NR AWHD
AU Houston,F.; Charleston,B.
TI Early events in scrapie pathogenesis: the role of phagocytic cells in scrapie susceptible and resistant sheep
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PA-28
PT Konferenz-Poster
AB Resistance and susceptibility to TSEs in sheep is under genetic control, being clearly associated with specific alleles of the gene encoding PrPc. However, the molecular mechanisms by which amino acid substitutions in the PrP protein result in resistance to infection are still unclear. They could have a direct effect of the stability and conformation of the protein, influencing the ease with which it can be converted to PrPsc, or produce indirect functional changes through interactions with other molecules. There is evidence that resistance to TSEs in sheep is associated with a failure to replicate in lymphoid tissues. In susceptible scrapie-infected sheep, PrPsc accumulates on follicular dendritic cells (FDC) in germinal centres of lymphoid tissues. Phagocytic cells, such as myeloid dendritic cells (DC), are thought to play a role in uptake and transport of the scrapie agent from the initial site of infection to FDC in the drainage lymph node, but may also digest and destroy the agent. In resistant sheep, failure to establish infection in lymphoid tissues could result from a) failure of uptake of the scrapie agent by phagocytes, b) more efficient degradation of the agent by phagocytes or c) inability of FDC to support replication. The main aim of this project is to determine whether resistance and susceptibility to scrapie in sheep is determined by the relative efficiency with which phagocytic cells take up and degrade the agent (represented by PrPsc) during the early stages of infection. Initially, we will isolate three different phagocytic cell types (neutrophils, monocyte-derived DC and monocyte-derived macrophages) the blood of scrapie-resistant and susceptible sheep. We will compare their ability to phagocytose and and degrade PrPsc in vitro. The relevance of in vitro findings will be confirmed by lymphatic cannulation of afferent lymphatics draining the site of inoculation in scrapie susceptible and resistant sheep, to identify cell types containing PrPsc. We will also compare the localisation and persistence of PrPsc in the drainage lymph nodes of susceptible and resistant sheep, focussing especially on the association with FDC.
AD Institute for Animal Health, Compton, Newbury, RG20 7NN, UK. E-mail: fiona.houston@bbsrc.ac.uk
SP englisch
PO Italien