IMMUNOPRION

EC contribution

: € 1 960 000

Duration

: 48 months

Starting date

: June 1, 2006

Instrument

: IP

Keywords

: food safety, prion, Transmissible Spongiform Encephalopathies, strain diversity, structural biology, immune system, dendritic cells, complement, data mining.

Project Number

: OOD-CT-2006-023144

Web-site

: -

An important parameter in cross-species infection resides in the degree of molecular homology between the infectious PrPSc and the host prion protein (PrPC). Cell-free systems confirmed the importance of molecular matching for efficient conversion of PrPC into PrPSc. Yet, such in vitro systems parallel only partially the in vivo reality, suggesting that molecular matching is not the unique parameter involved and that additional factors might control the species barrier effect. One of those factors could be the host immune system which is known to react vigorously against xenogeneic PrP and which, in doing so, could reduce the pathogenicity of foreign TSE agents.

Aim and expected results:

The diversity of strains
The strain properties of TSE agents are thought to be enciphered in the structural conformation of the pathogenic form of PrPSc. The project will provide a better definition of prion strains based on their structural and biochemical properties, and will establish relations with their physiological and pathological features. IMMUNOPRION began by producing in vitro synthetic variants of prions because they constitute a reliable and homogenous source, mimicking natural strain diversity. Then, the project will switch to naturally infectious strains in mice, hamsters and sheep. A new imaging technique was set up to identify structures of prion strains, by means of electron cryotomography reaching a four-nanometres resolution, which is not achievable with other methods. Macromolecular prion assemblies will then be analysed in gut follicular dendritic cells (FDCs), which are infected following oral contamination with different prion strains.

The prion contagion IMMUNOPRION aims to acquire a better understanding of the species barrier by carrying out research using rodents, to probe the transmission of TSE agents of animal origin to humans. The tropism of human prions is studied in vivo by means of a dedicated mouse model combining transgenic expressions of PrpC from various origins and the graft of a human immune system. This model allows direct testing on prions of concern, including BSE, CWD (Chronic Wasting Disease, in deer) and other emerging prions strains.

Several lines of evidence support that the immune system plays a key role during the stages of the disease. The project aims to understand how innate immunity, including dendritic cells and complement, mediates interactions with specific strains of prions. There are good reasons to believe that the host immune system is tolerant to all (or most) epitopes except those that are buried in PrPC and are revealed only in transconformed PrPSc. On the basis of PrPsc structure models, peptides buried inside the native PrpC are used in dedicated immunisation protocols to test for their ability to raise antibody responses in mouse models.

Potential applications:

A rational food safety policy cannot be attained without a detailed scientific knowledge of TSE pathogenesis. This is the reason for the importance of mouse models in many of the research activities. The project emphasises immunological parameters since it appears that the immune system is an accomplice of the TSE agent during lympho-invasion. However, it seems that it may also act as a highly sensitive alarm and first line of defence.

The potential development of an acquired immune response against uncovered epitopes of PrPSc may serve as a witness of infection and a tool for early diagnosis. Access to the structural features of various sources of prions will allow for determining the exact cartography of the major strains of prions, and will result in a well-standardised map of prion diversity, which will be used to relate the morphological specificities to the pathogenic profile. This will help European countries to define the highest possible standards of consumer protection, through better safety of food products. Therefore, the results of this research will have a major impact on the development of improved food safety measures.

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