Transmission and Pathogenesis of Chronic Wasting Disease (CWD)

慢性消耗性疾病（CWD）在鹿科动物中的独特传播必须支持其 在北美、亚洲和现在的欧洲，不受控制地扩大流行。这项研究的目的是 阐明慢性消耗病如何以及为什么在自然界中如此有效地传播，以及哪些因素促进了这一过程 或影响CWD可能造成的人畜共患风险。这项工作的中心假设是，外周CWD 朊病毒具有有利于增强生物利用度、感染性和可能改变的 人畜共患病风险 慢性消耗病的传播必须通过鼻或口腔粘膜暴露于非常低的 感染鹿分泌物和排泄物中朊病毒的浓度（比脑中低6-7 log 10）。它 同样，在自然界中，鹿科动物自然暴露于与颗粒结合的排泄朊病毒。 这种低水平粘膜暴露引发感染并促进 CWD传输在很大程度上仍然是神秘的，也是本提案的主题。 令人惊讶的是，朊病毒和病毒一样，可以（不可预测地）跨越物种障碍进化。人类和 动物共享被感染CWD的鹿科动物排出的朊病毒污染的环境和食物来源。的 外周组织和脱落朊病毒的实际影响以及它们在水平朊病毒传播中可能发挥的作用， 流行病学，以及对人类和动物构成的风险仍然相对不足，是第二个 这个提议的主题。 我们将通过利用我们建立的强大和敏感的体内和 使用天然鹿科动物和转基因鼠宿主的体外朊病毒检测方法， 感染性和生化特性的外周和脱落朊病毒。这些研究将得到我们独特的 慢性消耗病的经验、设施和组织库以及来自慢性消耗病纵向感染研究的排泄朊病毒 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特征 的CWD。这一目标将确定是否多个低剂量和/或颗粒结合的分泌朊病毒增强 透射效率与在单次曝光中遇到的相同总数。 目的2：确定外周与脑CWD朊病毒是否在生物化学或感染性方面不同。 我们将分析其生物物理和生化特性以及跨物种传染性和人畜共患病性 外周与中枢神经系统朊病毒的潜力。这一目标将决定是否脱落的慢性消耗病朊病毒具有独特的 特征或扩大的物种屏障。 这项研究的影响将阐明慢性消耗病在自然界中如何以及为什么如此有效地传播 以及什么因素促进了这一过程或影响CWD可能造成的人畜共患风险。

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.