Skip to main content
Log in

Role of cell death in the propagation of PrPSc in immune cells

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

A number of studies have suggested that macrophages, dendritic cells, and follicular dendritic cells play an important role in the propagation of PrPSc. Both accumulation and proteolysis of PrPSc have been demonstrated in peripheral macrophages. Macrophages may act as reservoirs for PrPSc particles if the cells die during transient PrPSc propagation. However, whether cell death plays a role in PrPSc propagation in macrophages remains unclear. In this study, we investigated the possibility of propagation and transmission of PrPSc between dead immune cells and living neural cells. We found that under specific conditions, transient PrPSc propagation occurs in dead cells, indicating that interaction between PrPC and PrPSc on plasma membrane lipid rafts might be important for PrPSc propagation. Co-culturing of killed donor PrPSc-infected macrophages with recipient N2a-3 neuroblastoma cells accelerated PrPSc transmission. Our results suggest that cell death may play an important role in PrPSc propagation, whereas transient PrPSc propagation in macrophages has little effect on PrPSc transmission.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Aguzzi A (2003) Prions and the immune system: a journey through gut, spleen, and nerves. Adv Immunol 81:123–171

    Article  CAS  PubMed  Google Scholar 

  2. Andréoletti Q, Berthon P, Marc D, Sarradin P, Grosclaude JJ, van Keulen L, Schelcher F, Elsen JM, 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 

  3. Beringue V, Couvreur P, Dormont D (2002) Involvement of macrophages in the pathogenesis of transmissible spongiform encephalopathies. Dev Immunol 9:19–27

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Bruce ME, Brown KL, Mabbot NA, Farquhar CF, Jeffrey M (2000) Follicular dendritic cells in TSE pathogenesis. Immunol Today 21:442–446

    Article  CAS  PubMed  Google Scholar 

  5. Campana V, Sarnataro D, Zurzolo C (2005) The highways and byways of prion protein trafficking. Trends Cell Biol 15:102–111

    Article  CAS  PubMed  Google Scholar 

  6. Chandler RL, Fisher J (1963) Experimental transmission of scrapie to rats. Lancet 2:1165

    Article  Google Scholar 

  7. Collinge JJ (2001) Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24:519–550

    Article  CAS  PubMed  Google Scholar 

  8. DebBurman SK, Raymond GJ, Caughey B, Lindquist S (1997) Chaperone-supervised conversion of prion protein to its protease-resistant form. Proc Natl Acad Sci USA 94:13938–13943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Deleault NR, Lucassen RW, Supattapone S (2003) RNA molecules stimulate prion protein conversion. Nature 425:717–720

    Article  CAS  PubMed  Google Scholar 

  10. Dubowchik GM, Padilla L, Edinger K, Firestone RA (1994) Reversal of doxorubicin resistance and catalytic neutralization of lysosomes by a lipophilic imidazole. Biochim Biophys Acta 1191:103–108

    Article  CAS  PubMed  Google Scholar 

  11. Elhelaly AE, Inoshima Y, Ishiguro N (2012) Alteration of cell responses to PrPSc in prolonged cell culture and its effect on transmission of PrPSc to neural cells. Arch Virol 158:651–658

    Article  PubMed  Google Scholar 

  12. Elhelaly AE, Inoshima Y, Ishiguro N (2013) Characterization of early transient accumulation of PrPSc in immune cells. Biochem Biophys Res Commun 439:340–345

    Article  CAS  PubMed  Google Scholar 

  13. Haïk S, Faucheux BA, Hauw JJ (2004) Brain targeting through the autonomous nervous system: lessons from prion diseases. Trends Mol Med 10:107–112

    Article  PubMed  Google Scholar 

  14. Herrmann LM, Cheevers WP, Davis WC, Knowles DP, O’Rourke KI (2003) CD21-positive follicular dendritic cells: a possible source of PrPSc in lymph node macrophages of scrapie-infected sheep. Am J Pathol 162:1075–1081

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kim CL, Umetani A, Matsui T, Ishiguro N, Shinagawa M, Horiuchi M (2004) Antigenic characterization of an abnormal isoform of prion protein using a new diverse panel of monoclonal antibodies. Virology 320:40–51

    Article  CAS  PubMed  Google Scholar 

  16. Kujala P, Raymond CR, Romeijn M, Godsave SF, van Kasteren SL, Wille H, Prusiner SB, Mabbott NA, Peters PJ (2011) Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog 7:e1002449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Prusiner SB (1991) Molecular biology of prion diseases. Science 252:1515–1522

    Article  CAS  PubMed  Google Scholar 

  18. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411:810–813

    Article  CAS  PubMed  Google Scholar 

  20. Sassa Y, Yamasaki T, Horiuchi M, Inoshima Y, Ishiguro N (2010) The effects of lysosomal and proteasomal inhibitors on abnormal forms of prion protein degradation in murine macrophages. Microbiol Immunol 54:763–768

    Article  CAS  PubMed  Google Scholar 

  21. Shinagawa M, Munekata E, Doi S, Takahashi K, Goto H, Sato G (1986) Immunoreactivity of a synthetic pentadecapeptide corresponding to the N-terminal region of the scrapie prion protein. J Gen Virol 67:1745–1750

    Article  CAS  PubMed  Google Scholar 

  22. Tanaka Y, Sadaike T, Inoshima Y, Ishiguro N (2012) Characterization of PrPSc transmission from immune cells to neuronal cells. Cell Immunol 279:145–150

    Article  CAS  PubMed  Google Scholar 

  23. Taraboulos A, Scott M, Semenov A, Avrahami D, Laszlo LL, Prusiner SB (1995) Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J Cell Biol 129:121–132

    Article  CAS  PubMed  Google Scholar 

  24. Uryu M, Karino A, Kamihara Y, Horiuchi M (2007) Characterization of prion susceptibility in Neuro2a mouse neuroblastoma cell subclones. Microbiol Immunol 51:661–669

    Article  CAS  PubMed  Google Scholar 

  25. Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J (2001) Tissue distribution of protease resistant prion protein in variant Creutzfeldt–Jakob disease using a highly sensitive immunoblotting assay. Lancet 358:171–180

    Article  CAS  PubMed  Google Scholar 

  26. Wong C, Xiong LW, Horiuchi M, Raymond L, Wehrly K, Chesebro B, Caughey B (2001) Sulfated glycans and elevated temperature stimulate PrPSc-dependent cell-free formation of protease-resistant prion protein. EMBO J 20:377–386

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant (22380165) from the Ministry of Education, Culture, Sports, Science, and Technology and by a grant from the Ministry of Health, Labour, and Welfare of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Naotaka Ishiguro.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahashi, K., Inoshima, Y. & Ishiguro, N. Role of cell death in the propagation of PrPSc in immune cells. Arch Virol 160, 693–699 (2015). https://doi.org/10.1007/s00705-014-2320-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-014-2320-z

Keywords

Navigation