Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection
Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection
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DOI：
10.1016/j.celrep.2020.03.032
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发表时间：
2020-03-31
期刊：
影响因子：
8.8
通讯作者：
Boddey, Justin A.
中科院分区：
文献类型：
--
作者：
Ebert, Gregor;Lopaticki, Sash;Boddey, Justin A.
疟原虫子孢子感染肝脏并发育成引发血液期疾病的红细胞外裂殖子。肝细胞的分子通路，允许或废除寄生虫复制和裂殖子形成尚未彻底探讨，更深入的了解可能会确定治疗策略，以减轻疟疾。细胞凋亡抑制因子（cIAP）蛋白调节细胞存活并被细胞内病原体吸收以支持发育。在这里，我们表明，cIAP 1水平在疟原虫肝脏感染过程中上调，并使用临床阶段拮抗剂的cIAPs的遗传或药理学靶向优先杀死感染的肝细胞，促进免疫。使用基因靶向小鼠，其机制被定义为TNF-TNFR 1介导的凋亡通过半胱天冬酶3和8来清除寄生虫。这项研究揭示了cIAP对疟原虫感染的重要性，并表明宿主导向的抗疟药物可以消除肝脏寄生虫并诱导免疫力，同时可能为寄生虫的耐药性提供高屏障。
Plasmodium sporozoites infect the liver and develop into exoerythrocytic merozoites that initiate blood-stage disease. The hepatocyte molecular pathways that permit or abrogate parasite replication and merozoite formation have not been thoroughly explored, and a deeper understanding may identify therapeutic strategies to mitigate malaria. Cellular inhibitor of apoptosis (cIAP) proteins regulate cell survival and are co-opted by intracellular pathogens to support development. Here, we show that cIAP1 levels are upregulated during Plasmodium liver infection and that genetic or pharmacological targeting of cIAPs using clinical-stage antagonists preferentially kills infected hepatocytes and promotes immunity. Using gene-targeted mice, the mechanism was defined as TNF-TNFR1-mediated apoptosis via caspases 3 and 8 to clear parasites. This study reveals the importance of cIAPs to Plasmodium infection and demonstrates that host-directed antimalarial drugs can eliminate liver parasites and induce immunity while likely providing a high barrier to resistance in the parasite.