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Abstract：
Erythrocytes possess an unusual programmed cell death mechanism termed eryptosis, and several compounds have been previously claimed to induce eryptosis in vitro. Malaria parasites (genus Plasmodium) reside in erythrocytes during the pathogenic part of their life cycle, and the potential of several eryptosis inducers to act as antimalarials has been tested in recent years. However, the eryptosis-inducing capacity of these compounds varies significantly between eryptosis-focused studies and malaria investigations. Here, we investigated the reasons for these discrepancies, we developed a protocol to investigate eryptosis in malaria cultures and we re-evaluated the potential of eryptosis inducers as antimalarials. First, we showed that eryptosis read-out in vitro is dependent on culture conditions. Indeed, conditions that have consistently been used to study eryptosis do not support P. falciparum growth and prime erythrocytes for eryptosis. Next, we defined culture conditions that allow the detection of eryptosis while supporting P. falciparum survival. Finally, we selected six eryptosis-inducers based on their clinical use, molecular target and antimalarial activities, and re-evaluated their eryptosis inducing capacities and their potential as antimalarials. We demonstrate that none of these compounds affect the viability of naïve or P. falciparum-infected erythrocytes in vitro. Nevertheless, three of these compounds impair parasite development, although through a mechanism unrelated to eryptosis and yet to be elucidated. We conclude that careful consideration of experimental set up is key for the accurate assessment of the eryptosis-inducing potential of compounds and their evaluation as potential antimalarials.
摘要：
红细胞具有一种不寻常的程序性细胞死亡机制，称为细胞凋亡，和几种化合物先前已声称在体外诱导细胞凋亡。疟疾寄生虫（疟原虫属）在其生命周期的致病部分驻留在红细胞中，近年来，已经测试了几种凋亡诱导剂作为抗疟疾药的潜力。然而,这些化合物的致衰能力在以死亡为重点的研究和疟疾研究之间有显著差异.这里,我们调查了这些差异的原因，我们制定了一项方案来调查疟疾培养物中的发病率,并重新评估了发病率诱导剂作为抗疟药物的潜力.首先,我们表明体外细胞凋亡的读出取决于培养条件。的确,一直用于研究赤霉病的条件不支持恶性疟原虫的生长和促进红细胞的赤霉病。接下来,我们定义了在支持恶性疟原虫存活的同时允许检测细胞凋亡的培养条件。最后,我们根据临床应用选择了6种凋亡诱导剂，分子靶标和抗疟活性，并重新评估了它们的致衰能力及其作为抗疟疾药的潜力。我们证明了这些化合物中没有一个在体外影响原始或恶性疟原虫感染的红细胞的活力。然而，其中三种化合物会损害寄生虫的发育，虽然是通过一种与死亡无关的机制，但仍有待阐明。我们得出的结论是，仔细考虑实验设置对于准确评估化合物的致炎潜力及其作为潜在抗疟药物的评估至关重要。
