1887

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Volume 91, Issue 10

Variability in disease phenotypes within a single genotype suggests the existence of multiple natural sheep scrapie strains within Europe Free

Abstract

Variability of pathological phenotypes within classical sheep scrapie cases has been reported for some time, but in many instances it has been attributed to differences in the genotype of the host. To address this issue we have examined by immunohistochemistry (IHC) and Western blotting (WB) for the disease-associated form of the prion protein (PrP), the brains of 23 sheep from five European countries, all of which were of the same ARQ/ARQ genotype. As a result of IHC examinations, sheep were distributed into five groups with different phenotypes and the groups were the same regardless of the scoring method used, ‘long’ or ‘short’ PrP profiling. The groups made did not respond to the geographical origin of the cases and did not correlate with the vacuolar lesion profiles, which showed a high individual variability. Discriminatory IHC and WB methods coincided to detect a ‘CH1641-like’ case but otherwise correlated poorly in the classification of disease phenotypes. No other polymorphisms of the gene were found that could account for the pathological differences, except perhaps for a sheep from Spain with a mutation at codon 103 and a unique pathological phenotype. Preliminary evidence indicates that those different IHC phenotypes correlate with distinct biological properties on bioassay, suggesting that they are indicative of strain diversity. We therefore conclude that natural scrapie strains exist and that they can be revealed by detailed pathological examinations, which can be harmonized between laboratories to produce comparable results.

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2010-10-01
2024-05-08
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References

  1. Acín, C., Martin-Burriel, I., Goldmann, W., Lyahyai, J., Monzón, M., Bolea, R., Smith, A., Rodellar, C., Badiola, J. J. & Zaragoza, P.(2004). Prion protein gene polymorphisms in healthy and scrapie-affected Spanish sheep. J Gen Virol 85, 2103–2110.[CrossRef] [Google Scholar]
  2. Acutis, P. L., Sbaiz, L., Verburg, F., Riina, M. V., Ru, G., Moda, G., Caramelli, M. & Bossers, A.(2004). 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 85, 3165–3172.[CrossRef] [Google Scholar]
  3. Baron, T. & Biacabe, A.-G.(2007). Molecular behaviours of “CH1641-like” sheep scrapie isolates in ovine transgenic mice (TgOvPrP4). J Virol 81, 7230–7237.[CrossRef] [Google Scholar]
  4. Baron, T., Bencsik, A., Vulin, J., Biacabe, A.-G., Morignat, E., Verchere, J. & Betemps, D.(2008). 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 4, e1000137.[CrossRef] [Google Scholar]
  5. Beck, K. E., Chaplin, M., Stack, M., Sallis, R. E., Simonini, S., Lockey, R. & Spiropoulos, J.(2010). Lesion profiling at primary isolation in RIII mice is insufficient in distinguishing BSE from classical scrapie. Brain Pathol 20, 313–322.[CrossRef] [Google Scholar]
  6. Begara-McGorum, I., González, L., Simmons, M., Hunter, N., Houston, F. & Jeffrey, M.(2002). Vacuolar lesion profile in sheep scrapie: factors influencing its variation and relationship to disease-specific PrP accumulation. J Comp Pathol 127, 59–68.[CrossRef] [Google Scholar]
  7. Benestad, S. L., Sarradin, P., Thu, B., Schonheit, J., Tranulis, M. A. & Bratberg, B.(2003). Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet Rec 153, 202–208.[CrossRef] [Google Scholar]
  8. Benestad, S. L., Arsac, J. N., Goldmann, W. & Noremark, M.(2008). Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res 39, 19.[CrossRef] [Google Scholar]
  9. Bruce, M. E.(2003). TSE strain variation. Br Med Bull 66, 99–108.[CrossRef] [Google Scholar]
  10. Buschmann, A., Biacabe, A. G., Ziegler, U., Bencsik, A., Madec, J. Y., Erhardt, G., Luhken, G., Baron, T. & Groschup, M. H.(2004). Atypical scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. J Virol Methods 117, 27–36.[CrossRef] [Google Scholar]
  11. Di Bari, M. A., Chianini, F., Vaccari, G., Esposito, E., Conte, M., Eaton, S. L., Hamilton, S., Finlayson, J., Steele, P. J. & other authors(2008). The bank vole (Myodes glareolus) as a sensitive bioassay for sheep scrapie. J Gen Virol 89, 2975–2985.[CrossRef] [Google Scholar]
  12. Fraser, H.(1976). The pathology of natural and experimental scrapie. In Slow Virus Diseases of Animals and Man, pp. 267–305. Edited by Kimberlin, R. H.. Amsterdam. : North Holland Publishing. Co. [Google Scholar]
  13. González, L., Martin, S., Begara-McGorum, I., Hunter, N., Houston, F., Simmons, M. & Jeffrey, M.(2002). Effects of agent strain and host genotype on PrP accumulation in the brain of sheep naturally and experimentally affected with scrapie. J Comp Pathol 126, 17–29.[CrossRef] [Google Scholar]
  14. González, L., Martin, S. & Jeffrey, M.(2003). Distinct profiles of PrPd immunoreactivity in the brain of scrapie- and BSE-infected sheep: implications on differential cell targeting and PrP processing. J Gen Virol 84, 1339–1350.[CrossRef] [Google Scholar]
  15. González, L., Martin, S., Houston, F. E., Hunter, N., Reid, H. W., Bellworthy, S. J. & Jeffrey, M.(2005). Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep. J Gen Virol 86, 827–838.[CrossRef] [Google Scholar]
  16. Gretzschel, A., Buschmann, A., Eiden, M., Ziegler, U., Lühken, G., Erhardt, G. & Groschup, M. H.(2005). Strain typing of German transmissible spongiform encephalopathies field cases in small ruminants by biochemical methods. J Vet Med B Infect Dis Vet Public Health 52, 55–63.[CrossRef] [Google Scholar]
  17. Jeffrey, M., Martin, S., González, L., Ryder, S. J., Bellworthy, S. J. & Jackman, R.(2001a). Differential diagnosis of infections with the bovine spongiform encephalopathy (BSE) and scrapie agents in sheep. J Comp Pathol 125, 271–284.[CrossRef] [Google Scholar]
  18. Jeffrey, M., Martin, S., Thomson, J. R., Dingwall, W. S., Begara-McGorum, I. & González, L.(2001b). Onset and distribution of tissue PrP accumulation in scrapie-affected Suffolk sheep as demonstrated by sequential necropsies and tonsilar biopsies. J Comp Pathol 125, 48–57.[CrossRef] [Google Scholar]
  19. Jeffrey, M., Martin, S. & González, L.(2003). Cell-associated variants of disease-specific prion protein immunolabelling are found in different sources of sheep transmissible spongiform encephalopathy. J Gen Virol 84, 1033–1045.[CrossRef] [Google Scholar]
  20. Jeffrey, M., González, L., Chong, A., Foster, J., Goldmann, W., Hunter, N. & Martin, S.(2006). Ovine infection with the agents of scrapie (CH1641 isolate) and bovine spongiform encephalopathy: immunochemical similarities can be resolved by immunohistochemistry. J Comp Pathol 134, 17–29.[CrossRef] [Google Scholar]
  21. Jeffrey, M., McGovern, G., Sisó, S. & González, L.(2010). Cellular and sub-cellular pathology of animal TSEs: relationships between morphologic change, PrPd accumulation and clinical disease. Acta Neuropathol (in press). doi: 10.1007/s00401-010-0700-3 [Google Scholar]
  22. Langeveld, J. P. M., Jacobs, J. G., Erkens, J. H. F., Bossers, A., van Zijderveld, F. G. & van Keulen, L. J. M.(2006). Rapid and discriminatory diagnosis of scrapie and BSE in retro-pharyngeal lymph nodes of sheep. BMC Vet Res 2, 19.[CrossRef] [Google Scholar]
  23. Lau, A. L., Yam, A. Y., Michelitsch, M. M., Wang, X., Gao, C., Goodson, R. J., Shimizu, R., Timoteo, G., Hall, J. & other authors(2007). Characterization of prion protein (PrP)-derived peptides that discriminate full-length PrPSc from PrPC. Proc Natl Acad Sci U S A 104, 11551–11556.[CrossRef] [Google Scholar]
  24. Ligios, C., Jeffrey, M., Ryder, S. J., Bellworthy, S. J. & Simmons, M. M.(2002). Distinction of scrapie phenotypes in sheep by lesion profiling. J Comp Pathol 127, 45–57.[CrossRef] [Google Scholar]
  25. Ligios, C., Dexter, G., Spiropoulos, J., Maestrale, C., Carta, A. & Simmons, M. M.(2004). Distribution of vascular amyloid in scrapie-affected sheep with different genotypes. J Comp Pathol 131, 271–276.[CrossRef] [Google Scholar]
  26. Lühken, G., Buschmann, A., Groschup, M. H. & Erhardt, G.(2004). Prion protein allele A(136) H(154) Q(171) is associated with high susceptibility to scrapie in purebred and crossbred German Merinoland sheep. Arch Virol 149, 1571–1580. [Google Scholar]
  27. Nonno, R., Esposito, E., Vaccari, G., Conte, M., Marcon, S., Di Bari, M., Ligios, C., Di Guardo, G. & Agrimi, U.(2003). Molecular analysis of cases of Italian sheep scrapie and comparison with cases of bovine spongiform encephalopathy (BSE) and experimental BSE in sheep. J Clin Microbiol 41, 4127–4133.[CrossRef] [Google Scholar]
  28. Prusiner, S. B.(1982). Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144.[CrossRef] [Google Scholar]
  29. Ryder, S. J., Spencer, Y. I., Bellerby, P. J. & March, S. A.(2001). Immunohistochemical detection of PrP in the medulla oblongata of sheep: the spectrum of staining in normal and scrapie-affected sheep. Vet Rec 148, 7–13.[CrossRef] [Google Scholar]
  30. Sisó, S., Jeffrey, M. & González, L.(2009). Neuroinvasion in sheep transmissible spongiform encephalopathies: the role of the haematogenous route. Neuropathol Appl Neurobiol 35, 232–246.[CrossRef] [Google Scholar]
  31. Sisó, S., Jeffrey, M., Martin, S., Chianini, F., Dagleish, M. P. & González, L.(2010). Characterization of sheep TSE strains using a short PrPd profiling method. J Comp Pathol 142, 300–310.[CrossRef] [Google Scholar]
  32. Spiropoulos, J., Casalone, C., Caramelli, M. & Simmons, M. M.(2007). Immunohistochemistry for PrPSc in natural scrapie reveals patterns which are associated with the PrP genotype. Neuropathol Appl Neurobiol 33, 398–409.[CrossRef] [Google Scholar]
  33. Stack, M. J., Chaplin, M. J. & Clark, J.(2002). Differentiation of prion protein glycoforms from naturally occurring sheep scrapie, sheep-passaged 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 104, 279–286. [Google Scholar]
  34. Stack, M. J., Jeffrey, M., Gubbins, S., Grimmer, S., González, L., Martin, S., Chaplin, M., Webb, P., Simmons, M. & other authors(2006). Monitoring for bovine spongiform encephalopathy in sheep in Great Britain, 1998–2004. J Gen Virol 87, 2099–2107.[CrossRef] [Google Scholar]
  35. Sweeney, T., Kuczius, T., McElroy, M., Gómez Parada, M. & Groschup, M.(2000). Molecular analysis of Irish sheep scrapie cases. J Gen Virol 81, 1621–1627. [Google Scholar]
  36. Thuring, C. M. A., Erkens, J. H. F., Jacobs, J., Bossers, A., van Keulen, L. J. M., Garssen, G. J., van Zijderveld, F. G., Ryder, S. J., Groschup, M. H. & other authors(2004). Discrimination between scrapie and bovine spongiform encephalopathy in sheep by molecular size, immunoreactivity and glycoprofile of prion protein. J Clin Microbiol 42, 972–980.[CrossRef] [Google Scholar]
  37. van Keulen, L. J. M., Schreuder, B. E. C., Meloen, R. H., Poelen-van den Berg, M., Mooij-Harkes, G., Vromans, M. E. W. & Langeveld, J. P. M.(1995). Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Vet Pathol 32, 299–308.[CrossRef] [Google Scholar]
  38. Wille, H., Michelitsch, M. D., Guenebaut, V., Supattapone, S., Serban, A., Cohen, F. E., Agard, D. A. & Prusiner, S. B.(2002). Structural studies of the scrapie prion protein by electron crystallography. Proc Natl Acad Sci U S A 99, 3563–3568.[CrossRef] [Google Scholar]
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Variability in disease phenotypes within a single PRNP genotype suggests the existence of multiple natural sheep scrapie strains within Europe
J. Gen. Virol. 91, 2630 (2010); https://doi.org/10.1099/vir.0.022574-0
/content/journal/jgv/10.1099/vir.0.022574-0
/content/journal/jgv/10.1099/vir.0.022574-0
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vol. , part 10, pp. 2630 - 2641

Short PrP profiles

Vacuolar lesion profiles

Summary of the correlation analyses of the vacuolar lesion profiles

Glycoprofile results and statistical analysis

Dendrogram for cluster analysis of short PrP profiles [Single PDF file](23 KB)

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