Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein.
Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein.
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DOI：
10.1371/journal.ppat.1009748
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Telling GC
中科院分区：
文献类型：
--
作者：
Bian J;Kim S;Kane SJ;Crowell J;Sun JL;Christiansen J;Saijo E;Moreno JA;DiLisio J;Burnett E;Pritzkow S;Gorski D;Soto C;Kreeger TJ;Balachandran A;Mitchell G;Miller MW;Nonno R;Vikøren T;Våge J;Madslien K;Tran L;Vuong TT;Benestad SL;Telling GC
Prion是一种感染性蛋白质，会导致动物和人类致命的、可传染的神经退行性疾病。复制涉及到宿主编码的蛋白PrPC通过其感染性构象PrPSc的模板导向的重折叠。1967年在圈养的科罗拉多州鹿身上发现这种疾病后，慢性消耗病(CWD)的不可控传染性传播导致自由放牧和圈养北美(NA)鹿群的地理范围扩大。大约50年后，在自由放养的挪威驯鹿和驼鹿身上发现了PrPSc，这标志着欧洲第一个CWD的迹象。为了评估这些新出现的NO PrP的性质，并将它们与NA CWD进行比较，我们使用了表达PrP的转基因(TG)和基因靶向(GT)小鼠，表达PrP的基因带有谷氨酰胺(Q)或谷氨酸(E)残基226位，这是野生型鹿PrP的一个变异，影响了NA鹿和麋鹿对Prion品系的选择。将没有驼鹿和驯鹿的普恩病毒传递给TG和GT小鼠，概括了自然宿主中CWD的特征，揭示了具有疾病动力学、神经病理学特征以及感染淋巴组织和培养细胞的能力的新的普恩病毒株，这些不同于导致NA CWD的病毒。为了支持品系变异，包括出现的无驼鹿和驯鹿CWD的PrPSc构象受制于与已建立的NA CWD不同的第226位变异所施加的选择效应。在表达E基因226的小鼠中传递特定的驼鹿CWD蛋白导致了一种动力学优化的构象的选择，随后的传递揭示了与NA CWD一致的性质。这些发现说明了在不稳定的NO普恩的繁殖过程中，适应性增强的菌株构象选择的潜力。它们的传染性传播潜力对欧洲新出现的CWD的风险分析和管理具有重要意义。最后，我们发现，表达生理控制的PrP水平的GT小鼠重现了自然发生的CWD菌株的淋巴特性，与过度表达TG的小鼠相比，它们对新出现的NO驯鹿普恩的易感性有所提高。这些发现强调了GT模型在探索在自然病毒传播过程中外周隔室菌株选择的机制和影响方面的改进优势。Prion在动物和人类中会导致致命的、可传染的神经退行性疾病。它们由一种具有感染性的神经毒性蛋白(PrP)组成，该蛋白通过将致病构象强加于其正常的宿主编码的对应物而进行复制。慢性消耗性疾病(CWD)是一种传染性的普恩疾病，威胁着越来越多的自由放养和圈养的北美鹿、麋鹿和驼鹿。虽然2016年在挪威驯鹿和驼鹿身上检测到CWD标志着疾病在欧洲的出现，但它的起源及其与北美CWD的关系最初尚不清楚。在这里，我们使用表达鹿或麋鹿PrP的基因工程小鼠表明，挪威驯鹿和驼鹿CWD是由具有与北美CWD不同特性的新型普恩病毒株引起的。我们发现北美和挪威CWD菌株的选择和繁殖是由宿主PrP上的一个关键氨基酸残基控制的。我们还发现，特定的挪威分离株在小鼠体内繁殖过程中适应，产生具有北美株特征的普恩病毒。我们的发现定义了新的挪威普恩病毒的传播特征，以及它们产生适应菌株的不稳定潜力，这些菌株具有更好的传染性传播适应性，这对欧洲新出现的慢性萎缩性脑病的风险分析和管理具有重要意义。
Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated the characteristic features of CWD in natural hosts, revealing novel prion strains with disease kinetics, neuropathological profiles, and capacities to infect lymphoid tissues and cultured cells that were distinct from those causing NA CWD. In support of strain variation, PrPSc conformers comprising emergent NO moose and reindeer CWD were subject to selective effects imposed by variation at residue 226 that were different from those controlling established NA CWD. Transmission of particular NO moose CWD prions in mice expressing E at 226 resulted in selection of a kinetically optimized conformer, subsequent transmission of which revealed properties consistent with NA CWD. These findings illustrate the potential for adaptive selection of strain conformers with improved fitness during propagation of unstable NO prions. Their potential for contagious transmission has implications for risk analyses and management of emergent European CWD. Finally, we found that Gt mice expressing physiologically controlled PrP levels recapitulated the lymphotropic properties of naturally occurring CWD strains resulting in improved susceptibilities to emergent NO reindeer prions compared with over-expressing Tg counterparts. These findings underscore the refined advantages of Gt models for exploring the mechanisms and impacts of strain selection in peripheral compartments during natural prion transmission. Prions cause fatal, transmissible neurodegenerative diseases in animals and humans. They are composed of an infectious, neurotoxic protein (PrP) which replicates by imposing pathogenic conformations on its normal, host-encoded counterpart. Chronic wasting disease (CWD) is a contagious prion disorder threatening increasing numbers of free-ranging and captive North American deer, elk, and moose. While CWD detection in Norwegian reindeer and moose in 2016 marked the advent of disease in Europe, its origins and relationship to North American CWD were initially unclear. Here we show, using mice engineered to express deer or elk PrP, that Norwegian reindeer and moose CWD are caused by novel prion strains with properties distinct from those of North American CWD. We found that selection and propagation of North American and Norwegian CWD strains was controlled by a key amino acid residue in host PrP. We also found that particular Norwegian isolates adapted during their propagation in mice to produce prions with characteristics of the North American strain. Our findings defining the transmission profiles of novel Norwegian prions and their unstable potential to produce adapted strains with improved fitness for contagious transmission have implications for risk analyses and management of emergent European CWD.
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DOI：
10.1073/pnas.1322377111
发表时间：
2014-04-22
影响因子：
11.1
作者：
Bian, Jifeng;Kang, Hae-Eun;Telling, Glenn C.
通讯作者：
Telling, Glenn C.
影响因子：
4.4
作者：
Benestad SL;Mitchell G;Simmons M;Ytrehus B;Vikøren T
通讯作者：
Vikøren T
影响因子：
5.4
作者：
Browning, SR;Mason, GL;Telling, GC
通讯作者：
Telling, GC
影响因子：
6.7
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
通讯作者：
Agrimi U
影响因子：
11.8
作者：
Angers RC;Seward TS;Napier D;Green M;Hoover E;Spraker T;O'Rourke K;Balachandran A;Telling GC
通讯作者：
Telling GC