In variant Creutzfeldt–Jakob disease, prions (PrPSc) enter the body with contaminated foodstuffs and can spread from the intestinal entry site to the central nervous system (CNS) by intercellular transfer from the lymphoid system to the peripheral nervous system (PNS)1. Although several means2,3,4 and different cell types5,6,7 have been proposed to have a role, the mechanism of cell-to-cell spreading remains elusive. Tunnelling nanotubes (TNTs) have been identified between cells8,9,10,11,12, both in vitro and in vivo10,11,13, and may represent a conserved means of cell-to-cell communication14,15,16. Here we show that TNTs allow transfer of exogenous and endogenous PrPSc between infected and naive neuronal CAD cells17. Significantly, transfer of endogenous PrPSc aggregates was detected exclusively when cells chronically infected with the 139A mouse prion strain were connected to mouse CAD cells by means of TNTs, identifying TNTs as an efficient route for PrPSc spreading in neuronal cells. In addition, we detected the transfer of labelled PrPSc from bone marrow-derived dendritic cells to primary neurons connected through TNTs. Because dendritic cells can interact with peripheral neurons in lymphoid organs, TNT-mediated intercellular transfer would allow neurons to transport prions retrogradely to the CNS1. We therefore propose that TNTs are involved in the spreading of PrPSc within neurons in the CNS and from the peripheral site of entry to the PNS by neuroimmune interactions with dendritic cells.
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We thank P. Lazarow, G. Guizzunti and C. Bowler for critical reading of the manuscript. We thank S. Blanchard and D. Bohl-Delfaud for their help in preparing the GFP–PrPwt-retroviral vector, and P. Casanova and J. Vinatier for technical help. We thank H. Laude, A. F. Hill, P. Cossart and M. Way for their gifts (cells, constructs and reagents). We are grateful for assistance with microscopes and image processing received from the Plate-Forme Imagerie Dynamique at the Pasteur Institut. K.G. is supported by the Pasteur Foundation Fellowship Program, E.S. received a fellowship (2004-07) from the Bavarian Research Foundation (BFS), D.B. received funding from the Fondation Canadienne Louis Pasteur, and Z.M. received funding from Ile-de-France. This work was supported by grants to C.Z. from the European Union (Strainbarrier (FP6 Contract No 023183 (Food)) and from Telethon GGP0414.
The authors declare no competing financial interests.
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Gousset, K., Schiff, E., Langevin, C. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol 11, 328–336 (2009). https://doi.org/10.1038/ncb1841
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