Assessing the Transmissibility of CWD to Humans

描述(申请人提供)：慢性消耗性疾病(CWD)，鹿(鹿和麋鹿)中的Pron疾病，在北美广泛流行。鹿的数量巨大(约2200万)，鹿肉在美国的消费量非常大。CWD的快速传播很难控制，如果它传播给人类，即使是以低速度传播，也可能对人类健康构成严重威胁。这项提议将使用转基因(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)？慢性萎缩性脑病能否通过第二宿主(牛或羊)传播给人类(目标2)？慢性萎缩性脑病是否已经向人类传播(目标3)？最终目标是确定CWD直接和间接传播给人类的风险，并建立一个监测计划，以监测受CWD普恩病毒感染的人类受试者。研究设计：对于AIMS 1和AIMS 2，人源化和宫颈切割化的Tg小鼠将在大脑内(即)接种来自患有散发性克雅氏病(CJD)的人的脑匀浆或来自受CWD影响的动物(包括：落基山脉麋鹿、骡鹿、白尾鹿、牛和羊)的脑匀浆；作为对照，也将接种绵羊瘙痒病。然后对接种动物的传播率、孵化时间、神经症状、PrP-SC在TG小鼠体内的蓄积和分布以及PrP-SC在转基因小鼠体内传代前后的糖形式和构象稳定性进行监测和比较。将进行二次传播，以检查无症状的病毒携带者是否具有传染性。CWD分离株在人源化TG小鼠接种后被证实具有感染性，将进行口服传播。对于目标3，将从CWD流行区食用鹿肉的CJD受试者以及未接触CWD的零星CJD受试者的脑匀浆接种宫颈切开的TG小鼠。将对所有涉及CJD的患者测定脑匀浆中的普恩病毒感染性滴度，并使用相同的传染性剂量进行接种。与未接触CWD的散发性CJD受试者相比，暴露于CWD的CJD患者的Prion的传播效率在统计学上显著更高，这表明CWD暴露的受试者很可能是从CWD获得的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.