Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, Australia.
Front Cell Infect Microbiol. 2021 Mar 12;11:630812. doi: 10.3389/fcimb.2021.630812. eCollection 2021.
Erythrocytes possess an unusual programmed cell death mechanism termed eryptosis, and several compounds have been previously claimed to induce eryptosis . Malaria parasites (genus ) 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 is dependent on culture conditions. Indeed, conditions that have consistently been used to study eryptosis do not support growth and prime erythrocytes for eryptosis. Next, we defined culture conditions that allow the detection of eryptosis while supporting 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 -infected erythrocytes . 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.
红细胞具有一种异常的程序性细胞死亡机制，称为红细胞凋亡，并且以前已经有几种化合物被声称可以诱导红细胞凋亡。疟原虫（属）在其生命周期的致病部分存在于红细胞中，近年来已经测试了几种红细胞凋亡诱导剂作为抗疟药物的潜力。然而，这些化合物诱导红细胞凋亡的能力在专注于红细胞凋亡的研究和疟疾研究之间存在显著差异。在这里，我们研究了这些差异的原因，我们开发了一种在疟疾培养物中研究红细胞凋亡的方案，并重新评估了红细胞凋亡诱导剂作为抗疟药物的潜力。首先，我们表明红细胞凋亡的读值取决于培养条件。实际上，一直用于研究红细胞凋亡的条件并不能支持生长并使红细胞成熟为红细胞凋亡。接下来，我们定义了允许检测红细胞凋亡同时支持生存的培养条件。最后，我们基于其临床用途、分子靶标和抗疟活性选择了六种红细胞凋亡诱导剂，并重新评估了它们诱导红细胞凋亡的能力及其作为抗疟药物的潜力。我们证明，这些化合物没有一种会影响未感染或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，尽管通过一种与红细胞凋亡无关且尚未阐明的机制。我们得出结论，仔细考虑实验设置是准确评估化合物诱导红细胞凋亡的潜力及其作为潜在抗疟药物进行评估的关键。
