New and distinct chronic wasting disease strains associated with cervid polymorphism at codon 116 of the Prnp gene

PLoS Pathog. 2021 Jul 26;17(7):e1009795. doi: 10.1371/journal.ppat.1009795. eCollection 2021 Jul.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arvicolinae
  • Cricetinae
  • Deer
  • Mesocricetus
  • Mice
  • Polymorphism, Single Nucleotide
  • Prion Proteins / genetics*
  • Wasting Disease, Chronic / genetics*
  • Wasting Disease, Chronic / transmission

Substances

  • Prion Proteins

Grants and funding

This project has been supported by grants from Genome Canada to S.G., H. W. and D.M. (https://www.genomecanada.ca/en) and Alberta Prion Research Institute and Alberta Agriculture and Forestry through Genome Alberta to S.G., H.W. and D.M. (http://genomealberta.ca/); the National Sciences and Engineering Research Council of Canada to S.G (http://www.nserc-crsng.gc.ca/index_eng.asp; Grant RGPIN-2019-05309); the Canada Research Chairs Program to S.G. (http://www.chairschaires.gc.ca/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.