Junaid Abidemi, Tang Huaqi, van Reeuwijk Anne, Abouleila Yasmine, Wuelfroth Petra, van Duinen Vincent, Stam Wendy, van Zonneveld Anton Jan, Hankemeier Thomas, Mashaghi Alireza
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2333 CC, Netherlands; Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden 2333 ZA, Netherlands; Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden 2333 CC, Netherlands.
iScience. 2020 Jan 24;23(1):100765. doi: 10.1016/j.isci.2019.100765. Epub 2019 Dec 12.
Ebola virus, for which we lack effective countermeasures, causes hemorrhagic fever in humans, with significant case fatality rates. Lack of experimental human models for Ebola hemorrhagic fever is a major obstacle that hinders the development of treatment strategies. Here, we model the Ebola hemorrhagic syndrome in a microvessel-on-a-chip system and demonstrate its applicability to drug studies. Luminal infusion of Ebola virus-like particles leads to albumin leakage from the engineered vessels. The process is mediated by the Rho/ROCK pathway and is associated with cytoskeleton remodeling. Infusion of Ebola glycoprotein (GP) generates a similar phenotype, indicating the key role of GP in this process. Finally, we measured the potency of a recently developed experimental drug FX06 and a novel drug candidate, melatonin, in phenotypic rescue. Our study confirms the effects of FX06 and identifies melatonin as an effective, safe, inexpensive therapeutic option that is worth investigating in animal models and human trials.
埃博拉病毒会导致人类出现出血热，病死率很高，而我们目前缺乏针对该病毒的有效应对措施。缺乏埃博拉出血热的实验性人体模型是阻碍治疗策略发展的一个主要障碍。在此，我们在芯片上微血管系统中模拟埃博拉出血热综合征，并证明其在药物研究中的适用性。向管腔内注入埃博拉病毒样颗粒会导致工程血管中白蛋白渗漏。这一过程由Rho/ROCK信号通路介导，并与细胞骨架重塑有关。注入埃博拉糖蛋白（GP）会产生类似的表型，表明GP在此过程中起关键作用。最后，我们测定了一种最近研发的实验性药物FX06和一种新型候选药物褪黑素在表型拯救方面的效力。我们的研究证实了FX06的效果，并确定褪黑素是一种有效、安全且廉价的治疗选择，值得在动物模型和人体试验中进行研究。
