1887

Abstract

In mammals, susceptibility to prion infection is primarily modulated by the host’s cellular prion protein (PrP) sequence. In the sheep scrapie model, a graded scale of susceptibility has been established both and based on PrP amino acids 136, 154 and 171, leading to global breeding programmes to reduce the prevalence of scrapie in sheep. Chronic wasting disease (CWD) resistance in cervids is often characterized as decreased prevalence and/or protracted disease progression in individuals with specific alleles; at present, no PrP allele conferring absolute resistance in cervids has been identified. To model the susceptibility of various naturally occurring and hypothetical cervid PrP alleles , we compared the amplification rates and amyloid extension efficiencies of eight distinct CWD isolates in recombinant cervid PrP substrates using real-time quaking-induced conversion. We hypothesized that the conversion characteristics of these isolates in cervid substrates would correlate to susceptibility – permitting susceptibility prediction for the rare alleles found in nature. We also predicted that hypothetical alleles with multiple resistance-associated codons would be more resistant to conversion than natural alleles with a single resistant codon. Our studies demonstrate that conversion metrics align with susceptibility, and that alleles with multiple amino acid substitutions, each influencing resistance independently, do not necessarily contribute additively to conversion resistance. Importantly, we found that the naturally occurring whitetail deer QGAK substrate exhibited the slowest amplification rate among those evaluated, suggesting that further investigation of this allele and its resistance is warranted.

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2017-11-01
2019-12-11
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