Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection.
Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection.
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DOI：
10.1371/journal.ppat.1003522
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Padmanaban G
中科院分区：
文献类型：
--
作者：
Nagaraj VA;Sundaram B;Varadarajan NM;Subramani PA;Kalappa DM;Ghosh SK;Padmanaban G
血红素代谢是疟疾寄生虫生物学的核心。寄生虫在红细胞内阶段从宿主血红蛋白中获得血红素，并将其储存为疟原虫色素以防止游离血红素毒性。寄生虫也可以合成血红素从头，和所有的酶的途径的特点。为了研究血红素双源在疟原虫生长发育中的作用，我们敲除了伯氏疟原虫（Plasmodium berghei，Pb）血红素生物合成途径中的第一个酶δ-氨基乙酰丙酸合成酶（δ-aminolevulinate synthase，ALAS）和最后一个酶亚铁螯合酶（ferrochelatase，FC）。野生型和敲除（KO）寄生虫在小鼠中具有相似的红细胞内生长模式。我们进行了体外放射性标记血红素在铅感染的小鼠网织红细胞和恶性疟原虫感染的人红细胞使用[4- 14 C]氨基乙酰丙酸（ALA）。我们发现，寄生虫纳入宿主血红蛋白血红素和寄生虫合成血红素成疟原虫色素和线粒体细胞色素。两种血红素来源的相似命运表明它们可以作为在红细胞内阶段提供血红素的备用机制。尽管如此，从头途径对于蚊子和肝脏阶段的寄生虫发育是绝对必要的。PbKO寄生虫形成急剧减少的卵囊，并且在唾液腺中不形成子孢子。当蚊子接受ALA补充剂时，PbALASKO寄生虫的卵囊生产恢复。PbALASKO子孢子只有在小鼠接受ALA补充时才能感染小鼠。我们的研究结果表明，针对血红素生物合成途径的寄生虫在蚊子和肝脏阶段的新的治疗干预的潜力。大约20年前，我们证明了疟原虫可以自己制造血红素，尽管它在感染的血液阶段从红细胞血红蛋白中输入血红素。我们通过敲除感染小鼠的伯氏疟原虫血红素生物合成途径中的两个基因，研究了寄生虫合成血红素在寄生虫生长的各个阶段中的作用。我们发现寄生虫合成的血红素在血液阶段补充血红蛋白血红素的功能。寄生虫合成的血红素似乎是一种备用机制。该寄生虫将血红素的两种来源结合成一种解毒产物--疟原虫色素，并结合成线粒体细胞色素。然而，寄生虫合成的血红素对于蚊子和肝脏阶段的寄生虫生长绝对必要。我们通过提供缺失的代谢物恢复了子孢子形成和敲除寄生虫的肝脏阶段发育。因此，血红素生物合成途径可能是蚊子和肝脏感染阶段抗疟治疗的目标。敲除寄生虫也可以测试其作为遗传减毒子孢子疫苗的潜力。
Heme metabolism is central to malaria parasite biology. The parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. The parasite can also synthesize heme de novo, and all the enzymes in the pathway are characterized. To study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, δ-aminolevulinate synthase (ALAS), and the last enzyme, ferrochelatase (FC), in the heme-biosynthetic pathway of Plasmodium berghei (Pb). The wild-type and knockout (KO) parasites had similar intraerythrocytic growth patterns in mice. We carried out in vitro radiolabeling of heme in Pb-infected mouse reticulocytes and Plasmodium falciparum-infected human RBCs using [4-14C] aminolevulinic acid (ALA). We found that the parasites incorporated both host hemoglobin-heme and parasite-synthesized heme into hemozoin and mitochondrial cytochromes. The similar fates of the two heme sources suggest that they may serve as backup mechanisms to provide heme in the intraerythrocytic stages. Nevertheless, the de novo pathway is absolutely essential for parasite development in the mosquito and liver stages. PbKO parasites formed drastically reduced oocysts and did not form sporozoites in the salivary glands. Oocyst production in PbALASKO parasites recovered when mosquitoes received an ALA supplement. PbALASKO sporozoites could infect mice only when the mice received an ALA supplement. Our results indicate the potential for new therapeutic interventions targeting the heme-biosynthetic pathway in the parasite during the mosquito and liver stages. We demonstrated about two decades ago that the malaria parasite could make heme on its own, although it imports heme from red blood cell hemoglobin during the blood stages of infection. We investigated the role of parasite-synthesized heme in all stages of parasite growth by knocking out two genes in the heme-biosynthetic pathway of Plasmodium berghei that infects mice. We found that the parasite-synthesized heme complements the function of hemoglobin-heme during the blood stages. The parasite-synthesized heme appears to be a backup mechanism. The parasite incorporates both sources of heme into hemozoin, a detoxification product, and into mitochondrial cytochromes. The parasite-synthesized heme is, however, absolutely essential for parasite growth during the mosquito and liver stages. We restored the sporozoite formation and liver-stage development of the knockout parasites by providing the missing metabolite. Thus, the heme-biosynthetic pathway could be a target for antimalarial therapies in the mosquito and liver stages of infection. The knockout parasite could also be tested for its potential as a genetically attenuated sporozoite vaccine.
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影响因子：
64.5
作者：
Ferreira, Ana;Marguti, Ivo;Soares, Miguel P.
通讯作者：
Soares, Miguel P.
DOI：
10.1073/pnas.0711067105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Elliott, David A.;McIntosh, Michael T.;Joiner, Keith A.
通讯作者：
Joiner, Keith A.
影响因子：
2
作者：
Lamarque, Mauld;Tastet, Christophe;Dubremetz, Jean-Francois
通讯作者：
Dubremetz, Jean-Francois
影响因子：
4.8
作者：
Bonday, ZQ;Taketani, S;Padmanaban, G
通讯作者：
Padmanaban, G
影响因子：
4.8
作者：
Campanale, N;Nickel, C;Tilley, L
通讯作者：
Tilley, L