A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes
A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes
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DOI：
10.1084/jem.20060559
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发表时间：
2006-10-02
影响因子：
15.3
通讯作者：
Andrews, Norma W.
中科院分区：
文献类型：
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作者：
Huynh, Chau;Sacks, David L.;Andrews, Norma W.
亚马逊利什曼原虫对哺乳动物宿主的感染取决于这些寄生虫在巨噬细胞吞噬溶酶体内复制的卓越能力。在这种恶劣的环境中生存的一个关键适应是获得铁的有效机制。在本研究中，我们鉴定并表征了 LIT1，这是一种新型亚马逊 L. amazonensis 膜蛋白，与来自拟南芥的 ZIP 家族亚铁转运蛋白 IRT1 具有广泛的相似性。 LIT1 促进铁转运的能力在酵母和 L. amazonensis LIT1 缺失无鞭毛体中表达后得到证实。内源性 LIT1 仅在细胞内复制的无鞭毛体中可检测到，并且其细胞内表达在预计会导致铁缺乏的条件下加速。尽管缺乏LIT1的亚马逊乳杆菌在无菌培养物中正常生长并且没有分化为感染形式的缺陷，但巨噬细胞内的复制被废除。与 LIT1 在无鞭毛体细胞内生长中的重要作用一致，Delta lit1 寄生虫是无毒的。接种到高度易感的小鼠体内后，即使经过很长一段时间也没有检测到病变。尽管不存在病理学，但从原始接种位点回收了活的 Delta lit1 寄生虫，这表明亚马逊乳杆菌可以在体内持续存在，而与在巨噬细胞中生长的能力无关。我们的研究结果强调了细胞内铁获取在利什曼原虫毒力中发挥的重要作用，并将该途径确定为治疗干预的有希望的目标。
Infection of mammalian hosts with Leishmania amazonensis depends on the remarkable ability of these parasites to replicate within macrophage phagolysosomes. A critical adaptation for survival in this harsh environment is an efficient mechanism for gaining access to iron. In this study, we identify and characterize LIT1, a novel L. amazonensis membrane protein with extensive similarity to IRT1, a ZIP family ferrous iron transporter from Arabidopsis thaliana. The ability of LIT1 to promote iron transport was demonstrated after expression in yeast and in L. amazonensis LIT1-null amastigotes. Endogenous LIT1 was only detectable in amastigotes replicating intracellularly, and its intracellular expression was accelerated under conditions predicted to result in iron deprivation. Although L. amazonensis lacking LIT1 grew normally in axenic culture and had no defects differentiating into infective forms, replication within macrophages was abolished. Consistent with an essential role for LIT1 in intracellular growth as amastigotes, Delta lit1 parasites were avirulent. After inoculation into highly susceptible mice, no lesions were detected, even after extensive periods of time. Despite the absence of pathology, viable Delta lit1 parasites were recovered from the original sites of inoculation, indicating that L. amazonensis can persist in vivo independently of the ability to grow in macrophages. Our findings highlight the essential role played by intracellular iron acquisition in Leishmania virulence and identify this pathway as a promising target for therapeutic intervention.