Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster
Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster
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DOI：
10.1073/pnas.1914830117
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发表时间：
2020-03-31
影响因子：
11.1
通讯作者：
Lemaitre, Bruno
中科院分区：
文献类型：
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作者：
Iatsenko, Igor;Marra, Alice;Lemaitre, Bruno
铁固存是一种公认的先天免疫机制，可抵抗由铁结合蛋白（转铁蛋白）介导的病原体入侵。尽管有许多关于转铁蛋白体外抗菌活性的研究，但对其在体内的具体功能了解甚少。本研究以黑腹果蝇为体内模型，研究转铁蛋白在宿主防御中的作用。我们发现，各种病原体的全身感染会引发苍蝇的低铁血症反应，即铁从血淋巴中撤出并在脂肪体中积累。值得注意的是，这种对感染的低铁血症需要果蝇核因子κ B （nf - κ B）免疫通路Toll和Imd，这表明这些通路也介导果蝇的营养免疫。接下来，我们证明了铁转运体Tsf1是由Toll和Imd途径下游的感染诱导的，并且是铁从血淋巴转移到脂肪体所必需的。与血淋巴中铁水平升高一致，Tsf1突变体对假单胞菌和Mucorales真菌的敏感性增加，这可以通过铁的化学螯合来拯救。此外，利用缺乏铁载体的铜绿假单胞菌，我们发现铁载体pyoverdine在野生型苍蝇的发病中是必需的，但在Tsf1突变体中，由于这些苍蝇的血淋巴中存在过量的铁，它就变得必不可少了。因此，我们的研究表明，与哺乳动物类似，果蝇利用铁限制作为一种由保守的铁转运蛋白介导的免疫防御机制。我们的体内工作，以及积累的体外研究，支持昆虫转铁蛋白通过铁保留策略抵抗感染的免疫作用。
Iron sequestration is a recognized innate immune mechanism against invading pathogens mediated by iron-binding proteins called transferrins. Despite many studies on antimicrobial activity of transferrins in vitro, their specific in vivo functions are poorly understood. Here we use Drosophila melanogaster as an in vivo model to investigate the role of transferrins in host defense. We find that systemic infections with a variety of pathogens trigger a hypoferremic response in flies, namely, iron withdrawal from the hemolymph and accumulation in the fat body. Notably, this hypoferremia to infection requires Drosophila nuclear factor kappa B (NF-kappa B) immune pathways, Toll and Imd, revealing that these pathways also mediate nutritional immunity in flies. Next, we show that the iron transporter Tsf1 is induced by infections downstream of the Toll and Imd pathways and is necessary for iron relocation from the hemolymph to the fat body. Consistent with elevated iron levels in the hemolymph, Tsf1 mutants exhibited increased susceptibility to Pseudomonas bacteria and Mucorales fungi, which could be rescued by chemical chelation of iron. Furthermore, using siderophore-deficient Pseudomonas aeruginosa, we discover that the siderophore pyoverdine is necessary for pathogenesis in wild-type flies, but it becomes dispensable in Tsf1 mutants due to excessive iron present in the hemolymph of these flies. As such, our study reveals that, similar to mammals, Drosophila uses iron limitation as an immune defense mechanism mediated by conserved iron-transporting proteins transferrins. Our in vivo work, together with accumulating in vitro studies, supports the immune role of insect transferrins against infections via an iron withholding strategy.