1887

Abstract

The occurrence of variant Creutzfeldt–Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the ‘species barrier’, which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6–8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.058958-0
2014-01-01
2019-11-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/1/231.html?itemId=/content/journal/jgv/10.1099/vir.0.058958-0&mimeType=html&fmt=ahah

References

  1. Andréoletti O. , Berthon P. , Marc D. , Sarradin P. , Grosclaude J. , van Keulen L. , Schelcher F. , Elsen J.-M. , Lantier F. . ( 2000; ). Early accumulation of PrPSc in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie. . J Gen Virol 81:, 3115–3126.[PubMed]
    [Google Scholar]
  2. Aydar Y. , Balogh P. , Tew J. G. , Szakal A. K. . ( 2002; ). Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of co-stimulation. . Eur J Immunol 32:, 2817–2826. [CrossRef] [PubMed]
    [Google Scholar]
  3. Aydar Y. , Balogh P. , Tew J. G. , Szakal A. K. . ( 2003; ). Altered regulation of Fc gamma RII on aged follicular dendritic cells correlates with immunoreceptor tyrosine-based inhibition motif signaling in B cells and reduced germinal center formation. . J Immunol 171:, 5975–5987.[PubMed] [CrossRef]
    [Google Scholar]
  4. Barron R. M. , Thomson V. , Jamieson E. , Melton D. W. , Ironside J. , Will R. , Manson J. C. . ( 2001; ). Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. . EMBO J 20:, 5070–5078. [CrossRef] [PubMed]
    [Google Scholar]
  5. Birjandi S. Z. , Ippolito J. A. , Ramadorai A. K. , Witte P. L. . ( 2011; ). Alterations in marginal zone macrophages and marginal zone B cells in old mice. . J Immunol 186:, 3441–3451. [CrossRef] [PubMed]
    [Google Scholar]
  6. Bishop M. T. , Hart P. , Aitchison L. , Baybutt H. N. , Plinston C. , Thomson V. , Tuzi N. L. , Head M. W. , Ironside J. W. , Will R. G. . ( 2006; ). Predicting susceptibility and incubation time of human-to-human transmission of vCJD. . Lancet Neurol 5:, 393–398. [CrossRef] [PubMed]
    [Google Scholar]
  7. Bishop M. T. , Diack A. B. , Ritchie D. L. , Ironside J. W. , Will R. G. , Manson J. C. . ( 2013; ). Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt–Jakob disease. . Brain 136:, 1139–1145. [CrossRef] [PubMed]
    [Google Scholar]
  8. Boëlle P.-Y. , Cesbron J.-Y. , Valleron A.-J. . ( 2004; ). Epidemiological evidence of higher susceptibility to vCJD in the young. . BMC Infect Dis 4:, 26. [CrossRef] [PubMed]
    [Google Scholar]
  9. Bolton D. C. , McKinley M. P. , Prusiner S. B. . ( 1982; ). Identification of a protein that purifies with the scrapie prion. . Science 218:, 1309–1311. [CrossRef] [PubMed]
    [Google Scholar]
  10. Brown K. L. , Stewart K. , Bruce M. E. , Fraser H. . ( 1997; ). Severely combined immunodeficient (SCID) mice resist infection with bovine spongiform encephalopathy. . J Gen Virol 78:, 2707–2710.[PubMed]
    [Google Scholar]
  11. Brown K. L. , Stewart K. , Ritchie D. L. , Mabbott N. A. , Williams A. , Fraser H. , Morrison W. I. , Bruce M. E. . ( 1999; ). Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. . Nat Med 5:, 1308–1312. [CrossRef] [PubMed]
    [Google Scholar]
  12. Brown K. L. , Wathne G. J. , Sales J. , Bruce M. E. , Mabbott N. A. . ( 2009; ). The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice. . J Immunol 183:, 5199–5207. [CrossRef] [PubMed]
    [Google Scholar]
  13. Brown K. L. , Gossner A. , Mok S. , Mabbott N. A. . ( 2012; ). The effects of host age on the transport of complement-bound complexes to the spleen and the pathogenesis of intravenous scrapie infection. . J Virol 86:, 25–35. [CrossRef] [PubMed]
    [Google Scholar]
  14. 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] [PubMed]
    [Google Scholar]
  15. Cancellotti E. , Mahal S. P. , Somerville R. , Diack A. , Brown D. , Piccardo P. , Weissmann C. , Manson J. C. . ( 2013; ). Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties. . EMBO J 32:, 756–769. [CrossRef] [PubMed]
    [Google Scholar]
  16. Cinamon G. , Zachariah M. A. , Lam O. M. , Foss F. W. Jr , Cyster J. G. . ( 2008; ). Follicular shuttling of marginal zone B cells facilitates antigen transport. . Nat Immunol 9:, 54–62. [CrossRef] [PubMed]
    [Google Scholar]
  17. Clewley J. P. , Kelly C. M. , Andrews N. , Vogliqi K. , Mallinson G. , Kaisar M. , Hilton D. A. , Ironside J. W. , Edwards P. . & other authors ( 2009; ). Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey. . BMJ 338:, b1442. [CrossRef] [PubMed]
    [Google Scholar]
  18. Farquhar C. F. , Somerville R. A. , Ritchie L. A. . ( 1989; ). Post-mortem immunodiagnosis of scrapie and bovine spongiform encephalopathy. . J Virol Methods 24:, 215–221. [CrossRef] [PubMed]
    [Google Scholar]
  19. Fraser H. , Bruce M. E. , Chree A. , McConnell I. , Wells G. A. H. . ( 1992; ). Transmission of bovine spongiform encephalopathy and scrapie to mice. . J Gen Virol 73:, 1891–1897. [CrossRef] [PubMed]
    [Google Scholar]
  20. Frigg R. , Klein M. A. , Hegyi I. , Zinkernagel R. M. , Aguzzi A. . ( 1999; ). Scrapie pathogenesis in subclinically infected B-cell-deficient mice. . J Virol 73:, 9584–9588.[PubMed]
    [Google Scholar]
  21. Garske T. , Ghani A. C. . ( 2010; ). Uncertainty in the tail of the variant Creutzfeldt–Jakob disease epidemic in the UK. . PLoS ONE 5:, e15626. [CrossRef] [PubMed]
    [Google Scholar]
  22. Ghani A. C. , Ferguson N. M. , Donnelly C. A. , Anderson R. M. . ( 2000; ). Predicted vCJD mortality in Great Britain. . Nature 406:, 583–584. [CrossRef] [PubMed]
    [Google Scholar]
  23. Hill A. F. , Joiner S. , Linehan J. , Desbruslais M. , Lantos P. L. , Collinge J. . ( 2000; ). Species-barrier-independent prion replication in apparently resistant species. . Proc Natl Acad Sci U S A 97:, 10248–10253. [CrossRef] [PubMed]
    [Google Scholar]
  24. Hilton D. A. , Fathers E. , Edwards P. , Ironside J. W. , Zajicek J. . ( 1998; ). Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt–Jakob disease. . Lancet 352:, 703–704. [CrossRef] [PubMed]
    [Google Scholar]
  25. Hilton D. A. , Ghani A. C. , Conyers L. , Edwards P. , McCardle L. , Penney M. , Ritchie D. , Ironside J. W. . ( 2002; ). Accumulation of prion protein in tonsil and appendix: review of tissue samples. . BMJ 325:, 633–634. [CrossRef] [PubMed]
    [Google Scholar]
  26. Hilton D. A. , Ghani A. C. , Conyers L. , Edwards P. , McCardle L. , Ritchie D. , Penney M. , Hegazy D. , Ironside J. W. . ( 2004; ). Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. . J Pathol 203:, 733–739. [CrossRef] [PubMed]
    [Google Scholar]
  27. Houston F. , Goldmann W. , Chong A. , Jeffrey M. , González L. , Foster J. , Parnham D. , Hunter N. . ( 2003; ). Prion diseases: BSE in sheep bred for resistance to infection. . Nature 423:, 498. [CrossRef] [PubMed]
    [Google Scholar]
  28. Klein M. A. , Kaeser P. S. , Schwarz P. , Weyd H. , Xenarios I. , Zinkernagel R. M. , Carroll M. C. , Verbeek J. S. , Botto M. . & other authors ( 2001; ). Complement facilitates early prion pathogenesis. . Nat Med 7:, 488–492. [CrossRef] [PubMed]
    [Google Scholar]
  29. Lanoue A. , Clatworthy M. R. , Smith P. , Green S. , Townsend M. J. , Jolin H. E. , Smith K. G. , Fallon P. G. , McKenzie A. N. . ( 2004; ). SIGN-R1 contributes to protection against lethal pneumococcal infection in mice. . J Exp Med 200:, 1383–1393. [CrossRef] [PubMed]
    [Google Scholar]
  30. Legname G. , Baskakov I. V. , Nguyen H.-O. B. , Riesner D. , Cohen F. E. , DeArmond S. J. , Prusiner S. B. . ( 2004; ). Synthetic mammalian prions. . Science 305:, 673–676. [CrossRef] [PubMed]
    [Google Scholar]
  31. Lloyd S. E. , Thompson S. R. , Beck J. A. , Linehan J. M. , Wadsworth J. D. F. , Brandner S. , Collinge J. , Fisher E. M. . ( 2004; ). Identification and characterization of a novel mouse prion gene allele. . Mamm Genome 15:, 383–389. [CrossRef] [PubMed]
    [Google Scholar]
  32. Mabbott N. A. . ( 2012; ). Prion pathogenesis and secondary lymphoid organs (SLO): tracking the SLO spread of prions to the brain. . Prion 6:, 322–333. [CrossRef] [PubMed]
    [Google Scholar]
  33. Mabbott N. A. , Mackay F. , Minns F. , Bruce M. E. . ( 2000; ). Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. . Nat Med 6:, 719–720. [CrossRef] [PubMed]
    [Google Scholar]
  34. Mabbott N. A. , Bruce M. E. , Botto M. , Walport M. J. , Pepys M. B. . ( 2001; ). Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. . Nat Med 7:, 485–487. [CrossRef] [PubMed]
    [Google Scholar]
  35. Mabbott N. A. , Young J. , McConnell I. , Bruce M. E. . ( 2003; ). Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. . J Virol 77:, 6845–6854. [CrossRef] [PubMed]
    [Google Scholar]
  36. McBride P. A. , Eikelenboom P. , Kraal G. , Fraser H. , Bruce M. E. . ( 1992; ). PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. . J Pathol 168:, 413–418. [CrossRef] [PubMed]
    [Google Scholar]
  37. McCulloch L. , Brown K. L. , Bradford B. M. , Hopkins J. , Bailey M. , Rajewsky K. , Manson J. C. , Mabbott N. A. . ( 2011; ). Follicular dendritic cell-specific prion protein (PrPC) expression alone is sufficient to sustain prion infection in the spleen. . PLoS Pathog 7:, e1002402. [CrossRef] [PubMed]
    [Google Scholar]
  38. McCulloch L. , Brown K. L. , Mabbott N. A. . ( 2013; ). Ablation of the cellular prion protein, PrPC, specifically on follicular dendritic cells has no effect on their maturation or function. . Immunology 138:, 246–257. [CrossRef] [PubMed]
    [Google Scholar]
  39. Mebius R. E. , Kraal G. . ( 2005; ). Structure and function of the spleen. . Nat Rev Immunol 5:, 606–616. [CrossRef] [PubMed]
    [Google Scholar]
  40. Michel B. , Ferguson A. , Johnson T. , Bender H. , Meyerett-Reid C. , Pulford B. , von Teichman A. , Seelig D. , Weis J. H. . & other authors ( 2012; ). Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease. . J Immunol 189:, 4520–4527. [CrossRef] [PubMed]
    [Google Scholar]
  41. Montrasio F. , Frigg R. , Glatzel M. , Klein M. A. , Mackay F. , Aguzzi A. , Weissmann C. . ( 2000; ). Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. . Science 288:, 1257–1259. [CrossRef] [PubMed]
    [Google Scholar]
  42. O’Connor T. , Frei N. , Sponarova J. , Schwarz P. , Heikenwalder M. , Aguzzi A. . ( 2012; ). Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes. . PLoS Pathog 8:, e1002867. [CrossRef] [PubMed]
    [Google Scholar]
  43. Peden A. H. , Head M. W. , Diane L. R. , Bell J. E. , Ironside J. W. . ( 2004; ). Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. . Lancet 364:, 527–529. [CrossRef] [PubMed]
    [Google Scholar]
  44. Prusiner S. B. , Scott M. , Foster D. , Pan K. M. , Groth D. , Mirenda C. , Torchia M. , Yang S. L. , Serban D. . & other authors ( 1990; ). Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. . Cell 63:, 673–686. [CrossRef] [PubMed]
    [Google Scholar]
  45. Schulz-Schaeffer W. J. , Tschöke S. , Kranefuss N. , Dröse W. , Hause-Reitner D. , Giese A. , Groschup M. H. , Kretzschmar H. A. . ( 2000; ). The paraffin-embedded tissue blot detects PrPSc early in the incubation time in prion diseases. . Am J Pathol 156:, 51–56. [CrossRef] [PubMed]
    [Google Scholar]
  46. Sigurdson C. J. , Williams E. S. , Miller M. W. , Spraker T. R. , O’Rourke K. I. , Hoover E. A. . ( 1999; ). Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). . J Gen Virol 80:, 2757–2764.[PubMed]
    [Google Scholar]
  47. 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] [PubMed]
    [Google Scholar]
  48. Taylor P. R. , Pickering M. C. , Kosco-Vilbois M. H. , Walport M. J. , Botto M. , Gordon S. , Martinez-Pomares L. . ( 2002; ). The follicular dendritic cell restricted epitope, FDC-M2, is complement C4; localization of immune complexes in mouse tissues. . Eur J Immunol 32:, 1883–1896. [CrossRef] [PubMed]
    [Google Scholar]
  49. Thackray A. M. , Klein M. A. , Bujdoso R. . ( 2003; ). Subclinical prion disease induced by oral inoculation. . J Virol 77:, 7991–7998. [CrossRef] [PubMed]
    [Google Scholar]
  50. Valleron A.-J. , Boelle P.-Y. , Will R. , Cesbron J.-Y. . ( 2001; ). Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. . Science 294:, 1726–1728. [CrossRef] [PubMed]
    [Google Scholar]
  51. Wilesmith J. W. . ( 1993; ). BSE: Epidemiological approaches, trials and tribulations. . Prev Vet Med 18:, 33–42. [CrossRef]
    [Google Scholar]
  52. Will R. G. , Ironside J. W. , Zeidler M. , Estibeiro K. , Cousens S. N. , Smith P. G. , Alperovitch A. , Poser S. , Pocchiari M. , Hofman A. . ( 1996; ). A new variant of Creutzfeldt–Jakob disease in the UK. . Lancet 347:, 921–925. [CrossRef] [PubMed]
    [Google Scholar]
  53. Zabel M. D. , Heikenwalder M. , Prinz M. , Arrighi I. , Schwarz P. , Kranich J. , von Teichman A. , Haas K. M. , Zeller N. . & other authors ( 2007; ). Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. . J Immunol 179:, 6144–6152.[PubMed] [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.058958-0
Loading
/content/journal/jgv/10.1099/vir.0.058958-0
Loading

Data & Media loading...

Supplements

Supplementary material 

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error