Pathogenesis, Transmission and Detection of Zoonotic Prion Diseases

 描述(由申请者提供)：我们广泛的、长期的目标是了解传染性普恩病毒在动物和人类中传播的基本特性和运行机制；在这个过程中特性如何变化；以及进化是否允许感染其他物种。《目标1》探讨了一个未得到充分认识但却很重要的现象。当普恩病毒感染一个新物种时，尽管它们在复制，但它们出人意料地没有引起疾病，但保持了杀死原始物种的能力。我们将量化这种病毒复制的数量和时间，并定义它们与常规病毒的生化和生物学特性的区别。目标2将解决与此相关的问题，即Pron菌株是如何繁殖的，Pron是如何表现出显性和隐性特征的。与受基因控制的病毒特征不同，缺乏核酸的普恩病毒必须使用不同的机制。我们发现，显性和隐性的Prion性状是在蛋白质-蛋白质相互作用水平上控制的。我们将使用一种创新的方法来监测这一过程中的分子事件，该方法涉及到区分细微的Prion差异的抗体，就像遗传学家在疾病期间区分替代基因的行为一样。在目标3中，我们将使用一个强大的新小鼠模型，它概括了慢性消耗性疾病(CWD)的重要方面，CWD是一种新出现的鹿、麋鹿和驼鹿流行病。这些小鼠使我们能够研究CWD的一些方面，这些方面解释了它独特的传染性传播。这三个目标都使用了强大和创新的方法，包括独特适合的转基因小鼠、细胞培养试验、无细胞扩增和区分Pron变体的抗体。这些目标旨在解决有关普恩如何发挥作用的基本悬而未决的问题，这一点很重要，因为普恩疾病以不可预测的流行病(例如疯牛病)的形式发生，是致命的，目前是无法治愈的。慢性萎缩性脑病是唯一一种已知的影响野生动物的普恩病毒疾病。其有效的传染性传播意味着它在地理范围内迅速增加。此外，慢性萎缩性胃病继续影响新的鹿类物种。CWD或其不断演变的形式是否会像疯牛病那样传播到其他物种或人类，目前尚不清楚，但对公共卫生具有重要意义。

 DESCRIPTION (as provided by applicant): Our broad, long-term objectives are to understand the fundamental properties and operative mechanisms of infectious prion transmission in animals and humans; how properties change during this process; and whether evolution allows infection of additional species. Aim 1 explores an underappreciated but important phenomenon. When prions infect a new species, despite replicating they unexpectedly cause no disease, but maintain the ability to kill the original species. We will quantify how much and when such prion replication occurs, and define biochemical and biological properties differentiating these from conventional prions. Aim 2 will address the related issue of how prion strains are propagated, and how prions manifest dominant and recessive traits. Unlike viral characteristics that are genetically controlled, prions, which lack nucleic acids must employ a different mechanism. We find that dominant and recessive prion traits are controlled at the level of protein-protein interactions. We will monitor molecular events in this process using an innovative approach involving antibodies that discriminate subtle prion differences, in much the same way that geneticists discriminate the actions of alternative genes during disease. In Aim 3, we will use a powerful new mouse model that recapitulates important aspects of chronic wasting disease (CWD), an emerging epidemic of deer, elk and moose. These mice enable us to study aspects of CWD that account for its uniquely contagious transmission. All three aims employ powerful and innovative approaches including uniquely suited genetically modified mice, cell culture assays, cell-free amplification, and antibodies that distinguish prion variants. These aims address basic, unresolved issues about how prions function which is important because prion diseases occur as unpredictable epidemics (e.g. mad cow disease), are lethal, and currently incurable. CWD is the only known prion disorder affecting wild animals. Its efficient contagious transmission means that it is rapidly increasing in geographic range. Also CWD continues to affect new cervid (antler-bearing) species. Whether CWD or its evolving forms will spread to other species, or to humans, as was the case for mad cow disease, is currently unknown but of significant importance to public health.