Assessing the Transmissibility of CWD to Humans

描述（由申请人提供）：慢性消耗性疾病（CWD），在鹿科动物（鹿和麋鹿）中的朊病毒疾病，在北美广泛传播。鹿科动物数量庞大（约2200万），鹿肉消费在美国非常重要。CWD传播速度快，难以控制，如果它传播给人类，即使是以低速率传播，也可能对人类健康构成严重威胁。该提案将使用转基因（Tg）小鼠模型来回答与慢性消耗病对人类构成的潜在危险相关的三个关键问题：慢性消耗病能否直接传播给人类（目标1）？慢性消耗病经第二宿主（牛或羊）传播后能否传染给人类（目标2）？慢性消耗病是否已经传播给人类（目标3）？最终目标是确定慢性消耗病直接和间接传播给人类的风险，并建立一个监测计划，以监测慢性消耗病朊病毒感染的人类受试者。研究设计：对于目的1和2，将人源化和宫颈化Tg小鼠脑内（即）接种来自患有散发性克雅氏病（CJD）的人类受试者或来自受CWD影响的动物的脑匀浆，所述动物包括：落基山麋鹿、黑尾鹿、白尾鹿、牛和绵羊;还将接种绵羊瘙痒病作为对照。然后监测接种动物，并比较在Tg小鼠中传代前后PrP-Sc的传播率、孵育时间、神经症状、蓄积和分布以及PrP-Sc的糖型和构象稳定性。将进行二次传播，以检查朊病毒感染性的无症状携带者。将对接种后在人源化Tg小鼠中表现出感染性的CWD分离株进行经口传播。对于目标3，将用来自食用来自CWD流行地区的鹿肉的CJD受试者以及来自未暴露于CWD的散发性CJD受试者的脑匀浆接种宫颈化的Tg小鼠。将测定所有涉及的CJD受试者的脑匀浆中朊病毒感染性升数，并将使用相同的感染性剂量进行接种。从“接触CWD”的CJD受试者中获得的朊病毒传播效率在统计学上显著高于未接触CWD的散发性CJD受试者，这表明“接触CWD”的受试者可能从CWD获得CJD。

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.