Role of human enterocytes and the 37 kDa/67 kDa laminin receptor LRP/LR on the develepment of zoonotic prion diseases

人肠上皮细胞和 37 kDa/67 kDa 层粘连蛋白受体 LRP/LR 在人畜共患朊病毒疾病发展中的作用

• 批准号: 42349162
• 负责人: Professor Dr. Stefan Weiss
• 金额: --
• 依托单位: School of Molecular and Cell Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/42349162?language=en
• 关键词: Role; human; enterocytes; 37; kDa

TSEs show a species-specific barrier depending on the kind of the incoming prion strain as well as the kind of target organism to be infected. The species barrier results either in altered disease incubation times, or even insusceptibility to specific prion strains.Recently, we found, that BSE-derived prions bound to and became internalized by human enterocytes, the major cell population of the intestinal epithelium, via the 37 kDa/67 kDa laminin receptor LRP/LR, acting as a receptor for the cellular prion protein PrPc and infectious PrPSc. In contrast, mouse adapted scrapie prions failed to bind to human enterocytes, which can be explained by a possible failure of this prion strain to bind to cell surface LRP/LR. This result might be a first hint that also scrapie prions from sheep might be unable to bind to human enterocytes and therefore, fail to cause a zoonosis.In the proposed study, we will investigate the species-specific entry barrier in the enterocyte cell system addressing the question whether different animal prion strains such as scrapie in sheep and chronic wasting disease (CWD) in elk and deer have the potential to cause a zoonotic disease. The role of LRP/LR in the binding and internalization processes will be investigated. With this in vitro cell system we mimic one of the first steps of non-human prions entering the human body. The intestine might represent the crucial barrier for prions deciding upon the development of a zoonotic prion disease, which might be caused by sheep scrapie and CWD. Very recently, infectious prions have been detected in blood and saliva of deer suffering from CWD. Since this finding enhances the infection risk for humans getting in contact with body fluids from cervids suffering from CWD, the investigation of a possible uptake of CWD prions by human enterocytes might significantly contribute to the estimation of an infection risk of humans by CDW prions.

热带病表现出一种物种特异性屏障，这取决于进入的朊病毒菌株的种类以及被感染的目标生物的种类。物种屏障导致疾病潜伏期改变，甚至对特定的朊病毒株不敏感。最近，我们发现疯牛病衍生的朊病毒通过37 kDa/67 kDa层粘连蛋白受体LRP/LR结合并被肠上皮的主要细胞群人肠细胞内化，作为细胞朊蛋白PrPc和感染性PrPSc的受体。相比之下，小鼠适应痒病朊病毒未能与人肠细胞结合，这可能是由于该朊病毒株未能与细胞表面LRP/LR结合。这一结果可能是第一个提示，来自绵羊的痒病朊病毒可能无法与人类肠细胞结合，因此不能引起人畜共患病。在拟议的研究中，我们将研究肠细胞系统中物种特异性的进入屏障，以解决不同动物朊病毒株（如绵羊的痒病和麋鹿和鹿的慢性消耗性疾病（CWD））是否有可能引起人畜共患疾病的问题。LRP/LR在结合和内化过程中的作用将被研究。通过这种体外细胞系统，我们模拟了非人类朊病毒进入人体的第一步。肠道可能是朊病毒决定人畜共患朊病毒疾病发展的关键屏障，这种疾病可能由羊痒病和CWD引起。最近，在患有CWD的鹿的血液和唾液中发现了传染性朊病毒。由于这一发现增加了与CWD患者体液接触的人的感染风险，因此对人肠细胞可能摄取CWD朊病毒的调查可能有助于估计人类被CWD朊病毒感染的风险。