1887

Journal of General Virology header logo

Volume 93, Issue 11

Infectious titres of sheep scrapie and bovine spongiform encephalopathy agents cannot be accurately predicted from quantitative laboratory test results Free

Abstract

It is widely accepted that abnormal forms of the prion protein (PrP) are the best surrogate marker for the infectious agent of prion diseases and, in practice, the detection of such disease-associated (PrP) and/or protease-resistant (PrP) forms of PrP is the cornerstone of diagnosis and surveillance of the transmissible spongiform encephalopathies (TSEs). Nevertheless, some studies question the consistent association between infectivity and abnormal PrP detection. To address this discrepancy, 11 brain samples of sheep affected with natural scrapie or experimental bovine spongiform encephalopathy were selected on the basis of the magnitude and predominant types of PrP accumulation, as shown by immunohistochemical (IHC) examination; contra-lateral hemi-brain samples were inoculated at three different dilutions into transgenic mice overexpressing ovine PrP and were also subjected to quantitative analysis by three biochemical tests (BCTs). Six samples gave ‘low’ infectious titres (10 to 10 LD g) and five gave ‘high titres’ (10 to ≥10 LD g) and, with the exception of the Western blot analysis, those two groups tended to correspond with samples with lower PrP/PrP results by IHC/BCTs. However, no statistical association could be confirmed due to high individual sample variability. It is concluded that although detection of abnormal forms of PrP by laboratory methods remains useful to confirm TSE infection, infectivity titres cannot be predicted from quantitative test results, at least for the TSE sources and host genotypes used in this study. Furthermore, the near inverse correlation between infectious titres and Western blot results (high protease pre-treatment) argues for a dissociation between infectivity and PrP.

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© 2012 Crown copyright
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2012-11-01
2024-04-26
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References

  1. Ayers J. I., Schutt C. R., Shikiya R. A., Aguzzi A., Kincaid A. E., Bartz J. C. 2011; The strain-encoded relationship between PrPSc replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 7:e1001317 [View Article]
     [Google Scholar]
  2. Balkema-Buschmann A., Eiden M., Hoffmann C., Kaatz M., Ziegler U., Keller M., Groschup M. H. 2011; BSE infectivity in the absence of detectable PrPSc accumulation in the tongue and nasal mucosa of terminally diseased cattle. J Gen Virol 92:467–476 [View Article][PubMed]
     [Google Scholar]
  3. Barron R. M., Manson J. C. 2003; A gene-targeted mouse model of P102L Gerstmann-Sträussler-Scheinker syndrome. Clin Lab Med 23:161–173 [View Article][PubMed]
     [Google Scholar]
  4. Barron R. M., Campbell S. L., King D., Bellon A., Chapman K. E., Williamson R. A., Manson J. C. 2007; High titers of transmissible spongiform encephalopathy infectivity associated with extremely low levels of PrPSc in vivo. J Biol Chem 282:35878–35886 [View Article][PubMed]
     [Google Scholar]
  5. Beck K. E., Sallis R. E., Lockey R., Simmons M. M., Spiropoulos J. 2010; Ovine PrP genotype is linked with lesion profile and immunohistochemistry patterns after primary transmission of classical scrapie to wild-type mice. J Neuropathol Exp Neurol 69:483–497 [View Article][PubMed]
     [Google Scholar]
  6. 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[PubMed]
     [Google Scholar]
  7. Caughey B., Raymond G. J., Kocisko D. A., Lansbury P. T. Jr 1997; Scrapie infectivity correlates with converting activity, protease resistance, and aggregation of scrapie-associated prion protein in guanidine denaturation studies. J Virol 71:4107–4110[PubMed]
     [Google Scholar]
  8. EFSA Panel on Biological Hazards 2009; Scientific opinion on analytical sensitivity of approved TSE rapid tests. EFSA Journal 7:1436
     [Google Scholar]
  9. Gambetti P., Dong Z., Yuan J., Xiao X., Zheng M., Alshekhlee A., Castellani R., Cohen M., Barria M. A.other authors 2008; A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 63:697–708 [View Article][PubMed]
     [Google Scholar]
  10. 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 [View Article][PubMed]
     [Google Scholar]
  11. González L., Martin S., Jeffrey M. 2003; Distinct profiles of PrPd immunoreactivity in the brain of scrapie- and BSE-infected sheep: implications for differential cell targeting and PrP processing. J Gen Virol 84:1339–1350 [View Article][PubMed]
     [Google Scholar]
  12. González L., Martin S., Houston F. E., Hunter N., Reid H. W., Bellworthy S. J., Jeffrey M. 2005a; Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep. J Gen Virol 86:827–838 [View Article][PubMed]
     [Google Scholar]
  13. González L., Terry L., Jeffrey M. 2005b; Expression of prion protein in the gut of mice infected orally with the 301V murine strain of the bovine spongiform encephalopathy agent. J Comp Pathol 132:273–282 [View Article][PubMed]
     [Google Scholar]
  14. González L., Chianini F., Martin S., Sisó S., Gibbard L., Reid H. W., Jeffrey M. 2007; Comparative titration of experimental ovine BSE infectivity in sheep and mice. J Gen Virol 88:714–717 [View Article][PubMed]
     [Google Scholar]
  15. González L., Martin S., Hawkins S. A. C., Goldmann W., Jeffrey M., Sisó S. 2010a; Pathogenesis of natural goat scrapie: modulation by host PRNP genotype and effect of co-existent conditions. Vet Res 41:48 [View Article][PubMed]
     [Google Scholar]
  16. González L., Sisó S., Monleón E., Casalone C., van Keulen L. J. M., Balkema-Buschmann A., Ortiz-Peláez A., Iulini B., Langeveld J. P. M.other authors 2010b; Variability in disease phenotypes within a single PRNP genotype suggests the existence of multiple natural sheep scrapie strains within Europe. J Gen Virol 91:2630–2641 [View Article][PubMed]
     [Google Scholar]
  17. González L., Jeffrey M., Dagleish M. P., Goldmann W., Sisó S., Eaton S. L., Martin S., Finlayson J., Stewart P.other authors 2012; Susceptibility to scrapie and disease phenotype in sheep: cross-Prnp genotype experimental transmissions with natural sources. Vet Res 43:55 [View Article][PubMed]
     [Google Scholar]
  18. Hamilton M. A., Russo R. C., Thurston R. V. 1977; Trimmed Spearman-Kärber method for estimating median lethal concentrations in toxicity bioassays. Environ Sci Technol 11:714–719 [View Article]
     [Google Scholar]
  19. Head M. W., Knight R., Zeidler M., Yull H., Barlow A., Ironside J. W. 2009; A case of protease sensitive prionopathy in a patient in the UK. Neuropathol Appl Neurobiol 35:628–632 [View Article][PubMed]
     [Google Scholar]
  20. Jeffrey M., Martin S., Barr J., Chong A., Fraser J. R. 2001a; Onset of accumulation of PrPres in murine ME7 scrapie in relation to pathological and PrP immunohistochemical changes. J Comp Pathol 124:20–28 [View Article][PubMed]
     [Google Scholar]
  21. 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 tonsillar biopsies. J Comp Pathol 125:48–57 [View Article][PubMed]
     [Google Scholar]
  22. 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 [View Article][PubMed]
     [Google Scholar]
  23. Jeffrey M., McGovern G., Sisó S., González L. 2011; Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease. Acta Neuropathol 121:113–134 [View Article][PubMed]
     [Google Scholar]
  24. Jeffrey M., McGovern G., Chambers E. V., King D., González L., Manson J. C., Ghetti B., Piccardo P., Barron R. M. 2012; Mechanism of PrP-amyloid formation in mice without transmissible spongiform encephalopathy. Brain Pathol 22:58–66 [View Article][PubMed]
     [Google Scholar]
  25. Konold T., Bone G. E., Phelan L. J., Simmons M. M., González L., Sisó S., Goldmann W., Cawthraw S., Hawkins S. A. C. 2010; Monitoring of clinical signs in goats with transmissible spongiform encephalopathies. BMC Vet Res 6:13 [View Article][PubMed]
     [Google Scholar]
  26. Kupfer L., Eiden M., Buschmann A., Groschup M. H. 2007; Amino acid sequence and prion strain specific effects on the in vitro and in vivo convertibility of ovine/murine and bovine/murine prion protein chimeras. Biochim Biophys Acta 1772:704–713 [View Article][PubMed]
     [Google Scholar]
  27. Lasmézas C. I., Deslys J. P., Robain O., Jaegly A., Beringue V., Peyrin J. M., Fournier J. G., Hauw J. J., Rossier J., Dormont D. 1997; Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275:402–404 [View Article][PubMed]
     [Google Scholar]
  28. McKinley M. P., Bolton D. C., Prusiner S. B. 1983; A protease-resistant protein is a structural component of the scrapie prion. Cell 35:57–62 [View Article][PubMed]
     [Google Scholar]
  29. Miyazawa K., Emmerling K., Manuelidis L. 2011; High CJD infectivity remains after prion protein is destroyed. J Cell Biochem 112:3630–3637 [View Article][PubMed]
     [Google Scholar]
  30. Mould D. L., Dawson A. M., Smith W. 1967; Determination of the dosage-response curve of mice inoculated with scrapie. J Comp Pathol 77:387–391 [View Article][PubMed]
     [Google Scholar]
  31. Piccardo P., Manson J. C., King D., Ghetti B., Barron R. M. 2007; Accumulation of prion protein in the brain that is not associated with transmissible disease. Proc Natl Acad Sci U S A 104:4712–4717 [View Article][PubMed]
     [Google Scholar]
  32. Rohwer R. G. 1991; The scrapie agent: “a virus by any other name”. Curr Top Microbiol Immunol 172:195–232 [View Article][PubMed]
     [Google Scholar]
  33. Safar J. G., Geschwind M. D., Deering C., Didorenko S., Sattavat M., Sanchez H., Serban A., Vey M., Baron H.other authors 2005; Diagnosis of human prion disease. Proc Natl Acad Sci U S A 102:3501–3506 [View Article][PubMed]
     [Google Scholar]
  34. Silveira J. R., Raymond G. J., Hughson A. G., Race R. E., Sim V. L., Hayes S. F., Caughey B. 2005; The most infectious prion protein particles. Nature 437:257–261 [View Article][PubMed]
     [Google Scholar]
  35. 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 [View Article][PubMed]
     [Google Scholar]
  36. Sisó S., Jeffrey M., Martin S., Chianini F., Dagleish M. P., González L. 2010; Characterization of strains of ovine transmissible spongiform encephalopathy with a short PrPd profiling method. J Comp Pathol 142:300–310 [View Article][PubMed]
     [Google Scholar]
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Infectious titres of sheep scrapie and bovine spongiform encephalopathy agents cannot be accurately predicted from quantitative laboratory test results
J. Gen. Virol. 93, 2518 (2012); https://doi.org/10.1099/vir.0.045849-0
/content/journal/jgv/10.1099/vir.0.045849-0
/content/journal/jgv/10.1099/vir.0.045849-0
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