Rodent models allow BSE discrimination of goat prions and reveal geographical differences in the biological properties of scrapie
Classical scrapie (CS) is a contagious TSE of small ruminants known to circulate in Europe for centuries. More than one TSE strain is responsible for CS, still our ability to identify scrapie strains remains limited, as it has been difficult so far to reconcile data obtained in different rodent models. After the discovery of BSE in two goats, a European-broad effort was undertaken in order to understand the diversity of goat TSE strains and to discriminate BSE from them. Here, we studied goat TSEs by their relative transmission efficiency in different animal models and by the PrPSc type(s) propagated in rodents. Thus, the biological properties of TSE isolates were inferred by their specific interaction with different recipient PrP species rather than by serial passage in a single model. Goat TSE isolates from seven countries and experimental goat-BSE were inoculated in seven models: tg-mice overexpressing sheep/goat ARQ, sheep VRQ, cattle or mouse PrPs; RIII mice and bank voles. The attack rate and the survival time were combined to obtain the ‘transmission efficiency’, a parameter used to build the ‘transmission profiles’ of individual isolates across all models. Goat-BSE and Nor98 showed distinctive transmission profiles, different among them and from all other isolates. Goat-BSE was the only isolate inducing 19kDa PrPSc in all rodent models, while Nor98 was associated with 8kDa PrPSc. CS isolates showed a strong variability of transmission profiles, which was in part explained by their geographical distribution, and could be grouped into four distinct categories. CS isolates in category 1 induced the propagation solely of 21kDa PrPSc, while isolates from CS categories 2-to-4 also induced, to a different extent depending on the model, a 19kDa PrPSc type distinct from BSE. Further investigation of CNS and LRS tissues from a goat herd showed that this phenomenon reflects the selective amplification in rodents of at least two co-existing ‘sub-strain components’, 21kDa and 19kDa, whose relative amount varies with different goat tissues/isolates. Our findings show that BSE can be discriminated from a wide range of biologically and geographically diverse goat TSEs. The geographical variation observed in CS suggests the existence of distinct CS strains, as also supported by the parallel studies by Pirisinu et al. and Marin-Moreno et al. Yet, CS isolates in categories 2-to-4 were mixtures of discrete sub-strains, where it could be envisaged that competition among sub-strains play a role in defining the biological properties of individual isolates and their evolution.