Role of dendritic cells in scrapie pathogenesis

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Transmissible spongiform encephalopathies (TSEs) are infectious, fatal, neurodegenerative diseases. Following peripheral infection (eg: ingestion), infectivity usually accumulates in lymhoid tissues before spreading to the CNS. In mice, follicular dendritic cells (FDCs) expressing the host prion protein (PrP) are essential for scrapie agent accumulation in lymphoid tissues. The accumulation of the scrapie agent on FDCs is critical for the efficient spread of infection to the brain. However, it is not known whether FDCs themselves replicate the scrapie agent, or simply accumulate infectivity produced by other cells. A transgenic mouse model will therefore be created in which PrP is expressed exclusively by FDCs. Expression of cre-recombinase (Cre) under the action of cell-specific promoters can induce or delete the expression of a target gene in specific cell populations. The mouse complement receptor type 2 gene (Cr2/CD21) is expressed by FDCs and B lymphocytes and the promoter has been extensively characterised. In mice where Cre expression is driven by the CD21 promoter (CD21-cre mice) strong expression of Cre occurs in FDCs and deletes the expression of `floxed¿ genes in these cells. The CD21-cre mouse line will then be crossed with floxed-PrP mouse lines to produce lines of mice in which PrP expression can be switched on or off, only in FDCs (Cre expression by B lymphocytes will be eliminated by ?-irradiation and grafting with Cre-deficient bone marrow). The cellular association of PrP will then be characterised in these mice by various techniques including: in situ hybridisation, immunoblotting, immunocytochemistry and FACs analysis. Subsequently, the mice will then be challenged with scrapie by various peripheral inoculation routes to determine the precise role of FDCs in the accumulation of scrapie in lymphoid tissues.

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