期刊
PLOS PATHOGENS
卷 17, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1009795
关键词
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资金
- Genome Canada
- Alberta Prion Research Institute
- Alberta Agriculture and Forestry through Genome Alberta
- National Sciences and Engineering Research Council of Canada [RGPIN-2019-05309]
- Canada Research Chairs Program
Chronic wasting disease (CWD) is a prion disease affecting cervids, with new strains emerging related to polymorphisms in the prion protein gene. The study shows that different prion strains co-exist within the CWD isolates, impacting infectivity and pathogenesis in wild animals. Understanding the emergence and adaptation of CWD strains is crucial to assessing the risk of infections across species.
Author summary Chronic wasting disease belongs to the family of prion diseases. It is considered the most contagious prion disease and the only one that affects free ranging wildlife. The disease range is expanding in North America and Northern Europe. This work describes the emergence and characterization of new chronic wasting disease strains related to a polymorphism in the prion protein gene. It supports the concept that strains are a dynamic mixture of substrains that can influence and interfere with each other. Because transmission barriers are governed by the compatibility of a particular prion strain with the new host's prion protein, it is critical to understand the emergence and variety of chronic wasting disease strains circulating in wild animals and their ability to infect new host species including humans. 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 (PrP(C)) 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 PrP(C) 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-PrP(C) 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-PrP(C) diverted 116A-PrP(C) 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.
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