Scrapie transmission following exposure through the skin is dependent on follicular dendritic cells in lymphoid tissues

Background : Transmissible spongiform encephalopathies (TSEs) are chronic infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrP Sc, an abnormal isoform of the host prion protein (PrP c). Following peripheral exposure, PrP Sc usually accumulates on follicular dendritic cells (FDCS) in lymphoid tissues before neuroinvasion. Studies in mice have shown that TSE exposure through scarified skin is an effective means of transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of scrapie to the brain as severe combined immunodeficiency (SCID) mice are refractory to infection. Until now, it was not known which components of the immune system are required for efficient scrapie neuroinvasion following skin scarification. Objective : To determine which cells are critical for the transmission of scrapie to the brain following inoculation via the skin. Methods : A chimeric mouse model was used, which had a mismatch in PrP c expression between FDCs and other bone marrow-derived cells within lymphoid tissues. These chimeric mice were challenged with scrapie by skin scarification to allow the separate roles of FDCs and lymphocytes in peripheral scrapie pathogenesis to be determined. Results : We show that mature FDCs are essential for the accumulation of scrapie within lymphoid tissues and the subsequent transmission of infection to the brain following TSE exposure by this route. Furthermore, we show that the accumulation of PrP Sc and infectivity in the spleen is independent of PrP expression by lymphocytes or other bone marrow-derived cells. Conclusion : Following inoculation with scrapie by skin scarification, replication in the spleen and subsequent neuroinvasion is critically dependent upon mature FDCs.