PMCA Detection of CWD Infection in Cervid and Non-Cervid Species

PMCA 检测鹿科动物和非鹿科动物的 CWD 感染

• 批准号: 9237318
• 负责人: EDWARD Arthur HOOVER
• 金额: $ 40.99万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237318
• 关键词: Address; Alzheimer' s Disease; Autopsy; Biochemical; Biological Assay; Blood; Body Fluids; Brain; Canada; Cells; Characteristics; Chronic Wasting Disease; Clinical; Confocal Microscopy; Deer; Detection; Development; Disease; Domestic Animals; Dose; Drug or chemical Tissue Distribution; Environmental Pollution; Epithelial; Feces; Fluorescence Microscopy; Future; Goals; Harvest; Histologic; Horizontal Disease Transmission; Human; Immunohistochemistry; Infection; Interruption; Kinetics; Korea; Lesion; Liquid substance; Longitudinal Studies; Methodology; Milk; Modeling; Mucous Membrane; Mus; Nerve Degeneration; Nose; Oral; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peripheral; PrPCWD; Prion Diseases; Prion Pathway; Prions; Process; Province; Research Design; Risk; Route; Saliva; Sample Size; Sampling; Severities; Site; Source; Tail; Time; Tissue Harvesting; Tissues; Urine; Variant; Work; biophysical properties; cervid; cohort; disease phenotype; in vivo; misfolded protein; prevent; prion hypothesis; protein misfolding; public health relevance; transmission process

DESCRIPTION (provided by applicant): Chronic wasting disease (CWD) of deer and elk is an emerging highly transmissible prion disease now recognized in 18 States, 2 Canadian provinces, and Korea. We have shown that Infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces, and in the tissues generating those body fluids and excreta, thereby leading to facile transmission by direct contact and environmental contamination. We have also shown that CWD can infect some non-cervid species, thus the potential risk CWD represents to domestic animal species and to humans remains unknown. Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are generated or modified in the proximate peripheral tissue sites, may differ in subtle ways from those generated in brain, or may be adapted for mucosal infection remain open questions. The increasing parallels in the pathogenesis between prion diseases and human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible protein misfolding disease. The overall goal of this work is to elucidate the process of CWD prion transmission from mucosal secretory and excretory tissue sites by addressing these questions: (a) What are the kinetics and magnitude of CWD prion shedding post-exposure? (b) Are excreted prions biochemically distinct, or not, from those in the CNS? (c) Are peripheral epithelial or CNS tissues, or both, the source of excreted prions? and (d) Are excreted prions adapted for horizontal transmission via natural/trans-mucosal routes? The specific aims of this proposal are: (1) To determine the onset and consistency of CWD prion shedding in deer and cervidized mice; (2); To compare the biochemical and biophysical properties of excretory vs. CNS prions; (3) To determine the capacity of peripheral tissues to support replication of CWD prions; (4) To determine the protease- sensitive infectious fraction of excreted vs. CNS prions; and (5) To compare the mucosal infectivity of excretory vs. CNS prions. Understanding the mechanisms that enable efficient prion dissemination and shedding will help elucidate how horizontally transmissible prions evolve and succeed, and is the basis of this proposal. Understanding how infectious misfolded proteins (prions) are generated, trafficked, shed, and transmitted will aid in preventing, treating, and managing the risks associated with these agents and the diseases they cause.

描述（由申请人提供）：鹿和麋鹿的慢性消耗性疾病 (CWD) 是一种新出现的高度传染性朊病毒病，现已在 18 个州、加拿大 2 个省和韩国得到认可。我们已经证明，受感染的鹿在唾液、血液、尿液和粪便中以及产生这些体液和排泄物的组织中含有和排出高水平的传染性朊病毒，从而导致通过直接接触和环境污染轻松传播。我们还表明，CWD 可以感染一些非鹿科动物物种，因此 CWD 对家畜物种和人类的潜在风险仍然未知。 血液、唾液、鼻液、乳汁或排泄物中携带的朊病毒是否在邻近的外周组织部位产生或修饰，是否可能与大脑中产生的朊病毒有细微的不同，或者是否适合粘膜感染，仍然是一个悬而未决的问题。朊病毒疾病和人类神经退行性疾病（例如阿尔茨海默病和帕金森病）之间的发病机制越来越相似，这增加了 CWD 作为一种可传播的蛋白质错误折叠疾病的相关性。 这项工作的总体目标是通过解决以下问题来阐明 CWD 朊病毒从粘膜分泌和排泄组织部位传播的过程： (a) 暴露后 CWD 朊病毒脱落的动力学和程度是什么？ (b) 排出的朊病毒在生物化学上是否与中枢神经系统中的朊病毒不同？ (c) 外周上皮或中枢神经系统组织或两者都是分泌朊病毒的来源？ (d) 排泄的朊病毒是否适合通过自然/跨粘膜途径水平传播？ 该提案的具体目的是：（1）确定鹿和鹿交配小鼠中 CWD 朊病毒脱落的发生和一致性； (2);比较排泄物与中枢神经系统朊病毒的生化和生物物理特性； (3) 确定外周组织支持CWD朊病毒复制的能力； (4) 确定分泌物与中枢神经系统朊病毒的蛋白酶敏感感染部分； (5) 比较排泄性朊病毒与中枢神经系统朊病毒的粘膜感染性。 了解朊病毒有效传播和脱落的机制将有助于阐明水平传播的朊病毒如何进化和成功，也是该提案的基础。了解传染性错误折叠蛋白（朊病毒）如何产生、贩运、脱落和传播将有助于预防、治疗和管理与这些病原体及其引起的疾病相关的风险。