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Third-party-funded project

Generation and spread of prions in an infected organism

Project management at the University of Würzburg:

Participating scientists:

Prion diseases or transmissible spongiform encephalopathies (TSEs) belong to a group of fatal neurodegenerative disorders which include Creutzfeldt-Jakob Disease (CJD) in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle. The occurrence of a new variant Creutzfeldt-Jakob Disease (vCJD) in the United Kingdom and in other countries of Europe has been linked to bovine prions. BSE can be experimentally transmitted to a variety of species, including humans, by the consumption of contaminated beef products. vCJD prions accumulate in lymphoid tissue probably long before neurological symptoms are detected in infected individuals.
After peripheral infection the involvement of the immune system in the transport of the infectious agent seems to be a prerequiste. Collectively, prions accumulate in the follicular dendritic network composed of follicular dendritic cells (FDC) and B-lymphocytes in secondary lymphoid structures. The data, which we have gathered thus far, point to a role of B-lymphocytes in the pathogenesis. Immunodeficient mice which lack mature B-cells are resistant to scrapie after peripheral inoculation. Interestingly, mature B cells are required for prion propagation in lymphoid tissue, not because they themselves harbour or multiply prions, but they are required for maintenance of the FDC network. Thus, PrPC expression on B cells is not necessary for neuroinvasion whereas the normal cellular prion protein (PrPC) which is converted into the abnormal form PrPSc is necessary to sustain the disease and mice deficient in PrPC fail to develop scrapie and do not propagate the infectious agent. The accumulation of prions within the FDC network is similar to the acquisition and retention of antigens in lymphoid organs. In a further attempt we investigated the role of the complement system, a part of the innate arm of the immune system, in peripheral prion pathogenesis. We demonstrated that early components of the complement system facilitate prion transport to the nervous system.
We intend to investigate an experimentally approach addressing the questions about interfering with the spread of the agent in an infected organism and to further dissect the basic cellular and molecular mechansims underlying peripheral prion pathogenesis.

Key words:
    Prion diseases
    immune system

Projekt period: from 07.2001 to 06.2003

Funding institution:
Landeshaushalt Wissenschaftsministerium ,Granting date: 02.07.2001