1887

Abstract

Peripherally acquired transmissible spongiform encephalopathies display strikingly long incubation periods, during which increasing amounts of prions can be detected in lymphoid tissues. While precise sites of peripheral accumulation have been described, the mechanisms of prion transport from mucosa and skin to lymphoid and nervous tissues remain unknown. Because of unique functional abilities, dendritic cells (DCs) have been suspected to participate in prion pathogenesis. In mice inoculated subcutaneously with scrapie-infected DCs, the incubation was shorter when cells were alive as compared with killed cells, suggesting that DC functions may facilitate prion neuroinvasion. However, early propagation in lymphoid tissues seemed not importantly affected by DC vitality. Mutant () mice that have deficient CCL19/CCL21 expression and DC migration displayed similar infection of secondary lymphoid organs as normal mice, regardless of the route of inoculation and scrapie strain. Under certain conditions of transcutaneous inoculation, the incubation and duration of disease were moderately prolonged in mice. This was not related to a milder neuropathogenesis, since and normal mice were equally susceptible to intracerebral prion challenge. We conclude that peripheral spreading of prions appears poorly dependent on cell migration through the chemokine/receptor system CCL19/CCL21/CCR7, although DCs might be able to help prions reach sites of neuroinvasion.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.82816-0
2007-08-01
2019-11-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/88/8/2353.html?itemId=/content/journal/jgv/10.1099/vir.0.82816-0&mimeType=html&fmt=ahah

References

  1. Aguzzi, A. & Heikenwalder, M. ( 2006; ). Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4, 765–775.[CrossRef]
    [Google Scholar]
  2. Andreoletti, O., Berthon, P., Marc, D., Sarradin, P., Grosclaude, J., vanKeulen, 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.
    [Google Scholar]
  3. Aucouturier, P. & Carnaud, C. ( 2002; ). The immune system and prion diseases: a relationship of complicity and blindness. J Leukoc Biol 72, 1075–1083.
    [Google Scholar]
  4. Aucouturier, P., Geissmann, F., Damotte, D., Saborio, G. P., Meeker, H. C., Kascsak, R., Kascsak, R., Carp, R. I. & Wisniewski, T. ( 2001; ). Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest 108, 703–708.[CrossRef]
    [Google Scholar]
  5. 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]
    [Google Scholar]
  6. Columba-Cabezas, S., Serafini, B., Ambrosini, E. & Aloisi, F. ( 2003; ). Lymphoid chemokines CCL19 and CCL21 are expressed in the central nervous system during experimental autoimmune encephalomyelitis: implications for the maintenance of chronic neuroinflammation. Brain Pathol 13, 38–51.
    [Google Scholar]
  7. Dijkstra, I. M., Hulshof, S., van der Valk, P., Boddeke, H. W. G. M. & Biber, K. ( 2004; ). Cutting edge: activity of human adult microglia in response to CC chemokine ligand 21. J Immunol 172, 2744–2747.[CrossRef]
    [Google Scholar]
  8. Glatzel, M., Heppner, F. L., Albers, K. M. & Aguzzi, A. ( 2001; ). Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31, 25–34.[CrossRef]
    [Google Scholar]
  9. Gunn, M. D., Kyuwa, S., Tam, C., Kakiuchi, T., Matsuzawa, A., Williams, L. T. & Nakano, H. ( 1999; ). Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189, 451–460.[CrossRef]
    [Google Scholar]
  10. Heikenwalder, M., Zeller, N., Seeger, H., Prinz, M., Klohn, P. C., Schwarz, P., Ruddle, N. H., Weissmann, C. & Aguzzi, A. ( 2005; ). Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307, 1107–1110.[CrossRef]
    [Google Scholar]
  11. Henning, G., Ohl, L., Junt, T., Reiterer, P., Brinkmann, V., Nakano, H., Hohenberger, W., Lipp, M. & Forster, R. ( 2001; ). CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med 194, 1875–1881.[CrossRef]
    [Google Scholar]
  12. Huang, F. P., Farquhar, C. F., Mabbott, N. A., Bruce, M. E. & MacPherson, G. G. ( 2002; ). Migrating intestinal dendritic cells transport PrPSc from the gut. J Gen Virol 83, 267–271.
    [Google Scholar]
  13. 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]
  14. Koperek, O., Kovacs, G. G., Ritchie, D., Ironside, J. W., Budka, H. & Wick, G. ( 2002; ). Disease-associated prion protein in vessel walls. Am J Pathol 161, 1979–1984.[CrossRef]
    [Google Scholar]
  15. 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. J Virol 70, 1292–1295.
    [Google Scholar]
  16. Luhr, K. M., Wallin, R. P. A., Ljunggren, H. G., Low, P., Taraboulos, A. & Kristensson, K. ( 2002; ). Processing and degradation of exogenous prion protein by CD11c+ myeloid dendritic cells in vitro. J Virol 76, 12259–12264.[CrossRef]
    [Google Scholar]
  17. Mabbott, N. A. & MacPherson, G. G. ( 2006; ). Prions and their lethal journey to the brain. Nat Rev Microbiol 4, 201–211.[CrossRef]
    [Google Scholar]
  18. Maignien, T., Lasmezas, C. I., Beringue, V., Dormont, D. & Deslys, J. P. ( 1999; ). Pathogenesis of the oral route of infection of mice with scrapie and bovine spongiform encephalopathy agents. J Gen Virol 80, 3035–3042.
    [Google Scholar]
  19. Matzinger, P. ( 2002; ). The danger model: a renewed sense of self. Science 296, 301–305.[CrossRef]
    [Google Scholar]
  20. McKintosh, E., Tabrizi, S. J. & Collinge, J. ( 2003; ). Prion diseases. J Neurovirol 9, 183–193.[CrossRef]
    [Google Scholar]
  21. Medzhitov, R. & Janeway, C. ( 2002; ). Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300.[CrossRef]
    [Google Scholar]
  22. Mohan, J., Bruce, M. E. & Mabbott, N. A. ( 2005; ). Neuroinvasion by scrapie following inoculation via the skin is independent of migratory Langerhans cells. J Virol 79, 1888–1897.[CrossRef]
    [Google Scholar]
  23. Mori, S., Nakano, H., Aritomi, K., Wang, C.-R., Gunn, M. D. & Kakiuchi, T. ( 2001; ). Mice lacking expression of the chemokines CCL21-Ser and CCL19 (plt mice) demonstrate delayed but enhanced T cell immune responses. J Exp Med 193, 207–217.[CrossRef]
    [Google Scholar]
  24. Nakano, H., Mori, S., Yonekawa, H., Nariuchi, H., Matsuzawa, A. & Kakiuchi, T. ( 1998; ). A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood 91, 2886–2895.
    [Google Scholar]
  25. Pashenkov, M., Teleshova, N. & Link, H. ( 2003; ). Inflammation in the central nervous system: the role for dendritic cells. Brain Pathol 13, 23–33.
    [Google Scholar]
  26. Prinz, M., Heikenwalder, M., Junt, T., Schwarz, P., Glatzel, M., Heppner, F. L., Fu, Y. X., Lipp, M. & Aguzzi, A. ( 2003; ). The distance between follicular dendritic cells and nerves controls prion neuroinvasion. Nature 425, 957–962.[CrossRef]
    [Google Scholar]
  27. Prusiner, S. B. ( 2001; ). Shattuck lecture – neurodegenerative diseases and prions. N Engl J Med 344, 1516–1526.[CrossRef]
    [Google Scholar]
  28. 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. J Virol 74, 828–833.[CrossRef]
    [Google Scholar]
  29. Raeber, A. J., Klein, M. A., Frigg, R., Flechsig, E., Aguzzi, A. & Weissmann, C. ( 1999; ). PrP-dependent association of prions with splenic but not circulating lymphocytes of scrapie-infected mice. EMBO J 18, 2702–2706.[CrossRef]
    [Google Scholar]
  30. Randolph, G. J., Angeli, V. & Swartz, M. A. ( 2005; ). Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 5, 617–628.[CrossRef]
    [Google Scholar]
  31. Rappert, A., Biber, K., Nolte, C., Lipp, M., Schubel, A., Lu, B., Gerard, N. P., Gerard, C., Boddeke, H. W. & Kettenmann, H. ( 2002; ). Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl current and chemotaxis in murine microglia. J Immunol 168, 3221–3226.[CrossRef]
    [Google Scholar]
  32. Rosicarelli, B., Serafini, B., Sbriccoli, M., Lu, M., Cardone, F., Pocchiari, M. & Aloisi, F. ( 2005; ). Migration of dendritic cells into the brain in a mouse model of prion disease. J Neuroimmunol 165, 114–120.[CrossRef]
    [Google Scholar]
  33. Rybner-Barnier, C., Jacquemot, C., Cuche, C., Dore, G., Majlessi, L., Gabellec, M. M., Moris, A., Schwartz, O., Di Santo, J. & other authors ( 2006; ). Processing of the bovine spongiform encephalopathy-specific prion protein by dendritic cells. J Virol 80, 4656–4663.[CrossRef]
    [Google Scholar]
  34. Teleshova, N., Frank, I. & Pope, M. ( 2003; ). Immunodeficiency virus exploitation of dendritic cells in the early steps of infection. J Leukoc Biol 74, 683–690.[CrossRef]
    [Google Scholar]
  35. Vassileva, G., Soto, H., Zlotnik, A., Nakano, H., Kakiuchi, T., Hedrick, J. A. & Lira, S. A. ( 1999; ). The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J Exp Med 190, 1183–1188.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.82816-0
Loading
/content/journal/jgv/10.1099/vir.0.82816-0
Loading

Data & Media loading...

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