1887

Abstract

Transmissible spongiform encephalopathies are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex: while lymphatic organs typically show early accumulation of prions, and B-cells and follicular dendritic cells are required for efficient neuroinvasion, actual entry into the central nervous system occurs probably via peripheral nerves and may utilize a PrP-dependent mechanism. This study shows that transgenic mice overexpressing PrP undergo rapid and efficient neuroinvasion upon intranerval and footpad inoculation of prions. These mice exhibited deposition of the pathological isoform of the prion protein (PrP) and infectivity in specific portions of the central and peripheral sensory pathways, but almost no splenic PrP accumulation. In contrast, wild-type mice always accumulated splenic PrP, and had widespread deposition of PrP throughout the central nervous system even when prions were injected directly into the sciatic nerve. These results indicate that a lympho-neural sequence of spread occurs in wild-type mice even upon intranerval inoculation, while overexpression of PrP leads to substantial predilection of intranerval over lymphoreticular spread. The rate of transport of infectivity in peripheral nerves was ca. 0·7 mm per day, and prion infectivity titres of sciatic nerves were much higher in a than in wild-type mice, suggesting that overexpression of PrP modulates the capacity for intranerval transport.

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2000-11-01
2019-10-16
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References

  1. Baldauf, E., Beekes, M. & Diringer, H. ( 1997; ). Evidence for an alternative direct route of access for the scrapie agent to the brain bypassing the spinal cord. Journal of General Virology 78, 1187-1197.
    [Google Scholar]
  2. Bassant, M. H., Baron, H., Gumpel, M., Cathala, F. & Court, L. ( 1986; ). Spread of scrapie agent to the central nervous system: study of a rat model. Brain Research 383, 397-401.[CrossRef]
    [Google Scholar]
  3. Beekes, M., McBride, P. A. & Baldauf, E. ( 1998; ). Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. Journal of General Virology 79, 601-607.
    [Google Scholar]
  4. Blättler, T., Brandner, S., Raeber, A. J., Klein, M. A., Voigtländer, T., Weissmann, C. & Aguzzi, A. ( 1997; ). PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389, 69-73.[CrossRef]
    [Google Scholar]
  5. Borchelt, D. R., Koliatsos, V. E., Guarnieri, M., Pardo, C. A., Sisodia, S. S. & Price, D. L. ( 1994; ). Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems. Journal of Biological Chemistry 269, 14711-14714.
    [Google Scholar]
  6. Brandner, S., Raeber, A., Sailer, A., Blättler, T., Fischer, M., Weissmann, C. & Aguzzi, A. ( 1996; ). Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. Proceedings of the National Academy of Sciences, USA 93, 13148-13151.[CrossRef]
    [Google Scholar]
  7. 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. Nature Medicine 5, 1308-1312.[CrossRef]
    [Google Scholar]
  8. Büeler, H. R., Aguzzi, A., Sailer, A., Greiner, R. A., Autenried, P., Aguet, M. & Weissmann, C. ( 1993; ). Mice devoid of PrP are resistant to scrapie. Cell 73, 1339-1347.[CrossRef]
    [Google Scholar]
  9. Cole, S. & Kimberlin, R. H. ( 1985; ). Pathogenesis of mouse scrapie: dynamics of vacuolation in brain and spinal cord after intraperitoneal infection. Neuropathology and Applied Neurobiology 11, 213-227.[CrossRef]
    [Google Scholar]
  10. Eklund, C. M., Kennedy, R. C. & Hadlow, W. J. ( 1967; ). Pathogenesis of scrapie virus infection in the mouse. Journal of Infectious Diseases 117, 15-22.[CrossRef]
    [Google Scholar]
  11. Farquhar, C. F., Dornan, J., Moore, R. C., Somerville, R. A., Tunstall, A. M. & Hope, J. ( 1996; ). Protease-resistant PrP deposition in brain and non-central nervous system tissues of a murine model of bovine spongiform encephalopathy. Journal of General Virology 77, 1941-1946.[CrossRef]
    [Google Scholar]
  12. Fischer, M., Rülicke, T., Raeber, A., Sailer, A., Moser, M., Oesch, B., Brandner, S., Aguzzi, A. & Weissmann, C. (1996). Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO Journal, 1255–1264.
  13. Glatzel, M., Flechsig, E., Navarro, B., Klein, M. A., Paterna, J. C., Bueler, H. & Aguzzi, A. ( 2000; ). Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proceedings of the National Academy of Sciences, USA 97, 442-447.[CrossRef]
    [Google Scholar]
  14. Groschup, M. H., Beekes, M., McBride, P. A., Hardt, M., Hainfellner, J. A. & Budka, H. ( 1999; ). Deposition of disease-associated prion protein involves the peripheral nervous system in experimental scrapie. Acta Neuropathologica 98, 453-457.[CrossRef]
    [Google Scholar]
  15. Hainfellner, J. A. & Budka, H. ( 1999; ). Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies. Acta Neuropathologica 98, 458-460.[CrossRef]
    [Google Scholar]
  16. 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.[CrossRef]
    [Google Scholar]
  17. Kimberlin, R. H. & Walker, C. A. ( 1986; ). Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. Journal of General Virology 67, 255-263.[CrossRef]
    [Google Scholar]
  18. Kimberlin, R. H. & Walker, C. A. ( 1988; ). Incubation periods in six models of intraperitoneally injected scrapie depend mainly on the dynamics of agent replication within the nervous system and not the lymphoreticular system. Journal of General Virology 69, 2953-2960.[CrossRef]
    [Google Scholar]
  19. Kimberlin, R. H. & Walker, C. A. ( 1989; ). The role of the spleen in the neuroinvasion of scrapie in mice. Virus Research 12, 201-211.[CrossRef]
    [Google Scholar]
  20. Kimberlin, R. H., Field, H. J. & Walker, C. A. ( 1983a; ). Pathogenesis of mouse scrapie: evidence for spread of infection from central to peripheral nervous system. Journal of General Virology 64, 713-716.[CrossRef]
    [Google Scholar]
  21. Kimberlin, R. H., Hall, S. M. & Walker, C. A. ( 1983b; ). Pathogenesis of mouse scrapie. Evidence for direct neural spread of infection to the CNS after injection of sciatic nerve. Journal of the Neurological Sciences 61, 315-325.[CrossRef]
    [Google Scholar]
  22. Klein, M. A., Frigg, R., Flechsig, E., Raeber, A. J., Kalinke, U., Bluethmann, H., Bootz, F., Suter, M., Zinkernagel, R. M. & Aguzzi, A. ( 1997; ). A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687-690.
    [Google Scholar]
  23. Klein, M. A., Frigg, R., Raeber, A. J., Flechsig, E., Hegyi, I., Zinkernagel, R. M., Weissman, C. & Aguzzi, A. ( 1998; ). PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Medicine 4, 1429-1433.[CrossRef]
    [Google Scholar]
  24. Korth, C., Stierli, B., Streit, P., Moser, M., Schaller, O., Fischer, R., Schulz-Schaeffer, W., Kretzschmar, H., Raeber, A., Braun, U., Ehrensperger, F., Hornemann, S., Glockshuber, R., Riek, R., Billeter, M., Wuthrich, K. & Oesch, B. ( 1997; ). Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390, 74-77.[CrossRef]
    [Google Scholar]
  25. Lasmezas, C. I., Cesbron, J. Y., Deslys, J. P., Demaimay, R., Adjou, K. T., Rioux, R., Lemaire, C., Locht, C. & Dormont, D. ( 1996; ). Immune system-dependent and -independent replication of the scrapie agent. Journal of Virology 70, 1292-1295.
    [Google Scholar]
  26. Mabbott, N. A., Farquhar, C. F., Brown, K. L. & Bruce, M. E. ( 1998; ). Involvement of the immune system in TSE pathogenesis. Immunology Today 19, 201-203.[CrossRef]
    [Google Scholar]
  27. McEwen, B. S. & Grafstein, B. ( 1968; ). Fast and slow components in axonal transport of protein. Journal of Cell Biology 38, 494-508.[CrossRef]
    [Google Scholar]
  28. Manson, J. C., Jamieson, E., Baybutt, H., Tuzi, N. L., Barron, R., McConnell, I., Somerville, R., Ironside, J., Will, R., Sy, M. S., Melton, D. W., Hope, J. & Bostock, C. ( 1999; ). A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO Journal 18, 6855-6864.[CrossRef]
    [Google Scholar]
  29. 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]
    [Google Scholar]
  30. Prusiner, S. B., Cochran, S. P., Groth, D. F., Downey, D. E., Bowman, K. A. & Martinez, H. M. ( 1982; ). Measurement of the scrapie agent using an incubation time interval assay. Annals of Neurology 11, 353-358.[CrossRef]
    [Google Scholar]
  31. Race, R., Oldstone, M. & Chesebro, B. ( 2000; ). Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. Journal of Virology 74, 828-833.[CrossRef]
    [Google Scholar]
  32. 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. Proceedings of the National Academy of Sciences, USA 96, 15137-15142.[CrossRef]
    [Google Scholar]
  33. Sidman, R. L., Angevine, J. B. & Taber Pierce, E. (1971). Atlas of the Mouse Brain and Spinal Cord, pp. 52–54. Cambridge, MA, USA: Harvard University Press.
  34. Taraboulos, A., Jendroska, K., Serban, D., Yang, S. L., DeArmond, S. J. & Prusiner, S. B. ( 1992; ). Regional mapping of prion proteins in brain. Proceedings of the National Academy of Sciences, USA 89, 7620-7624.[CrossRef]
    [Google Scholar]
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