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.

疟原虫子孢子虫感染肝脏并发展为引发血液阶段疾病的外红细胞子裂殖子。尚未彻底探讨允许或消除寄生虫复制和裂殖子形成的肝细胞分子途径，更深入的了解可能会确定减轻疟疾的治疗策略。细胞凋亡抑制蛋白（cIAP）调节细胞存活，并被细胞内病原体共同支持发育。在这里，我们显示了疟原虫期间cIAP1的水平上调肝感染以及使用临床阶段拮抗剂对cIAP进行遗传或药理靶向可优先杀死受感染的肝细胞并增强免疫力。使用靶向基因的小鼠，其机制被定义为通过胱天蛋白酶3和8清除寄生虫的TNF-TNFR1介导的凋亡。这项研究揭示了cIAP对疟原虫感染的重要性，并证明了针对宿主的抗疟疾药物可以消除肝脏寄生虫并诱导免疫力，同时可能对寄生虫产生抵抗力。