Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites
Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites
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DOI：
10.1038/mt.2015.18
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发表时间：
2015-05-01
影响因子：
12.4
通讯作者：
Kaushansky, Alexis
中科院分区：
文献类型：
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作者：
Douglass, Alyse N.;Kain, Heather S.;Kaushansky, Alexis
在无症状但专性肝脏感染阶段（LS）消除疟原虫将阻止疾病和随后的传播。不幸的是，只有一种获得许可的药物，针对所有LS，伯氨喹，是可用的。靶向宿主蛋白质可能会显着扩大抗疟疾预防药物的库。在这里，我们表明，Bcl-2抑制剂和P53激动剂显着降低LS负担在小鼠疟疾模型在体外和体内通过改变寄生虫依赖的关键肝细胞因子的活性。Bcl-2抑制剂主要通过诱导受感染肝细胞的细胞凋亡起作用，而P53激动剂以不依赖细胞凋亡的方式消除寄生虫。在组合中，Bcl-2抑制剂和P53激动剂协同作用以延迟并且在某些情况下完全预防血液期疾病的发作。这两个系列的药物在不会导致体外肝细胞大量死亡或体内肝损伤的剂量下都非常有效。P53激动剂和Bcl-2抑制剂也有效时，给予感染恶性疟原虫的人源化小鼠。我们的数据表明，基于宿主的预防可以发展成为一种有效的干预策略，在临床疾病发生之前消除LS寄生虫，从而为预防疟疾开辟了一条新的途径。
Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria.