Estimating chronic wasting disease susceptibility in cervids using real-time quaking-induced conversion
Estimating chronic wasting disease susceptibility in cervids using real-time quaking-induced conversion
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DOI：
10.1099/jgv.0.000952
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发表时间：
2017-11-01
影响因子：
3.8
通讯作者：
Richt, Juergen A.
中科院分区：
文献类型：
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作者：
Haley, Nicholas J.;Rielinger, Rachel;Richt, Juergen A.
在哺乳动物中，朊病毒感染的易感性主要由宿主的细胞朊病毒蛋白（PrPC）序列调节。在羊瘙痒症模型中，基于PrPC氨基酸136、154和171在体内和体外建立了易感性分级量表，从而导致全球育种计划以降低羊瘙痒症的患病率。鹿科动物对慢性消耗性疾病（CWD）的耐药性通常表现为具有特定等位基因的个体的患病率降低和/或疾病进展延长：目前，尚未发现赋予鹿科动物绝对耐药性的PrPC等位基因。为了模拟各种自然发生的和假设的鹿科PrPC等位基因在体外的易感性，我们比较了8个不同的CWD分离株的扩增率和淀粉样蛋白延伸效率的重组鹿科PrPC基板使用实时振荡诱导转换。我们假设这些分离株在鹿科动物基质中的体外转化特征与体内易感性相关-允许对自然界中发现的罕见等位基因进行易感性预测。我们还预测，具有多个抗性相关密码子的假设等位基因将比具有单个抗性密码子的天然等位基因对体外转化更具抗性。我们的研究表明，体外转化指标与体内易感性一致，并且具有多个氨基酸取代的等位基因（每个独立影响抗性）不一定对转化抗性有相加作用。重要的是，我们发现天然存在的白尾鹿QGAK底物在评估的那些中表现出最慢的扩增速率，这表明有必要进一步研究该等位基因及其体内抗性。
In mammals, susceptibility to prion infection is primarily modulated by the host's cellular prion protein (PrPC) sequence. In the sheep scrapie model, a graded scale of susceptibility has been established both in vivo and in vitro based on PrPC 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 PrPC allele conferring absolute resistance in cervids has been identified. To model the susceptibility of various naturally occurring and hypothetical cervid PrPC alleles in vitro, we compared the amplification rates and amyloid extension efficiencies of eight distinct CWD isolates in recombinant cervid PrPC substrates using real-time quaking-induced conversion. We hypothesized that the in vitro conversion characteristics of these isolates in cervid substrates would correlate to in vivo 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 in vitro conversion than natural alleles with a single resistant codon. Our studies demonstrate that in vitro conversion metrics align with in vivo 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 in vivo is warranted.