Prion strain competition and the evolution of new strains

** 慢性消耗性疾病（CWD）是一种新出现的朊病毒疾病，影响野生和养殖的鹿科动物种群。这种疾病目前在美国的24个州、加拿大的萨斯喀彻温省和阿尔伯塔以及韩国和挪威都有存在。由于慢性消耗病病原体的“传染性”性质，该疾病的地理范围和流行率继续扩大。我的研究小组和其他实验室的工作表明，慢性消耗病并不以单一的朊病毒“菌株”存在，而是存在多种慢性消耗病菌株。朊病毒疾病菌株在许多重要标准上不同，包括疾病的持续时间（潜伏期），受影响的大脑区域，疾病能够感染的物种（宿主范围）和病原体稳定性。菌株特异性受许多因素控制：特定细胞摄取感染性朊病毒的能力，免疫系统对特定菌株的反应能力和感染因子的构象。我们的工作假设是，随着CWD在不同的鹿科动物之间传播，独特的CWD菌株已经并将继续出现。这些研究的目的是表征朊病毒株，并阐明在传代至新宿主时株选择所涉及的细胞机制。在具体目标#1中，我们将在生物学和生物化学水平上表征我们在CWD种间传播时鉴定的新型朊病毒分离株。然后，将使用体外、离体和体内试验（具体目标#2）对这些新分离株的细胞和组织嗜性进行表征。为了阐明朊病毒因子决定菌株的特性，我们将使用各种理化方法来修饰朊病毒菌株（具体目标#3）。总之，这些方法将使我们能够确定CWD菌株的范围，预测它们的传播以及它们的稳定性，并提供改变菌株向性的机制。

******Chronic wasting disease (CWD) is an emerging prion disease affecting wild and farmed cervid populations. The disease is currently present in 24 states in the US, Saskatchewan and Alberta in Canada as well as in South Korea and Norway. Due to the “contagious” nature of the CWD agent, both the geographic range and prevalence of the disease continue to expand. Work from my research group and other laboratories indicate that CWD does not exist as a single “strain” of prion, but rather there are a variety of CWD strains. Prion disease strains differ in a number of important criteria including length of disease (incubation period), region of the brain affected, species the disease is capable of infecting (host range) and disease agent stability. Strain specificity is controlled by a number of factors: ability of specific cells to uptake infectious prions, ability of the immune system to respond to a specific strain and conformation of the infectious agent. Our working hypothesis is that as CWD is transmitted within and between different cervid species, unique CWD strains have and will continue to arise. It is the goal of these studies to characterize prion strains and elucidate the cellular mechanisms involved in strain selection upon passage to a new host. In the Specific Aim #1, we will characterize, at the biological and biochemical levels, novel prion isolates that we have identified upon inter-species transmission of CWD. These novel isolates will then be characterized with respect to their cell and tissue tropisms using in vitro, ex vivo and in vivo assays (specific aim #2). To elucidate the properties of a prion agent that dictate strain, we will use a variety of physiochemical approaches to modify the prion strain (specific aim #3). Together these approaches will allow us to determine the range of CWD strains, predict their spread as well as their stability and provide mechanism for changing strain tropisms.**************************************************