Castro Seoane, R.; (2011) Kinetics of prion accumulation in splenic cell types of the lymphoreticular system. Doctoral thesis , UCL (University College London).

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Abstract

Prions accumulate in the lymphoreticular system (LRS) at early stages of prion disease, long before they are detected in the brain. A considerable body of evidence showed that both haematopoietic and stromal cells play a role in prion pathogenesis. However, the contribution of different cell types to the accumulation and the spread of prions in the LRS are not well understood. Taking advantage of a quantitative in-vitro infectivity assay, the Scrapie Cell Assay (SCA) and high density magnetic-activated cell sorting (MACS), we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion disease. The determination of statistically robust infectious titres was achieved by statistical modelling using generalised linear model (GLM) regression. With this novel procedure time-dependent changes of prion titres were monitored in seven distinct splenic cells and identified two cell types that have previously not been associated to prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. Notably, in Prnp-/- mice, e.g. in absence of prion replication, infectivity was detected in macrophages and dendritic cells (DC) after 3 dpi, but not in lymphocytes, underscoring the importance of prion sequestration by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. Reports of the secretion of endosome-derived membrane particles, so called exosomes by immune-competent cells and prion-infected cell lines raised the question whether prion secretion could be a potential route for the spread of prions. We here present the first evidence that MACS-isolated lymphocytes and DCs from scrapie-infected mice secrete prions which are associated to the release of exosome-like membrane particles into the cell culture supernatant ex vivo.

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