Mechanisms of prion strain selection

描述(申请人提供)：Prion由PrPSc组成，PrPSc是非感染性宿主编码蛋白PrPC的错误折叠异构体。Prion病是包括人类在内的哺乳动物新出现的人畜共患传染病。在种间传播之后，Prion可以适应新的宿主物种，导致Prion对新的宿主物种具有更高的适合度和致病力。这一过程可能涉及最初存在于接种物中或在物种间传播过程中产生的普恩病毒菌株之间的干扰。最近的研究表明，Prion以准种的形式存在，也就是说，它是菌株的混合物。这些新的研究表明，Pron菌株的干扰可能在Pron菌株的整体动力学中发挥更大的作用。尽管菌种干扰在普恩病毒病的生物学中具有重要意义，但普恩病毒株干扰的机制(S)尚不清楚。我们已经在动物中开发了一种独特的应变干扰模型，最近发现在体外，蛋白质的错误折叠循环扩增概括了Pron干扰。使用这些组合的方法，我们已经确定了干扰的发生，与普通细胞类型中超级感染的PrPSc相比，阻断菌株PrPSc必须过剩，并且当阻断菌株阻止超级感染菌株复制时，它不会将所有可用的PrPC转化为PrPSc。我们假设阻断菌株PrPSc阻止超级感染菌株PrPSc获得PrPC或PrPC转换所需的其他因子，从而抑制复制。本申请的目的是调查菌株干扰是由于阻断菌株PrPSc将PrPC从超级感染菌株中隔离出来，还是阻断菌株PrPSc能够与超级感染菌株PrPSc结合并阻止其复制。这些研究的累积结果将提供一个详细的菌株干扰机制，并对Pron菌株的生物学和有助于Pron准种的维持的因素产生影响。最后，PrPSc不同构象如何与细胞环境相互作用的基本机制可能适用于人类的其他蛋白质错误折叠疾病。

DESCRIPTION (provided by applicant): Prions are comprised of PrPSc, a misfolded isoform of the non-infectious host encoded protein, PrPC. Prion diseases are emerging zoonotic infectious diseases of mammals including humans. Following interspecies transmission, prions can adapt to the new host species resulting in a prion with increased fitness and pathogenicity for the new host species. This process can involve interference between prion strains that are originally present in the inoculum or are generated during interspecies transmission. Recent studies indicate that prions exist as a quasispecies, that is, a mixture of strains. These new studies suggest that prion strain interference may play a larger role in overall dynamics of prion strains. Despite the significance of strain interference in the biology of prion disease, the mechanism(s) underling prion strain interference is not known. We have developed a unique model of strain interference in animals and have recently discovered that in vitro, protein misfolding cyclic amplification recapitulates prion interference. Using these combined approaches, we have determined for interference to occur, the blocking strain PrPSc must be in excess compared to the superinfecting PrPSc in a common cell type and the blocking strain does not convert all of the available PrPC to PrPSc when it prevents superinfecting strain replication. We hypothesize that the blocking strain PrPSc prevents the superinfecting strain PrPSc from gaining access to PrPC or other factors required for prion conversion, therefore inhibiting replication. The aims of this application will investigate if strain interference is due to the blocking strain PrPSc sequestering PrPC from the superinfecting strain or if the blocking strain PrPSc could bind to and prevent the superinfecting strain PrPSc from replicating. The cumulative results of these studies will provide a detailed mechanism of strain interference and have implications for the biology of prion strains and the factors that contribute to maintenance of the prion quasispecies. Finally, the basic mechanisms of how different conformations of PrPSc interact with each other and the cellular environment may be applicable to other protein misfolding diseases of humans.