Mechanisms of prion strain selection

描述（由申请人提供）：朊病毒由PrPSc组成，PrPSc是非传染性宿主编码蛋白PrPC的错误折叠异构体。朊病毒病是包括人类在内的哺乳动物中新出现的人畜共患传染病。在种间传播后，朊病毒可以适应新的宿主物种，从而使朊病毒对新的宿主物种具有更高的适应性和致病性。这一过程可能涉及原存在于接种物中或在种间传播过程中产生的朊病毒株之间的干扰。最近的研究表明，朊病毒是一种准种，即多种菌株的混合物。这些新的研究表明，朊病毒毒株干扰可能在朊病毒毒株的整体动力学中发挥更大的作用。尽管菌株干扰在朊病毒疾病的生物学中具有重要意义，但朊病毒菌株干扰的机制尚不清楚。我们已经在动物身上开发了一种独特的菌株干扰模型，并且最近发现，在体外，蛋白质错误折叠循环扩增再现了朊病毒干扰。使用这些组合方法，我们已经确定，为了发生干扰，阻断菌株PrPSc与普通细胞类型中的重复感染PrPSc相比必须过量，并且阻断菌株在阻止重复感染菌株复制时不会将所有可用的PrPC转化为PrPSc。我们假设阻断菌株PrPSc阻止了重复感染菌株PrPSc获得PrPC或其他朊病毒转化所需的因子，从而抑制了复制。本应用程序的目的是研究菌株干扰是否由于阻断菌株PrPSc将PrPC从重复感染菌株中隔离，或者阻断菌株PrPSc是否可以结合并阻止重复感染菌株PrPSc复制。这些研究的累积结果将提供菌株干扰的详细机制，并对朊病毒菌株的生物学和有助于维持朊病毒准种的因素具有重要意义。最后，PrPSc不同构象相互作用和细胞环境相互作用的基本机制可能适用于人类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.