Assessing the Transmissibility of CWD to Humans

评估 CWD 向人类传播的能力

• 批准号: 7232665
• 负责人: QINGZHONG KONG
• 金额: $ 33.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7232665
• 关键词: Address; Affect; Animals; Area; Biological Assay; Brain; CJD Variant (V-CJD); Canada; Cattle; Chronic; Chronic Wasting Disease; Consumption; Country; Creutzfeldt-Jakob Syndrome; Data; Deer; Detection; Dose; Environment; Equine mule; Exposure to; Future; Goals; Guidelines; Health; Human; In Vitro; Infection; Knowledge; Meat; Monitor; Mus; Neurologic; North America; Oral; Phenotype; Population; PrPSc Proteins; Prion Diseases; Prions; Procedures; Public Health; Publishing; Rate; Research Design; Research Personnel; Risk; Scrapie; Sheep; Statistically Significant; Surveillance Program; Symptoms; Tail; Time; Transgenic Organisms; United States; Wasting Syndrome; base; cervid; disease transmission; human PrP; human subject; mouse model; programs; research study; transmission process

DESCRIPTION (provided by applicant): Chronic wasting disease (CWD), the prion disease in cervids (deer and elk), is widespread in North America. The cervid population is huge (approximately 22 million) and venison consumption very significant in USA. The fast spreading CWD is hard to contain, and it may pose a serious threat to human health if it is transmissible to humans, even at a low rate. This proposal will use transgenic (Tg) mouse models to answer three critical questions pertinent to the potential dangers posed by CWD to humans: Can CWD be transmitted to humans directly (Aim 1)? Can CWD be transmitted to humans after passage through secondary hosts (cattle or sheep) (Aim 2)? Has CWD transmission to humans already occurred (Aim 3)? The ultimate goals are to define the risks of direct and indirect CWD transmission to humans and to establish a surveillance program to monitor for human subjects infected by CWD prions. Research Design: For Aims 1 and 2, humanized and cervidized Tg mice will be intracerebrally (i.e.) inoculated with brain homogenates either from human subjects with sporadic Creutzfeldt-Jakob disease (CJD) or from CWD-affected animals including: Rocky Mountain elk, mule deer, white-tail deer, cattle, and sheep; sheep scrapie will also be inoculated as a control. The inoculated animals will then be monitored and compared for the transmission rate, incubation time, neurological symptoms, accumulation and distribution of PrP-Sc, and the glycoforms and conformational stability of PrP-Sc before and after passage in the Tg mice. Secondary transmissions will be done to examine for asymptomatic carriers of prion infectivity. Oral transmissions will be performed for CWD isolates that demonstrated infectivity in humanized Tg mice after i.e. inoculation. For Aim 3, cervidized Tg mice will be i.e. inoculated with brain homogenates from CJD subjects who had consumed venison from CWD endemic areas as well as from sporadic CJD subjects not exposed to CWD. The prion infectivity liters in the brain homogenates will be determined for all involved CJD subjects, and the same infectivity dose will be used for inoculation. A statistically significant higher transmission efficiency of prions from "CWD-exposed" CJD subjects than that of the sporadic CJD subjects unexposed to CWD will suggest that the "CWD-exposed" subject likely acquired his CJD from CWD.

描述（由申请人提供）：慢性消耗性疾病（CWD）是一种动物（鹿和麋鹿）的朊病毒疾病，在北美广泛传播。在美国，鹿科动物的数量巨大（大约2200万），鹿肉的消费量非常大。快速传播的CWD难以控制，如果传播给人类，即使传播率很低，也可能对人类健康构成严重威胁。该提案将使用转基因（Tg）小鼠模型来回答与CWD对人类构成的潜在危险相关的三个关键问题：CWD能否直接传播给人类（目标1）？CWD能否通过第二宿主（牛或羊）传播给人类（目标2）？CWD向人类的传播是否已经发生（目标3）？最终目标是确定CWD直接和间接传播给人类的风险，并建立监测计划，以监测感染CWD朊病毒的人类受试者。研究设计：在目标1和目标2中，人源化和颈化的Tg小鼠将在脑内（即）接种散发性克雅氏病（CJD）的人类受试者或ccd感染动物的脑匀浆，包括：落基山麋鹿、骡子鹿、白尾鹿、牛和羊；绵羊痒病也将作为对照接种。然后监测和比较接种动物的传播率、孵育时间、神经症状、PrP-Sc的积累和分布，以及PrP-Sc在Tg小鼠传代前后的糖型和构象稳定性。将进行二次传播以检查无症状的朊病毒传染性携带者。经口传播的CWD分离株在接种后对人源化Tg小鼠具有传染性。在第3项试验中，接种的Tg小鼠将分别接种从CWD流行地区食用鹿肉的CJD患者和未暴露于CWD的散发性CJD患者的脑匀浆。测定所有涉及的CJD受试者脑匀浆中的朊病毒传染性升数，接种时使用相同的传染性剂量。从统计学上看，“暴露于CWD”的CJD患者的朊病毒传播效率高于未暴露于CWD的散发性CJD患者，这表明“暴露于CWD”的患者可能是由CWD感染的。