Microfluidic modeling of cell-cell interactions in malaria pathogenesis.
Microfluidic modeling of cell-cell interactions in malaria pathogenesis.
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DOI：
10.1371/journal.ppat.0030099
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发表时间：
2007-07
期刊：
影响因子：
6.7
通讯作者：
Rathod, Pradipsinh K
中科院分区：
文献类型：
--
作者：
Antia, Meher;Herricks, Thurston;Rathod, Pradipsinh K
人类感染恶性疟原虫的临床结果仍然高度不可预测。要全面了解宿主细胞和寄生虫之间复杂的相互作用，需要体外实验模型同时捕获与发病机制相关的多种宿主-寄生虫相互作用。在这里，我们表明，先进的微流体装置同时模型（a）感染的红细胞粘附到宿主细胞配体，（B）流变学响应的形状和大小类似于小血管的毛细血管的尺寸变化，和（c）巨噬细胞吞噬感染的红细胞。所有这些都是在生理相关的流动条件下长达20小时完成的。使用选择的例子，我们展示了这种使能技术可以应用于新的，综合的方式来解剖宿主细胞配体和寄生的红细胞在合成毛细管之间的相互作用。这些设备便宜、便携，所需样本量小;因此，它们有可能广泛用于研究实验室和能够获得新鲜患者样本的现场。疟疾每年有5亿多个临床病例，100万人死亡，是一个毁灭性的全球健康问题。来自患有严重疾病的患者的样本表明，疟疾感染的红细胞（iRBC）与宿主哺乳动物细胞的结合在促成可导致器官衰竭的血管阻塞中起着重要作用。然而，在流行国家的一些人携带寄生虫而没有显著的临床症状。为了帮助探索疾病结果的变化，我们开发了模拟严重疾病的许多潜在特征的微流体通道。合成的微流体通道，其大小和形状类似于小毛细管网络，用纯宿主蛋白质或表达宿主配体的培养的哺乳动物细胞涂覆。因此，我们可以在真实的毛细管环境中模拟iRBC在高压流体流动下的结合。通过跟踪单个iRBC的命运，我们观察到寄生虫与寄生虫之间的粘附变化，以及当iRBC通过最薄的毛细血管时粘附的意外下降。我们还显示了在流体流动下吞噬细胞对iRBC的吞噬。微流控装置应该作为了解严重疟疾的强大现场工具，因为该系统易于使用，需要非常小的样本量，并且是便携式的，可用于现场分析患者样本。
The clinical outcomes of human infections by Plasmodium falciparum remain highly unpredictable. A complete understanding of the complex interactions between host cells and the parasite will require in vitro experimental models that simultaneously capture diverse host–parasite interactions relevant to pathogenesis. Here we show that advanced microfluidic devices concurrently model (a) adhesion of infected red blood cells to host cell ligands, (b) rheological responses to changing dimensions of capillaries with shapes and sizes similar to small blood vessels, and (c) phagocytosis of infected erythrocytes by macrophages. All of this is accomplished under physiologically relevant flow conditions for up to 20 h. Using select examples, we demonstrate how this enabling technology can be applied in novel, integrated ways to dissect interactions between host cell ligands and parasitized erythrocytes in synthetic capillaries. The devices are cheap and portable and require small sample volumes; thus, they have the potential to be widely used in research laboratories and at field sites with access to fresh patient samples. With over 500 million clinical cases and 1 million deaths per year, malaria presents a devastating global health problem. Samples from patients with severe disease suggest that binding of malaria-infected red blood cells (iRBCs) to host mammalian cells plays an important role in precipitating blood vessel blockages that can cause organ failure. Yet, some individuals in endemic countries harbor parasites without significant clinical symptoms. To help explore variations in disease outcomes, we developed microfluidic channels that mimic many potential features of severe disease. Synthetic microfluidic channels, with sizes and shapes resembling small capillary networks, were coated with pure host proteins or cultured mammalian cells expressing host ligands. We could therefore simulate binding of iRBCs under high-pressure fluid flow in a realistic capillary environment. By tracking the fate of individual iRBCs, we observed parasite-to-parasite variation in adhesion and an unexpected drop in adhesion when iRBCs passed through the thinnest capillaries. We also showed engulfment of iRBCs by phagocytic cells under fluid flow. The microfluidic devices should serve as powerful field tools for understanding severe malaria because the system is easy to use, requires very small sample volumes, and is portable for on-site analysis of patient samples in the field.