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

PLoS Pathogens

Mick Bailey¹  Klaus Rajewsky²  Jean C. Manson³  Barry M. Bradford³  John Hopkins³  Laura McCulloch³  Karen L. Brown³  Neil A. Mabbott³ 

[1] Division of Veterinary Pathology, Infection and Immunity, School of Clinical Veterinary Science, University of Bristol, Avon, United Kingdom;Program in Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts, United States of America;The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Midlothian, United Kingdom

关键词: Spleen;    Animal prion diseases;    B cells;    Mouse models;    Prion diseases;    Scrapie;    Immune complex;    Macrophages;   

DOI  :  10.1371/journal.ppat.1002402

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Prion diseases are characterised by the accumulation of PrPSc, an abnormally folded isoform of the cellular prion protein (PrPC), in affected tissues. Following peripheral exposure high levels of prion-specific PrPSc accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the CNS. Expression of PrPC 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 PrPC expression was specifically “switched on” or “off” only on FDC. We show that PrPC-expression only on FDC is sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrPC-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 PrPC expression on FDC.

【 授权许可】

CC BY