Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures
Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures
复制标题
DOI：
10.1038/nm.3461
复制
发表时间：
2014-03-01
期刊：
影响因子：
82.9
通讯作者：
Mazier, Dominique
中科院分区：
文献类型：
--
作者：
Dembele, Laurent;Franetich, Jean-Francois;Mazier, Dominique
由间日疟原虫和卵形疟原虫的静止肝休眠子激活引起的疟疾复发阻碍了全球控制和消除疟疾的努力。由于伯氨喹是唯一能够消除催眠虫的药物，不适合大规模给药，因此迫切需要替代药物。目前，催眠虫的分析，包括筛选化合物，将消除他们，只能使用常见的猕猴模型，主要是恒河猴和食蟹猴，实验感染复发的食蟹猴疟原虫。在这里，我们提出了一个长期在体外培养的食蟹猴P感染M。束状原代肝细胞，在此期间休眠子持续存在并激活以恢复正常发育。在一个概念验证实验中，我们获得的证据表明，暴露于组蛋白修饰酶的抑制剂，涉及基因表达的表观遗传控制诱导催眠子激活的加速率。提出的协议可能进一步使调查催眠虫生物学和寻找杀死催眠虫或破坏其静止的化合物。
Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.