Efficient Interspecies Transmission Of Synthetic Prions

Author summary Prions have zoonotic potential as illustrated by the interspecies transmission of bovine spongiform encephalopathy to humans resulting in the emergence of a novel human prion disease. It is unknown if other prion diseases of animals, such as chronic wasting disease, can be transmitted to other species. Models to predict prion zoonotic potential do not exist, in part, due to the lack of understanding of how the structure of PrPSc from one species can convert PrP(C) from another species. Towards this end, we determined that murine synthetic prions, made from minimal components, can efficiently establish infection in hamsters whose transmission history, clinical features, pathology and biochemical properties of PrPSc are consistent with the reisolation of a known prion strain. We conclude that murine synthetic prions can recapitulate interspecies transmission and adaptation allowing for a more detailed mechanistic analysis in a simplified, trackable system.Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrP(C). Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission. To investigate this, we inoculated Syrian hamsters with murine synthetic prions. We found that all the animals inoculated with murine synthetic prions developed prion disease characterized by a striking uniformity of clinical onset and signs of disease. Serial intraspecies transmission resulted in a rapid adaptation to hamsters. During the adaptation process, PrPSc electrophoretic migration, glycoform ratios, conformational stability and biological activity as measured by protein misfolding cyclic amplification remained constant. Interestingly, the strain that emerged shares a strikingly similar transmission history, incubation period, clinical course of disease, pathology and biochemical and biological features of PrPSc with 139H, a hamster adapted form of the murine strain 139A. Combined, these data suggest that murine synthetic prions are comprised of bona fide PrPSc with 139A-like strain properties that efficiently crosses the species barrier and rapidly adapts to hamsters resulting in the emergence of a single strain. The efficiency and specificity of interspecies transmission of murine synthetic prions to hamsters, with relevance to brain derived prions, could be a useful model for identification of structure function relationships between PrPSc and PrP(C) from different species.