Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria.
Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria.
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DOI：
10.1128/mbio.00725-15
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发表时间：
2015-06-02
期刊：
影响因子：
6.4
通讯作者：
Pierce SK
中科院分区：
文献类型：
--
作者：
Gordon EB;Hart GT;Tran TM;Waisberg M;Akkaya M;Skinner J;Zinöcker S;Pena M;Yazew T;Qi CF;Miller LH;Pierce SK
疟疾是一种由几种疟原虫寄生虫引起的传染病，脑型疟疾（CM）是一种常见的严重疟疾，每年仅在非洲就造成近70万人死亡。目前，CM没有辅助治疗方法。虽然CM的发病机制尚不完全清楚，但很可能是寄生虫的内在特征和人类宿主的免疫反应都导致了疾病。哺乳动物雷帕霉素激酶靶点（mTOR）是免疫反应的中枢调节因子，抑制mTOR通路的药物已被证明具有抗寄生虫作用。在小鼠CM模型，实验性CM （ECM）中，我们发现mTOR抑制剂雷帕霉素在感染的头4天内给予抗ECM。雷帕霉素治疗提高了生存率，阻断了血脑屏障的破坏和脑出血，减少了CD4+和CD8+ T细胞流入大脑和寄生红细胞在大脑中的积累。雷帕霉素在感染小鼠的大脑中诱导了显著的转录变化，转录谱的分析预测雷帕霉素阻断了白细胞向大脑的运输和增殖。值得注意的是，尽管雷帕霉素治疗显著增加了脑和脾脏感染引起的炎症反应，但动物对ECM有保护作用。这些结果为通过靶向调节宿主和寄生虫代谢的途径开发高选择性的CM辅助疗法开辟了新的途径。疟疾是由几种疟原虫的寄生虫引起的一种高度流行的传染病。疟疾通常不复杂，并随着时间的推移而消退；然而，在大约1%的病例中，几乎全部是幼儿，疟疾变得严重并危及生命，每年仅在非洲就造成近70万人死亡。恶性疟原虫感染最严重的并发症之一是脑型疟疾，尽管有抗疟药物治疗，但死亡率仍为15%至20%。脑型疟疾对非洲儿童造成了第二种伤害，使幸存者面临使人衰弱的神经系统缺陷的高风险。目前，我们没有针对脑型疟疾的有效辅助疗法，而开发这种疗法将对拯救非洲年轻生命产生重大影响。在这里，我们报告的结果为通过靶向调节宿主和寄生虫代谢的途径开发高选择性脑疟疾辅助疗法开辟了新的途径。
Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host’s immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.