Investigating the role of follicular dendritic cells in TSE agent neuroinvasion from lymphoid tissues
Lead Research Organisation:
Roslin Institute
Department Name: UNLISTED
Abstract
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.
Technical Summary
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.
Organisations
Publications
Glaysher BR
(2007)
Isolated lymphoid follicle maturation induces the development of follicular dendritic cells.
in Immunology
McCulloch, L
(2008)
The role of follicular dendritic cells in scrapie pathogenesis
in Joint Funders TSE Workshop
MAbbott, N
(2008)
Determining the influence of the host immune system on TSE pathogenesis
in EBRC Launch
Mucculloch, L.
(2009)
Determining the role of follicular dendritic cells in scrapie pathogenesis
in Prion 2009
Brown KL
(2009)
The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice.
in Journal of immunology (Baltimore, Md. : 1950)
McGovern, G.
(2009)
Scrapie alters immune complex trapping and the maturation cycle of follicular dendritic cells
in Prion 2009
McGovern G
(2009)
Scrapie affects the maturation cycle and immune complex trapping by follicular dendritic cells in mice.
in PloS one
McCulloch, L.
(2010)
Investigating the role of follicular dendritic cells (FDCs) in scrapie pathogenesis
in 14th International Congress of Immunology
McCulloch L
(2011)
Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen.
in PLoS pathogens
Kujala P
(2011)
Prion uptake in the gut: identification of the first uptake and replication sites.
in PLoS pathogens
Description | -Demonstrated for the first time that follicular dendritic cells alone are the important sites of TSE agent accumulation in lymphoid tissues. -Demonstrated for the first time that the specific ablation of PrPC expression only on FDC blocked TSE agent accumulation in lymphoid tissues and subsequent neuroinvasion. -Demonstrated that the effects of aging on FDC dramatically reduce susceptibility to peripherally-acquired prion infections. |
Exploitation Route | Our data demonstrate that PrPC-expressing FDC are the essential sites of prion accumulation in lymphoid tissues. Indeed, PrPC-expression on FDC alone was sufficient to sustain high levels of PrPSc accumulation. In contrast, the specific ablation of PrPC expression on FDC blocked prion accumulation. Although FDC have the capacity to bind exosomes and immune complexes which may contain PrPSc, this finding clearly demonstrates that FDC do not simply passively acquire prions from other infected cell populations such as neurones. Previous data show treatments which impair the status or immune complex-trapping function of FDC reduce prion susceptibility after peripheral exposure. The demonstration that Prnp-ablation only on FDC blocked splenic prion accumulation without apparent consequences for FDC status represents a novel opportunity to prevent neuroinvasion by modulation of PrPC expression on FDC. |
Sectors | Agriculture, Food and Drink,Healthcare |
Description | Our data showing that the effects of aging on follicular dendritic cells dramatically reduce susceptibility to peripherally-acquired prion infections were discussed at the November 2009 meeting of the UK Spongiform Encephalopathies Advisory Committee (for minutes see http://www.seac.gov.uk/papers/103-2.pdf) and received significant media interest (eg: BBC website http://news.bbc.co.uk/1/hi/scotland/edinburgh_and_east/8307551.stm). |
First Year Of Impact | 2009 |
Sector | Agriculture, Food and Drink,Healthcare |
Description | Keeping bugs at Bay: a Public Engagement Activity at the Roslin Institute 2014 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | This activity aims to teach people how the immune system fights bugs. |
Year(s) Of Engagement Activity | 2014 |
Description | Keeping bugs at Bay: a Public Engagement Activity at the Royal Highland Show 2015 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | This activity aims to teach people how the immune system fights bugs. |
Year(s) Of Engagement Activity | 2015 |
Description | Protein sheds insight into spread of vCJD to the brain |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press release describing our study published in PLoS Pathogens: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002402 |
Year(s) Of Engagement Activity | 2011 |
URL | http://www.bbc.co.uk/news/uk-scotland-edinburgh-east-fife-15988283 |