Abstract
Chronic wasting disease (CWD) is a prion disease affecting cervids. Polymorphisms in the prion protein gene can result in extended survival of CWD-infected animals. However, the impact of polymorphisms on cellular prion protein (PrPC) and prion properties is less understood. Previously, we characterized the effects of a polymorphism at codon 116 (A>G) of the white-tailed deer (WTD) prion protein and determined that it destabilizes PrPC structure. Comparing CWD isolates from WTD expressing homozygous wild-type (116AA) or heterozygous (116AG) PrP, we found that 116AG-prions were conformationally less stable, more sensitive to proteases, with lower seeding activity in cell-free conversion and reduced infectivity. Here, we aimed to understand CWD strain emergence and adaptation. We show that the WTD-116AG isolate contains two different prion strains, distinguished by their host range, biochemical properties, and pathogenesis from WTD-116AA prions (Wisc-1). Serial passages of WTD-116AG prions in tg(CerPrP)1536+/+ mice overexpressing wild-type deer-PrPC revealed two populations of mice with short and long incubation periods, respectively, and remarkably prolonged clinical phase upon inoculation with WTD-116AG prions. Inoculation of serially diluted brain homogenates confirmed the presence of two strains in the 116AG isolate with distinct pathology in the brain. Interestingly, deglycosylation revealed proteinase K-resistant fragments with different electrophoretic mobility in both tg(CerPrP)1536+/+ mice and Syrian golden hamsters infected with WTD-116AG. Infection of tg60 mice expressing deer S96-PrP with 116AG, but not Wisc-1 prions induced clinical disease. On the contrary, bank voles resisted 116AG prions, but not Wisc-1 infection. Our data indicate that two strains co-existed in the WTD-116AG isolate, expanding the variety of CWD prion strains. We argue that the 116AG isolate does not contain Wisc-1 prions, indicating that the presence of 116G-PrPC diverted 116A-PrPC from adopting a Wisc-1 structure. This can have important implications for their possible distinct capacities to cross species barriers into both cervids and non-cervids.
Highlights
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal and infectious neurodegenerative disorders
Chronic wasting disease belongs to the family of prion diseases
This work describes the emergence and characterization of new chronic wasting disease strains related to a polymorphism in the prion protein gene
Summary
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal and infectious neurodegenerative disorders. TSEs include Creutzfeldt-Jakob disease (CJD) in humans [1], bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goat and chronic wasting disease (CWD) in cervids [2]. Despite the absence of a nucleic acid genome, experimental studies have revealed the existence of multiple prion strains that exhibit specific phenotypic traits in a given host species that are transmissible upon passages [1,5]. Properties that differentiate prion strains include incubation time, neuropathological features, PrPSc biochemical properties, host range and tissue tropism [6,7]. All evidence suggests that PrPSc conformation is responsible for the prion strain diversity, especially the tertiary and/or quaternary structures [8]
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