Department of Pathology, Wolstein Research Building, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH- 44106, USA.
Mol Brain. 2010 Apr 29;3:14. doi: 10.1186/1756-6606-3-14.
The spread of Chronic Wasting Disease (CWD) in the deer and elk population has caused serious public health concerns due to its potential to infect farm animals and humans. Like other prion disorders such a sporadic Creutzfeldt-Jakob-disease of humans and Mad Cow Disease of cattle, CWD is caused by PrP-scrapie (PrPSc), a beta-sheet rich isoform of a normal cell surface glycoprotein, the prion protein (PrPC). Since PrPSc is sufficient to cause infection and neurotoxicity if ingested by a susceptible host, it is important to understand the mechanism by which it crosses the stringent epithelial cell barrier of the small intestine. Possible mechanisms include co-transport with ferritin in ingested food and uptake by dendritic cells. Since ferritin is ubiquitously expressed and shares considerable homology among species, co-transport of PrPSc with ferritin can result in cross-species spread with deleterious consequences. We have used a combination of in vitro and in vivo models of intestinal epithelial cell barrier to understand the role of ferritin in mediating PrPSc uptake and transport. In this report, we demonstrate that PrPSc and ferritin from CWD affected deer and elk brains and scrapie from sheep resist degradation by digestive enzymes, and are transcytosed across a tight monolayer of human epithelial cells with significant efficiency. Likewise, ferritin from hamster brains is taken up by mouse intestinal epithelial cells in vivo, indicating that uptake of ferritin is not limited by species differences as described for prions. More importantly, the iron content of ferritin determines its efficiency of uptake and transport by Caco-2 cells and mouse models, providing insight into the mechanism(s) of ferritin and PrPSc uptake by intestinal epithelial cells.
慢性消瘦病（CWD）在鹿和麋鹿种群中的传播引起了严重的公共卫生关注，因为它有可能感染农场动物和人类。与其他朊病毒疾病（如人类的散发性克雅氏病和牛的疯牛病）一样，CWD是由 PrP-scrapie（PrPSc）引起的，PrPSc 是一种富含β-片层的正常细胞表面糖蛋白朊病毒蛋白（PrPC）的异构体。由于 PrPSc 如果被易感宿主摄入，足以引起感染和神经毒性，因此了解它穿过小肠严格的上皮细胞屏障的机制非常重要。可能的机制包括与摄入食物中的铁蛋白共转运和被树突状细胞摄取。由于铁蛋白在物种间广泛表达且具有相当大的同源性，因此 PrPSc 与铁蛋白的共转运可能导致具有有害后果的跨物种传播。我们使用了体外和体内肠上皮细胞屏障模型的组合来了解铁蛋白在介导 PrPSc 摄取和转运中的作用。在本报告中，我们证明了来自 CWD 感染鹿和麋鹿大脑的 PrPSc 和铁蛋白以及来自绵羊的瘙痒病抵抗消化酶的降解，并以显著的效率穿过紧密的单层人上皮细胞进行易位。同样，来自仓鼠大脑的铁蛋白在体内被小鼠肠上皮细胞摄取，表明铁蛋白的摄取不受物种差异的限制，如描述的朊病毒。更重要的是，铁蛋白的铁含量决定了其被 Caco-2 细胞和小鼠模型摄取和转运的效率，为了解铁蛋白和 PrPSc 被肠上皮细胞摄取的机制提供了线索。
