Prions hijack tunnelling nanotubes for intercellular spread

Abstract

In variant Creutzfeldt-Jakob disease, prions (PrP(Sc)) 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). Although several means and different cell types have been proposed to have a role, the mechanism of cell-to-cell spreading remains elusive. Tunnelling nanotubes (TNTs) have been identified between cells, both in vitro and in vivo, and may represent a conserved means of cell-to-cell communication. Here we show that TNTs allow transfer of exogenous and endogenous PrP(Sc) between infected and naive neuronal CAD cells. Significantly, transfer of endogenous PrP(Sc) 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 PrP(Sc) spreading in neuronal cells. In addition, we detected the transfer of labelled PrP(Sc) 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 CNS. We therefore propose that TNTs are involved in the spreading of PrP(Sc) within neurons in the CNS and from the peripheral site of entry to the PNS by neuroimmune interactions with dendritic cells.

Spreading of prions from the immune to the peripheral nervous system: a potential implication of dendritic cells

“…Similar results have been obtained within sheep Peyer's patches (Marruchella et al 2007;Chiocchetti et al 2008). The molecular basis of these neuroimmune interfaces between DCs and PNS could implicate a ligand-receptor connection via the muscarinic acetylcholine M2 receptor (Ma et al 2007) or involve TNT (Gousset et al 2009). …”

“…These structures, referred to as tunneling nanotubes (TNT) were shown to facilitate the transport of various cellular components (Rustom et al 2004). Some authors have hypothesized that some small pathogens, such as prions, can be disseminated by these exchange processes (Caughey and Baron 2006;Gousset et al 2009). Several arguments attest of the implication of TNT in prions spreading.…”

“…Several arguments attest of the implication of TNT in prions spreading. (1) Gousset et al demonstrated that BMDCs can transmit prions to primary neurons from the CNS (Gousset et al 2009). (2) Peripheral neurons are particularly competent to generate TNT (Rustom et al 2004).…”

“…Recent studies have demonstrated that the temporary depletion of dendritic cell impaired neuroinvasion following oral inoculation (Raymond et al 2007) and intraperitoneal infection (Cordier-Dirikoc and Chabry 2008). An up-todate in vitro study has shown that infected dendritic cells are able to transmit prions to primary neurons from the CNS by the intermediary of tunneling nanotubes (TNT) (Gousset et al 2009). Previously we have also demonstrated that CD11c-DCs established a lot of contacts with the nerve Wbers inside the mouse Peyer's patches in physiological conditions and following a scrapie challenge (Defaweux et al 2005;Dorban et al 2007a).…”

Tunneling nanotubes: Emerging view of their molecular components and formation mechanisms

“…Another pathogenic protein, the self-propagating aggregated isoform of prion protein PrP Sc , also exploits TNTs as an intercellular route for spreading across cells [22]. PrP C is a GPI-anchored glycoprotein predominantly localized on the outer leaflet of the plasma membrane and endosomal/lysosomal membranes, whereas the pathogenic PrP Sc is located on the luminal side of lysosomal structures.…”