Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein

Author summary Prions cause fatal, transmissible neurodegenerative diseases in animals and humans. They are composed of an infectious, neurotoxic protein (PrP) which replicates by imposing pathogenic conformations on its normal, host-encoded counterpart. Chronic wasting disease (CWD) is a contagious prion disorder threatening increasing numbers of free-ranging and captive North American deer, elk, and moose. While CWD detection in Norwegian reindeer and moose in 2016 marked the advent of disease in Europe, its origins and relationship to North American CWD were initially unclear. Here we show, using mice engineered to express deer or elk PrP, that Norwegian reindeer and moose CWD are caused by novel prion strains with properties distinct from those of North American CWD. We found that selection and propagation of North American and Norwegian CWD strains was controlled by a key amino acid residue in host PrP. We also found that particular Norwegian isolates adapted during their propagation in mice to produce prions with characteristics of the North American strain. Our findings defining the transmission profiles of novel Norwegian prions and their unstable potential to produce adapted strains with improved fitness for contagious transmission have implications for risk analyses and management of emergent European CWD. Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrP(C), by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated the characteristic features of CWD in natural hosts, revealing novel prion strains with disease kinetics, neuropathological profiles, and capacities to infect lympho