Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection.
Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection.
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DOI：
10.1371/journal.ppat.0030128
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发表时间：
2007-09-28
期刊：
影响因子：
6.7
通讯作者：
Haas, Hubertus
中科院分区：
文献类型：
--
作者：
Schrettl, Markus;Bignell, Elaine;Kragl, Claudia;Sabiha, Yasmin;Loss, Omar;Eisendle, Martin;Wallner, Anja;Arst, Herbert N Jr;Haynes, Ken;Haas, Hubertus
高致死性霉菌烟曲霉的铁载体生物合成对于毒力至关重要，但在人类中并不存在，这为针对这种病原体制定治疗策略提供了难得的机会。我们之前已经证明烟曲霉分泌镰刀菌素C和三乙酰镰刀菌素C来捕获细胞外铁，并利用铁红素来储存菌丝铁。在这里，我们描绘了细胞内和细胞外铁载体生物合成的途径，并表明烟曲霉合成了一种发育调节的第四种铁载体，称为羟基铁载体，用于分生孢子铁储存。通过非核糖体肽合成酶 SidC 的失活，我们证明细胞内铁载体是芽管形成、无性孢子形成、氧化应激抵抗、过氧化氢酶 A 活性和毒力所必需的。分生孢子羟基铁红素含量的恢复部分恢复了非致病性铁载体无效突变体ΔsidA的毒力，证明了分生孢子铁载体在感染起始过程中的重要作用。酰基转移酶 SidF 或非核糖体肽合成酶 SidD 失活后细胞外铁载体生物合成的废除导致在铁限制条件下生长完全依赖还原性铁同化，对氧化应激部分敏感，并且毒力显着降低，尽管胚芽管形成正常。我们的研究结果揭示了哺乳动物曲霉感染期间细胞内和细胞外铁载体的独特细胞和疾病相关作用。由于癌症治疗、艾滋病毒/艾滋病、器官移植或遗传性疾病而导致免疫系统受到抑制的患者，感染普遍存在的真菌病原体烟曲霉的风险很高。这种疾病（统称为侵袭性曲霉病）的治疗通常不成功，生存前景也很渺茫。烟曲霉产生小分子，称为铁载体，用于获取和储存铁，铁是生长所必需的元素。我们发现这些铁载体对于烟曲霉的毒力至关重要，因为它们的去除（通过基因删除）可以预防或减轻侵袭性曲霉病小鼠模型的疾病。铁载体不是由人类产生的，因此它们为新疗法提供了良好的前景，因为专门针对铁载体产生而不是人类和真菌共有的活动的药物不太可能对患者产生不利影响。
Siderophore biosynthesis by the highly lethal mould Aspergillus fumigatus is essential for virulence, but non-existent in humans, presenting a rare opportunity to strategize therapeutically against this pathogen. We have previously demonstrated that A. fumigatus excretes fusarinine C and triacetylfusarinine C to capture extracellular iron, and uses ferricrocin for hyphal iron storage. Here, we delineate pathways of intra- and extracellular siderophore biosynthesis and show that A. fumigatus synthesizes a developmentally regulated fourth siderophore, termed hydroxyferricrocin, employed for conidial iron storage. By inactivation of the nonribosomal peptide synthetase SidC, we demonstrate that the intracellular siderophores are required for germ tube formation, asexual sporulation, resistance to oxidative stress, catalase A activity, and virulence. Restoration of the conidial hydroxyferricrocin content partially rescues the virulence of the apathogenic siderophore null mutant ΔsidA, demonstrating an important role for the conidial siderophore during initiation of infection. Abrogation of extracellular siderophore biosynthesis following inactivation of the acyl transferase SidF or the nonribosomal peptide synthetase SidD leads to complete dependence upon reductive iron assimilation for growth under iron-limiting conditions, partial sensitivity to oxidative stress, and significantly reduced virulence, despite normal germ tube formation. Our findings reveal distinct cellular and disease-related roles for intra- and extracellular siderophores during mammalian Aspergillus infection. Patients with suppressed immune systems due to cancer treatments, HIV/AIDS, organ transplantation, or genetic disorders are at high risk of infection with the ubiquitously present fungal pathogen Aspergillus fumigatus. Treatments for this disease, collectively termed invasive aspergillosis, are often not successful, and prospects for survival can be slim. A. fumigatus produces small molecules, termed siderophores, for acquisition and storage of iron, an element essential for growth. We found that these siderophores are crucial for virulence of A. fumigatus because their removal (by gene deletion) prevents or lessens disease in a mouse model of invasive aspergillosis. Siderophores are not produced by humans so they present good prospects for new therapies, as drugs that specifically target siderophore production, rather than activities shared by humans and fungi, are less likely to affect patients adversely.