Transmission and Pathogenesis of Chronic Wasting Disease (CWD)

慢性消耗性疾病 (CWD) 的传播和发病机制

• 批准号: 9906274
• 负责人: EDWARD Arthur HOOVER
• 金额: $ 45.45万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906274
• 关键词: Address; Animals; Asia; Binding; Biochemical; Biological Availability; Biophysics; Brain; Characteristics; Chronic Wasting Disease; Deer; Density Gradient Centrifugation; Detection; Dose; Environment; Epidemiology; Europe; Exhibits; Exposure to; Food; Goals; Human; Immunoblotting; In Vitro; Infection; Lead; Lymphoid; Methods; Molecular Conformation; Mucous Membrane; Mus; Nature; North America; Oral; Oral mucous membrane structure; Particulate; Pathogenesis; Peptide Hydrolases; Peripheral; Play; Prevalence; Prion Diseases; Prions; Process; Property; Research; Risk; Role; Source; Structure of mucous membrane of nose; Tissue Banks; Tissues; Transgenic Mice; Transgenic Organisms; Virus; Work; Zoonoses; biophysical properties; cervid; disease transmission; experience; glycosylation; human PrP; in vivo; lymph nodes; molecular mass; particle; trait; transmission process

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.

慢性消耗性疾病（CWD）在鹿科动物中独特且容易传播，这一定是其传播的基础。 在北美、亚洲和现在的欧洲，患病率不受控制地不断扩大。这项研究的目标是 阐明 CWD 在自然界中如何以及为何如此有效地传播，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、感染性并可能改变的特征 人畜共患风险。 CWD 传播必须通过鼻腔或口腔粘膜暴露于极低的环境中而发生。 感染鹿科动物分泌物和排泄物中的朊病毒浓度（比脑中低 6-7 log10）。它 同样可能的是，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。 这种低水平的粘膜暴露引发感染并促进的因素和机制 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，像病毒一样，朊病毒可以（不可预测地）进化以跨越物种障碍。人类和 动物共享被 CWD 感染的鹿科动物释放的朊病毒污染的环境和食物来源。这 外周组织和脱落朊病毒的实际影响及其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造成的风险的研究仍然相对不足，是第二个 本提案的主题。 我们将通过利用我们已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来评估 外周和脱落朊病毒的感染性和生化特征。这些研究将以我们独特的 CWD 的经验、设施以及来自纵向感染研究的组织和排泄朊病毒的储存库 鹿。研究目的是： 目标 1：确定导致独特有效传播的自然暴露特征 的 CWD。该目标将确定排泄朊病毒的多个低剂量和/或颗粒结合是否增强 传输效率与单次曝光中遇到的相同总传输效率。 目标 2：确定外周与大脑 CWD 朊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性 外周朊病毒与中枢神经系统朊病毒的潜力。这一目标将确定脱落的 CWD 朊病毒是否具有独特的 性状或扩大的物种壁垒。 这项研究的影响将阐明 CWD 在自然界中如何以及为何如此有效地传播 哪些因素促进这一过程或影响 CWD 可能造成的人畜共患风险。