Sima, A. A. & other authors ( 1996; ). Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 39, 767–778.[CrossRef]
    [Google Scholar]
  22. Parchi, P., Giese, A., Capellari, S., Brown, P., Schulz-Schaeffer, W., Windl, O., Zerr, I., Budka, H., Kopp, N. & other authors ( 1999; ). Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46, 224–233.[CrossRef]
    [Google Scholar]
  23. Peden, A. H., Head, M. W., Ritchie, D. L., Bell, J. E. & Ironside, J. W. ( 2004; ). Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527–529.[CrossRef]
    [Google Scholar]
  24. Prusiner, S. B. ( 1982; ). Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144.[CrossRef]
    [Google Scholar]
  25. Sabattini, E., Bisgaard, K., Ascani, S., Poggi, S., Piccioli, M., Ceccarelli, C., Pieri, F., Fraternali-Orcioni, G. & Pileri, S. A. ( 1998; ). The EnVision++ system: a new immunohistochemical method for diagnostics and research. Critical comparison with the APAAP, ChemMate, CSA, LABC, and SABC techniques. J Clin Pathol 51, 506–511.[CrossRef]
    [Google Scholar]
  26. Scott, M. R., Will, R., Ironside, J., Nguyen, H. O., Tremblay, P., DeArmond, S. J. & Prusiner, S. B. ( 1999; ). Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci U S A 96, 15137–15142.[CrossRef]
    [Google Scholar]
  27. Somerville, R. A., Hamilton, S. & Fernie, K. ( 2005; ). Transmissible spongiform encephalopathy strain, PrP genotype and brain region all affect the degree of glycosylation of PrPSc. J Gen Virol 86, 241–246.[CrossRef]
    [Google Scholar]
  28. Spassov, S., Beekes, M. & Naumann, D. ( 2006; ). Structural differences between TSEs strains investigated by FT-IR spectroscopy. Biochim Biophys Acta 1760, 1138–1149.[CrossRef]
    [Google Scholar]
  29. Telling, G. C., Parchi, P., DeArmond, S. J., Cortelli, P., Montagna, P., Gabizon, R., Mastrianni, J., Lugaresi, E., Gambetti, P. & Prusiner, S. B. ( 1996; ). Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274, 2079–2082.[CrossRef]
    [Google Scholar]
  30. Thomzig, A., Spassov, S., Friedrich, M., Naumann, D. & Beekes, M. ( 2004; ). Discriminating scrapie and bovine spongiform encephalopathy isolates by infrared spectroscopy of pathological prion protein. J Biol Chem 279, 33847–33854.[CrossRef]
    [Google Scholar]
  31. Wells, G. A., Scott, A. C., Johnson, C. T., Gunning, R. F., Hancock, R. D., Jeffrey, M., Dawson, M. & Bradley, R. ( 1987; ). A novel progressive spongiform encephalopathy in cattle. Vet Rec 121, 419–420.[CrossRef]
    [Google Scholar]
  32. Westaway, D., Goodman, P. A., Mirenda, C. A., McKinley, M. P., Carlson, G. A. & Prusiner, S. B. ( 1987; ). Distinct prion proteins in short and long scrapie incubation period mice. Cell 51, 651–662.[CrossRef]
    [Google Scholar]
  33. Will, R. G., Ironside, J. W., Zeidler, M., Cousens, S. N., Estibeiro, K., Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A. & Smith, P. G. ( 1996; ). A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347, 921–925.[CrossRef]
    [Google Scholar]
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Mean lesion profiles from the first and second mouse-to-mouse passage of vCJD 1, vCJD 2 and BSE 1 and BSE 2 in RIII, C57BL, VM and C57BL x VM mice. [PDF of Figure](44 KB)

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