Prion Strain Competition and the Evolution of New Strains

慢性消耗病（CWD）是一种影响野生和养殖子宫颈种群的新型朊病毒疾病。这种疾病目前在美国19个州、加拿大的萨斯喀彻温省和阿尔伯塔省以及韩国都有发现。由于CWD病原体的“传染性”性质，该疾病的地理范围继续扩大。我课题组和其他实验室的工作表明，CWD不是作为单一的朊病毒“菌株”存在，而是存在多种CWD菌株。朊病毒疾病毒株在许多重要标准上有所不同，包括疾病的长度（潜伏期）、受影响的大脑区域、疾病能够感染的物种（宿主范围）和疾病病原体的稳定性。我们的工作假设是，随着CWD在不同的cervid物种内部和之间传播，独特的CWD菌株已经出现，并且随着疾病传播到新的地理区域，这种菌株产生的过程将继续下去。这些研究的目标是鉴定、分离和表征CWD菌株。从地方性CWD的3个主要地理疫源地（阿尔伯塔/萨斯喀彻温省、科罗拉多州/怀俄明州和威斯康星州/伊利诺伊州）的白尾鹿、骡子鹿、麋鹿、驼鹿（包括多态Prnp变体）分离的CWD将在生物学水平上通过确定潜伏期/滴度、组织病理学病变的发生和朊病毒蛋白感染形式的沉积来表征（具体目标1）。将对每个分离株的朊病毒蛋白（PrPSc）的疾病特异性构象进行生化和生物物理分析，以确定分离株之间是否存在构象差异（特异性目的#2）。将开发用于区分体内和体外CWD菌株的光学成像方法（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，预测它们的传播及其潜在的环境稳定性，并指导开发针对散养动物的这些传染病的管理方法。

Chronic wasting disease (CWD) is an emerging prion disease affecting wild and farmed cervid populations. The disease is currently present in 19 states in the US, Saskatchewan and Alberta in Canada and in South Korea. Due to the "contagious" nature of the CWD agent, the geographic range of the disease continues to expand. Work from my research group and other laboratories indicates 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. Our working hypothesis is that as CWD has been transmitted within and between different cervid species, unique CWD strains have arisen and that this process of strain generation will continue as the disease spreads to new geographic regions. It is the goal of these studies to identify, isolate and characterize CWD strains. CWD isolates from white-tailed deer, mule deer, elk, moose (including polymorphic Prnp variants) from the 3 major geographic foci of endemic CWD (Alberta/Saskatchewan, Colorado/Wyoming, and Wisconsin/Illinois) will be characterized, at the biological level, by determining incubation period/titre as well as occurrence of histopathological lesions and deposition of the infectious form of the prion protein (specific aim #1). The disease-specific conformation of the prion protein (PrPSc) from each isolate will be analyzed biochemically and biophysically to determine whether there are conformational differences between the isolates (specific aim #2). Optical imaging approaches for discriminating between the CWD strains, both in vivo and in vitro, will be developed (specific aim #3). Together, these approaches will allow us to determine the range of CWD strains, predict their spread as well as their potential environmental stability and guide the development of management approaches for these infectious diseases of free-ranging cervids.