Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases.
Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases.
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DOI：
10.1371/journal.ppat.1003219
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Agrimi U
中科院分区：
文献类型：
--
作者：
Di Bari MA;Nonno R;Castilla J;D'Agostino C;Pirisinu L;Riccardi G;Conte M;Richt J;Kunkle R;Langeveld J;Vaccari G;Agrimi U
为了评估银行田鼠慢性消耗病（CWD）的易感性，我们接种田鼠携带异亮氨酸或蛋氨酸密码子109（Bv 109 I和Bv 109 M，分别）与CWD分离物从麋鹿，骡鹿和白尾鹿。观察到有效传播率（100%），平均存活时间为156至281天接种后。在Bv 109 I中的后续传代使我们能够从所有CWD来源中分离出相同的田鼠适应CWD菌株（Bv 109 ICWD），其典型特征是前所未有的25-28天的短孵育时间和约35天的存活时间。Bv 109 ICWD的神经病理学和分子生物学特征表明，脑内接种后不到一个月，哺乳动物朊病毒病的典型特征全部重现。Bv 109 ICWD的特征是在相同的脑区中有轻度和离散的海绵状组织分布和相对较低水平的蛋白酶抗性PrPSc（PrPres）。尽管PrPres水平较低且其积累时间较短，但终点滴定显示，来自终末期患病田鼠的脑中含有高达108.4 i.c. ID 50感染单位/克。Bv 109 ICWD通过蛋白质错误折叠循环扩增（PMCA）有效复制，并且在体外忠实地产生感染性，如通过在Bv 109 I中重新分离时保留特有的Bv 109 ICWD菌株特征所证明的。总体而言，我们提供的证据表明，相同的CWD菌株中分离Bv 109 I从三个鹿科物种。Bv 109 ICWD表现出独特的“毒力”、低PrPres积累和高感染性的特征，从而为提高对PrPSc、神经变性和感染性之间关系的基础知识提供了极好的机会。慢性消耗性疾病（CWD）是一种朊病毒疾病，影响自由放养和圈养的鹿科动物，并在美国和加拿大日益扩大。动物模型在朊病毒疾病的研究中至关重要，但长期以来，由于其对野生型小鼠的传播效率非常低，因此慢性消耗病的发展一直受到阻碍。在高表达鹿PrP基因的转基因小鼠的建立方面取得了重大进展。在这里，我们表明，银行田鼠（Myodes glareolus），一种野生啮齿动物物种，我们证明是容易受到许多动物和人类朊病毒疾病，也非常容易受到CWD从麋鹿，黑尾鹿和白尾鹿。CWD适应银行田鼠导致分离的朊病毒株具有独特的特征：前所未有的短潜伏期和存活时间，分别为25-28和1.35天，与其他田鼠适应朊病毒株相比，PrPSc水平低，感染滴度高。这些功能都忠实地保持在该菌株在体外产生蛋白质错误折叠循环扩增。朊病毒疾病模型的开发，导致疾病在不到一个月的时间内积累高感染滴度，但低PrPSc水平，代表了一个重要的工具，研究朊病毒疾病中PrPSc，神经变性和感染性之间的关系尚不清楚。
In order to assess the susceptibility of bank voles to chronic wasting disease (CWD), we inoculated voles carrying isoleucine or methionine at codon 109 (Bv109I and Bv109M, respectively) with CWD isolates from elk, mule deer and white-tailed deer. Efficient transmission rate (100%) was observed with mean survival times ranging from 156 to 281 days post inoculation. Subsequent passages in Bv109I allowed us to isolate from all CWD sources the same vole-adapted CWD strain (Bv109ICWD), typified by unprecedented short incubation times of 25–28 days and survival times of ∼35 days. Neuropathological and molecular characterisation of Bv109ICWD showed that the classical features of mammalian prion diseases were all recapitulated in less than one month after intracerebral inoculation. Bv109ICWD was characterised by a mild and discrete distribution of spongiosis and relatively low levels of protease-resistant PrPSc (PrPres) in the same brain regions. Despite the low PrPres levels and the short time lapse available for its accumulation, end-point titration revealed that brains from terminally-ill voles contained up to 108,4 i.c. ID50 infectious units per gram. Bv109ICWD was efficiently replicated by protein misfolding cyclic amplification (PMCA) and the infectivity faithfully generated in vitro, as demonstrated by the preservation of the peculiar Bv109ICWD strain features on re-isolation in Bv109I. Overall, we provide evidence that the same CWD strain was isolated in Bv109I from the three-cervid species. Bv109ICWD showed unique characteristics of “virulence”, low PrPres accumulation and high infectivity, thus providing exceptional opportunities to improve basic knowledge of the relationship between PrPSc, neurodegeneration and infectivity. Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids and is expanding increasingly in the USA and Canada. Animal models are of key importance in the study of prion diseases but their development for CWD has long been hampered by its very inefficient transmission to wild-type mice. Significant progress was made following the generation of transgenic mice over-expressing cervid PrP. Here we show that the bank vole (Myodes glareolus), a wild rodent species that we demonstrated to be susceptible to many animal and human prion diseases, is also very susceptible to CWD from elk, mule deer and white-tailed deer. Adaptation of CWD to bank vole led to the isolation of a prion strain with peculiar characteristics: unprecedented short incubation and survival times, respectively of 25–28 and ∼35 days, low PrPSc levels compared with other vole-adapted prion strains and high infectious titre. These features were all faithfully maintained upon the generation of this strain in vitro by protein misfolding cyclic amplification. The development of a model for prion diseases that led to disease in less than one month accumulating high infectious titres but low PrPSc levels, represents a significant tool for investigating the still unclear relationship between PrPSc, neurodegeneration and infectivity in prion diseases.
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影响因子：
5.4
作者：
Heisey, Dennis M.;Mickelsen, Natalie A.;Barr, Daniel J.
通讯作者：
Barr, Daniel J.
DOI：
10.1016/j.jchromb.2006.08.016
发表时间：
2007-04-15
影响因子：
3
作者：
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影响因子：
6.7
作者：
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通讯作者：
Lipp HP
影响因子：
2.4
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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