Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.
Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.
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DOI：
10.1016/j.chom.2012.06.007
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发表时间：
2012-08-16
影响因子：
30.3
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
LaMonte G;Philip N;Reardon J;Lacsina JR;Majoros W;Chapman L;Thornburg CD;Telen MJ;Ohler U;Nicchitta CV;Haystead T;Chi JT
携带变异血红蛋白等位基因（HbS）的红细胞可抵抗疟疾寄生虫恶性疟原虫的感染，该等位基因可导致镰状细胞病。这种耐药性的分子基础一直被认为是多因素的，但仍然没有完全弄清楚。在这里，我们表明杂合HbAS或纯合HbSS红细胞的microRNA组成失调有助于对恶性疟原虫的抵抗力。在恶性疟原虫的红细胞内生命周期中，红细胞microRNA的一个子集易位到寄生虫中。两种microRNA，miR-451和let-7i，在HbAS和HbSS红细胞中高度富集，并且这些miRNA，沿着miR-223，负调节寄生虫生长。令人惊讶的是，我们发现miR-451和let-7i整合到必需的寄生虫mRNA中，并通过受损的核糖体加载，导致翻译抑制。因此，镰状红细胞表现出细胞内在的抗疟疾，部分通过一个非典型的microRNA活性，这可能是一个独特的宿主防御策略，对复杂的真核病原体。
Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease, resist infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic lifecycle of P. falciparum, a subset of erythrocyte microRNAs translocate into the parasite. Two microRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite mRNAs and, via impaired ribosomal loading, resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical microRNA activity which may represent a unique host defense strategy against complex eukaryotic pathogens.
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