Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species
Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species
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DOI：
10.1128/ec.00290-12
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Lorenz, Michael C.
中科院分区：
文献类型：
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作者：
Jimenez-Lopez, Claudia;Collette, John R.;Lorenz, Michael C.
白色念珠菌与宿主先天免疫系统的吞噬细胞的相互作用是高度动态的，其结果直接影响感染的进展。虽然巨噬细胞内向菌丝生长的转变是最明显的生理反应，但大部分遗传反应反映了营养匮乏：翻译抑制和替代碳代谢的诱导。氨基酸代谢没有发生变化，但精氨酸生物合成除外，精氨酸生物合成在与巨噬细胞共培养期间整体上调。使用单细胞报告基因，我们在此表明精氨酸生物合成基因是在吞噬细胞中特异性诱导的。这种诱导的强度低于体外精氨酸饥饿期间的水平，并且不是由吞噬细胞内的精氨酸缺乏引起的，而是由暴露于活性氧（ROS）引起的。奇怪的是，这些基因是在亚致死 ROS 浓度的狭窄窗口内诱导的。被缺乏吞噬细胞氧化酶 gp91(phox) 亚基的原代巨噬细胞吞噬的白色念珠菌细胞不表达 ARG 途径，表明诱导依赖于吞噬细胞氧化爆发。白色念珠菌 arg 途径突变体在巨噬细胞内的芽管和菌丝形成方面受到阻滞，但对 ROS 并没有明显更敏感。我们还发现，ARG 通路不是由一般氨基酸控制反应调节，而是由类似于酿酒酵母 ArgR 复合体的转录调节因子调节。总之，吞噬作用以 ROS 依赖性方式诱导这种单一氨基酸生物合成途径。
The interaction of Candida albicans with phagocytes of the host's innate immune system is highly dynamic, and its outcome directly impacts the progression of infection. While the switch to hyphal growth within the macrophage is the most obvious physiological response, much of the genetic response reflects nutrient starvation: translational repression and induction of alternative carbon metabolism. Changes in amino acid metabolism are not seen, with the striking exception of arginine biosynthesis, which is upregulated in its entirety during coculture with macrophages. Using single-cell reporters, we showed here that arginine biosynthetic genes are induced specifically in phagocytosed cells. This induction is lower in magnitude than during arginine starvation in vitro and is driven not by an arginine deficiency within the phagocyte but instead by exposure to reactive oxygen species (ROS). Curiously, these genes are induced in a narrow window of sublethal ROS concentrations. C. albicans cells phagocytosed by primary macrophages deficient in the gp91(phox) subunit of the phagocyte oxidase do not express the ARG pathway, indicating that the induction is dependent on the phagocyte oxidative burst. C. albicans arg pathway mutants are retarded in germ tube and hypha formation within macrophages but are not notably more sensitive to ROS. We also find that the ARG pathway is regulated not by the general amino acid control response but by transcriptional regulators similar to the Saccharomyces cerevisiae ArgR complex. In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner.