NADPH oxidase-driven phagocyte recruitment controls Candida albicans filamentous growth and prevents mortality.
NADPH oxidase-driven phagocyte recruitment controls Candida albicans filamentous growth and prevents mortality.
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DOI：
10.1371/journal.ppat.1003634
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Wheeler RT
中科院分区：
文献类型：
--
作者：
Brothers KM;Gratacap RL;Barker SE;Newman ZR;Norum A;Wheeler RT
白色念珠菌是一种重要的人类肠道和临床真菌病原体，在人类、小鼠和斑马鱼感染过程中以酵母和菌丝形式生长。由NADPH氧化酶产生的活性氧在免疫中起着多种作用，包括其作为杀微生物氧化剂的长期功能。在这里，我们证明了NADPH氧化酶在促进吞噬细胞趋化性和细胞内遏制真菌限制丝状生长的非传统机制作用。我们利用透明的斑马鱼模型来显示失败的NADPH氧化酶依赖的吞噬细胞募集到C。在感染后的前四个小时内，白色念珠菌允许真菌在细胞外萌发并杀死宿主。我们结合联合收割机化学和遗传工具与高分辨率延时显微镜牵连吞噬细胞氧化酶和双特异性氧化酶的招聘，这表明骨髓和非骨髓细胞促进趋化性。我们表明，早期非侵入性成像提供了一个强大的工具，预后，强烈连接有效的早期免疫反应与生存。最后，我们证明了一个新的作用，酵母菌菌丝开关程序在吞噬细胞介导的遏制的关键调节，这表明有种特异性的方法来调节NADPH氧化酶独立的免疫反应。ROS驱动的趋化性和真菌二型性之间的这些新联系扩展了我们对关键宿主防御机制的看法，并对发病机制具有重要意义。45年前，慢性肉芽肿性疾病（CGD）被归因于中性粒细胞无法进行呼吸爆发，现在已知它是由吞噬细胞NADPH氧化酶复合物中的原发性遗传缺陷引起的。最近的研究表明，NADPH氧化酶产生的活性氧具有其他重要功能，如成熟激素和促进蛋白激酶信号转导。白色念珠菌是一种机会致病菌，它会捕食免疫功能低下的患者，导致致命的念珠菌血症。我们使用透明的斑马鱼幼体描述了吞噬细胞氧化酶和双特异性NADPH氧化酶在指导吞噬细胞募集到C。白色念珠菌感染灶。我们证明，NADPH氧化酶依赖的中性粒细胞和巨噬细胞的吸引力是有助于有效遏制酵母菌内的吞噬细胞，防止酵母菌菌丝形态发生开关，并限制死亡率。值得注意的是，当真菌形态发生开关被突变阻止时，有效的真菌遏制不再需要NADPH氧化酶活性。我们的研究表明，CGD的缺陷可能超出了减少超氧化物的微生物杀灭，包括趋化性的损害，并提供了一个基础，探索这种替代功能在哺乳动物中。
Candida albicans is a human commensal and clinically important fungal pathogen that grows as both yeast and hyphal forms during human, mouse and zebrafish infection. Reactive oxygen species (ROS) produced by NADPH oxidases play diverse roles in immunity, including their long-appreciated function as microbicidal oxidants. Here we demonstrate a non-traditional mechanistic role of NADPH oxidase in promoting phagocyte chemotaxis and intracellular containment of fungi to limit filamentous growth. We exploit the transparent zebrafish model to show that failed NADPH oxidase-dependent phagocyte recruitment to C. albicans in the first four hours post-infection permits fungi to germinate extracellularly and kill the host. We combine chemical and genetic tools with high-resolution time-lapse microscopy to implicate both phagocyte oxidase and dual-specific oxidase in recruitment, suggesting that both myeloid and non-myeloid cells promote chemotaxis. We show that early non-invasive imaging provides a robust tool for prognosis, strongly connecting effective early immune response with survival. Finally, we demonstrate a new role of a key regulator of the yeast-to-hyphal switching program in phagocyte-mediated containment, suggesting that there are species-specific methods for modulation of NADPH oxidase-independent immune responses. These novel links between ROS-driven chemotaxis and fungal dimorphism expand our view of a key host defense mechanism and have important implications for pathogenesis. Over 45 years ago chronic granulomatous disease (CGD) was ascribed to a failure of neutrophils to mount a respiratory burst, and it is now known to result from primary genetic deficiencies in the phagocyte NADPH oxidase complex. Recent work suggests that reactive oxygen species produced by NADPH oxidases have other important functions as diverse as maturing hormones and promoting protein kinase signal transduction. Candida albicans is an opportunistic pathogen that preys on immunocompromised patients to cause lethal candidemia. We used the transparent zebrafish larva to describe a novel function of both phagocyte oxidase and dual-specific NADPH oxidase in directing phagocyte recruitment to C. albicans infection foci. We demonstrate that NADPH oxidase-dependent attraction of neutrophils and macrophages is instrumental in effective containment of yeast within phagocytes, which prevents the yeast-to-hyphal morphogenetic switch and limits mortality. Remarkably, when the fungal morphogenetic switch is prevented by mutation, NADPH oxidase activity is no longer required for effective fungal containment. Our study suggests that defects in CGD may extend beyond reduced microbial killing by superoxide to include impairment of chemotaxis, and provide a basis for exploring this alternative function in mammals.
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影响因子：
6.4
作者：
Christin, L;Wysong, DR;Diamond, RD
通讯作者：
Diamond, RD
DOI：
10.1016/j.bbrc.2010.08.037
发表时间：
2010-09-10
影响因子：
3.1
作者：
Flores, Maria Vega;Crawford, Katie C.;Crosier, Philip S.
通讯作者：
Crosier, Philip S.
影响因子：
--
作者：
Brothers, Kimberly M.;Newman, Zachary R.;Wheeler, Robert T.
通讯作者：
Wheeler, Robert T.
影响因子：
10.5
作者：
Chen, H;Fink, GR
通讯作者：
Fink, GR
影响因子：
3.3
作者：
Carlisle, Patricia L.;Kadosh, David
通讯作者：
Kadosh, David