Follicular Dendritic Cell-Specific Prion Protein (PrP ^c) Expression Alone Is Sufficient to Sustain Prion Infection in the Spleen

Abstract

Prion diseases are characterised by the accumulation of PrP ^Sc, an abnormally folded isoform of the cellular prion protein (PrP ^C), in affected tissues. Following peripheral exposure high levels of prion-specific PrP ^Sc accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the CNS. Expression of PrP ^C is mandatory for cells to sustain prion infection and FDC appear to express high levels. However, whether FDC actively replicate prions or simply acquire them from other infected cells is uncertain. In the attempts to-date to establish the role of FDC in prion pathogenesis it was not possible to dissociate the Prnp expression of FDC from that of the nervous system and all other non-haematopoietic lineages. This is important as FDC may simply acquire prions after synthesis by other infected cells. To establish the role of FDC in prion pathogenesis transgenic mice were created in which PrP ^C expression was specifically “switched on” or “off” only on FDC. We show that PrP ^C-expression only on FDC is sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrP ^C-expression is specifically ablated only on FDC. These data definitively demonstrate that FDC are the essential sites of prion replication in lymphoid tissues. The demonstration that Prnp-ablation only on FDC blocked splenic prion accumulation without apparent consequences for FDC status represents a novel opportunity to prevent neuroinvasion by modulation of PrP ^C expression on FDC.

Author Summary

Prion diseases are infectious neurological disorders and are considered to be caused by an abnormally folded infectious protein termed PrP ^Sc. Soon after infection prions accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the brain where they cause damage to nerve cells. Cells must express the normal cellular prion protein PrP ^C to become infected with prions. However, whether FDC are infected with prions or simply acquire them from other infected cells is unknown. To establish the role of FDC in prion disease PrP ^C expression was specifically “switched on” or “off” only on FDC. We show that PrP ^C-expressing FDC alone are sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrP ^C-expression is switched off only on FDC. These data definitively demonstrate that FDC are the essential sites of prion replication in lymphoid tissues.