Understanding prion strains and species barriers and devising novel diagnostic approaches
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease (CJD) of humans, scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or 'Mad cow disease', chronic wasting disease (CWD) of deer in North America, and others. TSEs are caused by prions (Prusiner, 1982), unique proteinaceous pathogens that appear to propagate without the help of nucleic acid genes. Rather, prions 'replicate' by refolding a normal protein of the host, PrPC, into a pathogenic protein called PrPSc. This exclusive mechanism explains how TSE can be either inherited, acquired through infection, or occur sporadically.
The emergence of BSE in the late 1980s and its subsequent transmission to humans (as variant CJD) has illustrated the grave risks that prions pose to public health. Because incubation time is exceedingly long, most diagnosis methods rely on the immune detection of PrPSc (which is often distinguished from PrPC by its resistance to proteolysis).
A puzzling property of prions is that they occur in different 'strains' within a given host. Prion strains differ in clinical features and disease course, and also in their contagious potential. The current view is that prion strains differ in the three-dimensional folding of PrPSc. Strains greatly complicate the prion problem and increase the dangers presented by TSE, because they are difficult to diagnose and since some strains are 'promiscuous', they jumpwith ease among species. StrainBarrier is an EUfunded consortium that strives to achieve the following: (1) to better understand the structure, biology and epidemiology of prion strains, and (2) to devise accurate methods to distinguish between them.
The added complexity and unpredictability of prion strains is unsettling. New strains can emerge unheralded, with novel clinical presentation and unexpected epidemiological properties.
The BSE case:
Based on its typical neuropathology, clinical signs, and the biochemical properties of associated PrPSc, BSE is a distinct strain. Its emergence in the late 1980s was unpredictable, as no TSE cases had ever been observed in cattle. Disquietingly, BSE is very infectious, transmitting easily among cattle. Even more worrisome is the ease with which it infects other species, thus crossing the so-called 'species barrier'. Upon infection of sheep, BSE establishes a novel and distinct sheep prion strain different from scrapie. While there have been no reports of 'classical' sheep scrapie having infected humans, this may not be true for the more 'promiscuous' sheep BSE.
Problems presented by prion strains:
Prion strains appear to be much more numerous and unstable than once thought. Sheep scrapie may comprise several substrains, such as the newly discovered Nor98. PrPSc denoting 'atypical' and perhaps 'latent' TSE have been detected by veterinary surveillance facilities and in research laboratories. However, in most cases, distinguishing between strains by biochemical tests is not yet possible. In some strains, the properties of PrPSc (e.g. its sensitivity to proteolysis) may preclude its detection by current methods. In summary, prion strains increase the risk of contaminating the food chain and are difficult to diagnose at present.
StrainBarrier's aims are to study fundamental and applied aspects of prion strains and their relationship to the species barrier, to use this knowledge to devise strain-specific diagnostic methodologies and to predict the epidemiological behaviour of strains.
Specific goals are as follows.
These efforts are expected to provide many applicable results. First, the consortium will obtain a better understanding of the natural history of strains, of their infectious potential, and of their epidemiology. This should help health, veterinary and food safety authorities in their efforts to keep the food chain safe. Second, the idiosyncrasy of strains will be better understood and characterised at the molecular, structural and cellular levels. Third, the consortium hopes to create novel, strainspecific monoclonal antibodies and other reagents such as cell-p based bioassays. Last, the knowledge and reagents generated by StrainBarrier will be used to devise novel methodologies to diagnose prion strains.
Several findings and products of this project should be readily applicable. Novel diagnostic methods and reagents (e.g. monoclonal antibodies and cell culture-based bioassays) will find their use in veterinary screening programmes and perhaps in hospitals. Novel epidemiological knowledge will be used by veterinary planning authorities. Reagents and fundamental knowledge will help life science researchers to further their understanding of prions.