Malaria parasite liver stages render host hepatocytes susceptible to mitochondria-initiated apoptosis.
Malaria parasite liver stages render host hepatocytes susceptible to mitochondria-initiated apoptosis.
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DOI：
10.1038/cddis.2013.286
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发表时间：
2013-08-08
影响因子：
9
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中科院分区：
文献类型：
--
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胞内真核寄生虫及其宿主细胞构成复杂的、共同进化的细胞相互作用系统，经常引起疾病。其中，疟原虫对人类造成严重的健康负担，每年导致多达100万人死亡。疟原虫通过蚊子传播后，要在哺乳动物宿主中成功传播，必须在肝细胞内完成细胞内复制，然后将新的感染形式释放到血液中。利用约利疟原虫啮齿动物疟疾寄生虫，我们发现一些肝期（LS）感染的肝细胞在没有外部触发的情况下发生凋亡，但大多数感染的细胞不发生凋亡，并且也可以抵抗fas介导的凋亡。相比之下，被减毒寄生虫感染的肝细胞凋亡显著增加。此外，我们发现阻断宿主细胞总凋亡或线粒体启动的凋亡会增加小鼠LS寄生虫的负担，这表明抗凋亡的宿主环境促进了寄生虫的存活。引人注目的是，尽管LS感染对外源性宿主肝细胞凋亡具有很强的抵抗力，但当抗凋亡线粒体蛋白被抑制时，感染的肝细胞失去了抵抗凋亡的能力。我们发现b细胞淋巴瘤2家族抑制剂优先诱导LS感染的肝细胞凋亡，并显著降低小鼠LS寄生虫负担，证明了这一点。因此，针对ls感染宿主细胞的敏感点可能为疟疾预防提供新的途径。
Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS)-infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria-initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti-apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis.
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影响因子：
8.8
作者：
Kaushansky A;Ye AS;Austin LS;Mikolajczak SA;Vaughan AM;Camargo N;Metzger PG;Douglass AN;MacBeath G;Kappe SH
通讯作者：
Kappe SH
影响因子：
56.9
作者：
Sturm, Angelika;Amino, Rogerio;Heussler, Volker T.
通讯作者：
Heussler, Volker T.
影响因子：
3.1
作者：
Labaied, Mehdi;Harupa, Anke;Kappe, Stefan H. I.
通讯作者：
Kappe, Stefan H. I.
影响因子：
56.9
作者：
Mota, MM;Pradel, G;Rodríguez, A
通讯作者：
Rodríguez, A
影响因子：
32.4
作者：
Strasser, Andreas;Jost, Philipp J.;Nagata, Shigekazu
通讯作者：
Nagata, Shigekazu