Investigating the role of follicular dendritic cells in TSE agent neuroinvasion from lymphoid tissues

Transmissible spongiform encephalophathies (TSEs) are fatal neurodegenerative diseases. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep and goats. Most natural transmissions of TSE agents occur by peripheral exposure, eg: ingestion (oral). After inoculation, TSE agents usually accumulate upon follicular dendritic cells (FDCs) in lymphoid tissues before they infect the central nervous system (CNS). FDCs are critical for the spread of disease to the CNS (neuroinvasion) as in their absence agent accumulation in lymphoid tissues and neuroinvasion are impaired. The nature of the TSE agent is not known, but an abnormal isoform (PrPSc) of the host cellular prion protein (PrPc), co-purifies with infectivity. Indeed, PrPSc is detected upon FDCs after inoculation with some TSE agents. Cells must express cellular PrPc to replicate TSE agents. Although PrPc is detected on FDCs in uninfected mice, it is not known if FDCs express PrPc and replicate TSE agents. Treatments that deplete FDCs reduce susceptibility to TSE agents. Thus, a thorough understanding of the involvement of FDCs in TSE pathogenesis is important when determining risk, and designing therapeutic strategies against peripherally-acquired TSEs. FDCs trap and retain native antigens on their surfaces for long durations. Thus their involvement in TSE pathogenesis may be to trap TSE agents released from infected cells and mediate their transfer to neurones. Many cell types secrete exosomes enriched in cell-specific protein. FDCs can bind exosomes, and as a consequence display proteins on their surfaces that they do not express at the mRNA level. PrPc and PrPSc can be released in exosomes, providing a mechanism by which FDCs might acquire PrPc and TSE agents from other infected cells. Experiments have excluded bone marrow-derived cells as major providers of the PrPc and PrPSc detected on FDCs. However, the involvement of non-haematopoietic cells (eg: muscle, endothelial, epithelial or nerve cells) cannot be excluded. We will use novel approaches to provide important information on FDC biology and their involvement in TSE pathogenesis. In particular we will address the following objectives: O-1: Do FDCs express PrPc or acquire it from other host cells? O-2: Do FDCs replicate TSE agents, or acquire them from other infected host cells? Increased understanding of the FDCs involvement in TSE pathogenesis may aid the development of therapeutic strategies.

Transmissible spongiform encephalophathies (TSEs) are fatal neurodegenerative diseases. Examples include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in mule deer and elk, and scrapie in sheep and goats. Most natural transmissions of TSE agents occur by peripheral exposure, eg: ingestion (oral). After inoculation, TSE agents usually accumulate upon follicular dendritic cells (FDCs) in lymphoid tissues before they infect the central nervous system (CNS). FDCs are critical for the spread of disease to the CNS (neuroinvasion) as in their absence agent accumulation in lymphoid tissues and neuroinvasion are impaired. The nature of the TSE agent is not known, but an abnormal isoform (PrPSc) of the host cellular prion protein (PrPc), co-purifies with infectivity. Indeed, PrPSc is detected upon FDCs after inoculation with some TSE agents. Cells must express cellular PrPc to replicate TSE agents. Although PrPc is detected on FDCs in uninfected mice, it is not known if FDCs express PrPc and replicate TSE agents. Treatments that deplete FDCs reduce susceptibility to TSE agents. Thus, a thorough understanding of the involvement of FDCs in TSE pathogenesis is important when determining risk, and designing therapeutic strategies against peripherally-acquired TSEs. FDCs trap and retain native antigens on their surfaces for long durations. Thus their involvement in TSE pathogenesis may be to trap TSE agents released from infected cells and mediate their transfer to neurones. Many cell types secrete exosomes enriched in cell-specific protein. FDCs can bind exosomes, and as a consequence display proteins on their surfaces that they do not express at the mRNA level. PrPc and PrPSc can be released in exosomes, providing a mechanism by which FDCs might acquire PrPc and TSE agents from other infected cells. Experiments have excluded bone marrow-derived cells as major providers of the PrPc and PrPSc detected on FDCs. However, the involvement of non-haematopoietic cells (eg: muscle, endothelial, epithelial or nerve cells) cannot be excluded. We will use novel approaches to provide important information on FDC biology and their involvement in TSE pathogenesis. In particular we will address the following objectives: O-1: Do FDCs express PrPc or acquire it from other host cells? O-2: Do FDCs replicate TSE agents, or acquire them from other infected host cells? Increased understanding of the FDCs involvement in TSE pathogenesis may aid the development of therapeutic strategies.