Pathogenesis, Transmission and Detection of Zoonotic Prion Diseases

 描述（由申请人提供）：我们广泛的长期目标是了解动物和人类中传染性朊病毒传播的基本特性和操作机制;在此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探讨了一个未被重视但重要的现象。当朊病毒感染一个新的物种时，尽管它们在复制，但出乎意料地不会引起疾病，而是保持了杀死原始物种的能力。我们将量化多少，何时发生这种朊病毒复制，并定义生化和生物学特性区分这些从传统的朊病毒。目标2将解决朊病毒株如何繁殖，以及朊病毒如何表现显性和隐性特征的相关问题。与受基因控制的病毒特征不同，缺乏核酸的朊病毒必须采用不同的机制。我们发现，显性和隐性朊病毒性状的蛋白质-蛋白质相互作用的水平上控制。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，这种方法涉及区分朊病毒细微差异的抗体，就像遗传学家在疾病期间区分替代基因的作用一样。在目标3中，我们将使用一种强大的新小鼠模型，该模型概括了慢性消耗性疾病（CWD）的重要方面，慢性消耗性疾病是鹿、麋鹿和驼鹿的一种新兴流行病。这些小鼠使我们能够研究慢性消耗病的各个方面，解释其独特的传染性传播。所有这三个目标都采用了强大的创新方法，包括独特适合的转基因小鼠，细胞培养试验，无细胞扩增和区分朊病毒变体的抗体。这些目标解决了关于朊病毒如何发挥作用的基本的、未解决的问题，这一点很重要，因为朊病毒疾病作为不可预测的流行病（例如疯牛病）发生，是致命的，目前无法治愈。慢性消耗病是唯一已知的影响野生动物的朊病毒疾病。它的高效传染性传播意味着它的地理范围正在迅速扩大。此外，慢性消耗病继续影响新的鹿科（鹿角）物种。慢性消耗病或其演变形式是否会传播到其他物种或人类，就像疯牛病一样，目前尚不清楚，但对公共卫生至关重要。

 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.