Role of mononuclear phagocytes in prion pathogenesis
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Bradford, Barry Matthew
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Prion diseases are fatal infectious neurodegenerative disorders hypothesised to be caused by misfolding of the prion protein. Following prion infection, the infectious agent is sequestered to and replicates upon follicular dendritic cells (FDC) within lymphoid follicles prior to neuroinvasion. The mechanism of transport of the prion infectious agent from the site of infection to FDC is unknown. One of the postulated routes of transport is the specific migration of antigen presenting cells (APC) to FDC. APC specifically capture antigenic material and transport and present that material to effector cells and FDC in order to generate an appropriate acquired immune response. FDC reside within the B-cell follicle of secondary lymphoid organs. FDC organise and maintain the B-cell follicular structure by secretion of the chemokine CXCL13 which stimulates chemotactic movement of cells which express the CXCR5 receptor, e.g. B cells. Dendritic cells are specialised APC that are commonly characterised by their expression of CD11c. Transport of the prion infectious agent from the site of infection to FDC was observed to be blocked or severely delayed following depletion of CD11c+ cells. To determine whether CD11c+ cells acquire prions and subsequently deliver them to the FDC, the chemokine receptor CXCR5 was depleted from CD11c+ cells using a conditional transgenic mouse model. These mice were characterised for normal lymphoid organogenesis and monitored for their responses to oral infection with either prions or intestinal helminths. Data in this thesis show that the CD11c-mediated depletion of CXCR5 resulted in a delay in peripheral prion pathogenesis after oral exposure and significantly reduced disease susceptibility. These data suggest that efficient prion transport to FDC requires delivery by APC and is potentially mediated by CXCR5 chemotaxis. Following oral exposure to the intestinal helminth (Trichuris muris) CD11c-mediated depletion of CXCR5 prevented the establishment of a protective TH2 response. As a consequence the mice mounted a TH1-dominated response and were unable to clear the infection. These data also confirm that the effective generation of TH2 responses to oral helminth infection also requires APC localisation to B-cell follicles via CXCR5.