Transmission and Pathogenesis of Chronic Wasting Disease (CWD)

慢性消耗性疾病(CWD)在宫颈中的独特易传播性必须支持其 在北美、亚洲和现在的欧洲不受控制地扩大流行。这项研究的目标是 阐明CWD在自然界中如何和为什么如此有效地传播，以及哪些因素促进了这一过程 或影响CWD可能构成的人畜共患风险。这项工作的中心假设是外周CWD Prion具有有利于提高生物利用度、感染性和可能改变的特性 人畜共患病风险。 慢性萎缩性鼻炎的传播必须通过鼻或口腔粘膜暴露在极低的环境中而发生。 感染宫颈分泌物和排泄物中的Prion浓度(比脑中低6-7log10)。它 同样可能的是，在自然界中，鹿类自然地暴露在与颗粒物结合的排泄的普恩病毒中。 这种低水平的粘膜暴露引发感染并促进感染的因素和机制 CWD的传播在很大程度上仍然是一个谜，也是这项提议的主题。 令人惊讶的是，像病毒一样，普恩病毒可以(不可预测地)进化，跨越物种障碍。人类和 动物共享环境和食物来源，这些环境和食物来源受到CWD感染的鹿颈腺分泌的普恩病毒的污染。这个 外周组织和脱落的普恩病毒的实际影响及其在水平普恩病毒传播中可能发挥的作用 流行病学以及对人和动物构成的风险仍然相对研究不足，是第二个 这项提案的主题。 我们将通过利用我们建立的强大和敏感的体内和 使用自然宫颈和转基因小鼠宿主的体外Prion检测方法评估 外周和脱落蛋白的感染性和生化特性。这些研究将得到我们独特的 CWD的经验、设施和组织和从纵向感染研究中排出的Prion的储存库 鹿。研究的目的是： 目标1：确定导致独特有效传播的自然暴露的特征 CWD的。这一目标将确定多个低剂量和/或粒子结合的排泄物是否会增强 传输效率与在一次曝光中遇到的相同总数的对比。 目的2：确定外周CWD和脑部CWD病毒在生化或感染性方面是否存在差异。 我们将分析生物物理和生化特性以及跨物种传染性和人畜共患病 外周与中枢神经系统蛋白的潜势。这一目标将决定CWD脱落的Prion是否具有独特的 特征或拓宽的物种障碍。 这项研究的影响将阐明CWD在自然界中如何以及为什么会如此有效地传播 以及哪些因素促进了这一过程或影响了CWD可能构成的人畜共患病风险。

The uniquely facile transmission of chronic wasting disease (CWD) among cervids must underpin its uncontrolled expanding prevalence in North America, Asia and now Europe. The goal of this research is to elucidate how and why CWD is transmitted so efficiently in nature and what factors facilitate this process or influence the zoonotic risk CWD may pose. The central hypothesis for this work is that peripheral CWD prions possess characteristics that favor enhanced bioavailability, infectivity and perhaps altered zoonotic risk. CWD transmission must occur via exposure of nasal or oral mucosae to the very low concentrations of prions shed in secreta and excreta of infected cervids (6-7 log10 lower than in brain). It is likewise likely that in nature cervids are naturally exposed to excreted prions that are bound to particulates. The factors and mechanisms by which this low-level mucosal exposure initiates infection and facilitates CWD transmission remain largely mysterious and are the subject of this proposal. Amazingly, like viruses, prions can (unpredictably) evolve to cross species barriers. Humans and animals share environments and food sources contaminated with prions shed by CWD-infected cervids. The practical impact of peripheral tissue and shed prions and the role they may play in horizontal prion transmission, epidemiology, and risk posed to humans and animals remains relatively under-studied, and is the second subject of this proposal. We will address the above questions by harnessing our established robust and sensitive in vivo and in vitro prion detection methods using both native cervid and transgenic murine hosts to assess the infectivity and biochemical traits of peripheral and shed prions. These studies will be under-pinned by our unique CWD experience, facilities, and repository of tissues and excreted prions from longitudinal infection studies in deer. The study Aims are: Aim 1: To determine features of natural exposure that lead to the uniquely efficient transmission of CWD. This aim will determine if multiple low dose and/or particle binding of excreted prions enhances transmission efficiency vs. the same total encountered in a single exposure. Aim 2: To determine whether peripheral vs. brain CWD prions differ biochemically or in infectivity. We will analyze the biophysical and biochemical properties as well as cross-species infectivity and zoonotic potential of peripheral vs. CNS prions. This aim will determine whether shed CWD prions possess unique traits or broadened species barriers. The impact of this research will elucidate how and why CWD is transmitted so efficiently in nature and what factors facilitate this process or influence the zoonotic risk CWD may pose.