Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion.
Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion.
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DOI：
10.1371/journal.ppat.1004958
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发表时间：
2015-07
期刊：
影响因子：
6.7
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Wang X;McGovern G;Zhang Y;Wang F;Zha L;Jeffrey M;Ma J
朊病毒假说假定传染性海绵状脑病（TSE）的病原体是一种非正统的蛋白质构象为基础的代理。最近成功地产生哺乳动物朊病毒在体外与细菌表达的重组朊病毒蛋白提供了强有力的支持的假设。然而，合成产生的朊病毒（rec-Prion）的致病特性是否概括了天然存在的朊病毒的致病特性仍然没有得到解决。采用终点滴定法，我们表明体外制备的rec-Prion具有约104 LD 50/ μg的感染滴度。此外，腹膜内（i. p.）用rec-Prion接种野生型小鼠引起朊病毒病，接种后平均存活时间为210 - 220天。详细的病理学分析表明，rec-Prion引起的病变包括海绵状改变、疾病特异性朊蛋白积聚（PrP-d）、PrP-d在淋巴和周围神经系统组织中的播散、神经侵袭的途径和机制都是典型的啮齿类朊病毒。我们的研究结果表明，类似于天然存在的朊病毒，rec-Prion具有可滴定的感染性，并能够通过直接脑内攻击以外的途径引起朊病毒疾病。更重要的是，我们的研究结果证实，rec-Prion引起的疾病在病原学和病理学上与自然发生的传染性TSE相同，支持构象改变的蛋白质试剂负责TSE中的传染性的概念。传染性海绵状脑病（transmissible spongiform encephalopathies，TSE）是一组影响人类和动物的传染性神经退行性疾病。朊病毒假说假定朊病毒是负责TSE感染性的基于蛋白质构象的感染因子。朊病毒已在体外合成产生，但仍不清楚合成产生的朊病毒的性质是否与TSE因子的性质相同，以及合成产生的朊病毒引起的疾病是否与天然存在的TSE相同。在这项研究中，我们证明，类似于经典的TSE剂，合成产生的朊病毒具有可滴定的感染性，并能够通过直接脑内接种以外的途径在野生型小鼠中引起朊病毒疾病。更重要的是，我们发现，合成产生的朊病毒引起的病理变化，包括疾病特异性朊病毒蛋白积聚的传播和神经侵袭的途径和机制，都是典型的TSE。这些结果证明了合成产生的朊病毒与TSE中的感染因子的相似性，为朊病毒假说提供了强有力的证据。
The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs) is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion) recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50 / μg. In addition, intraperitoneal (i.p.) inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210 – 220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d) and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs. The transmissible spongiform encephalopathies (TSEs) are a group of infectious neurodegenerative diseases affecting both humans and animals. The prion hypothesis postulates that prions are protein conformation based infectious agents responsible for TSE infectivity. Prions have been synthetically generated in vitro, but it remains unclear whether the properties of synthetically generated prion are the same as those of TSE agents and whether the disease caused by synthetically generated prion is identical to naturally occurring TSEs. In this study, we demonstrated that similar to the classical TSE agents, the synthetically generated prion has a titratable infectivity and is able to cause prion disease in wild-type mice via routes other than direct intra-cerebral inoculation. More importantly, we showed that the synthetically generated prion induced pathological changes, including the dissemination of disease-specific prion protein accumulation and the route and mechanism of neuroinvasion, were all typical of classical TSEs. These results demonstrate the similarity of synthetically generated prion to the infectious agent in TSEs, providing strong evidence supporting the prion hypothesis.
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影响因子：
0.8
作者：
Gonzalez, L.;Pitarch, J. L.;Jeffrey, M.
通讯作者：
Jeffrey, M.
影响因子：
11.4
作者：
HOPE, J;MORTON, LJD;KIMBERLIN, RH
通讯作者：
KIMBERLIN, RH
影响因子：
--
作者：
Choi, Jin-Kyu;Park, Seok-Ju;Kim, Yong-Sun
通讯作者：
Kim, Yong-Sun
影响因子：
6.4
作者：
Crozet, Carole;Lezmi, Stephane;Bencsik, Anna
通讯作者：
Bencsik, Anna
DOI：
10.1107/s0907444912037328
发表时间：
2012-11-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Baral, Pravas Kumar;Wieland, Barbara;James, Michael N. G.
通讯作者：
James, Michael N. G.