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

TSE表现出一种物种特异性屏障，这取决于传入朊病毒株的种类以及被感染的靶生物的种类。最近，我们发现，BSE-衍生的朊病毒结合到人肠上皮细胞，肠道上皮的主要细胞群，并成为内化通过37 kDa/67 kDa的层粘连蛋白受体LRP/LR，作为一个受体的细胞朊蛋白PrPc和传染性PrPSc。与此相反，小鼠适应性羊瘙痒症朊病毒未能与人肠上皮细胞结合，这可以解释为该朊病毒株可能未能与细胞表面LRP/LR结合。这一结果可能是第一个提示，羊瘙痒症朊病毒也可能无法与人类肠上皮细胞结合，因此无法引起人畜共患病。我们将研究肠上皮细胞系统中的物种特异性进入屏障，以解决不同的动物朊病毒株，如羊瘙痒病和慢性消耗病（CWD），麋鹿和鹿体内的病毒有可能导致人畜共患疾病。LRP/LR在结合和内化过程中的作用将被研究。利用这种体外细胞系统，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病发展的关键屏障，人畜共患朊病毒病可能由羊瘙痒病和慢性消耗病引起。最近，在患有慢性消耗病的鹿的血液和唾液中检测到传染性朊病毒。由于这一发现增加了人类接触患有CWD的鹿科动物体液的感染风险，因此对人类肠细胞可能摄取CWD朊病毒的研究可能显著有助于评估人类被CDW朊病毒感染的风险。

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.