锌簇转录因子改变白色念珠菌的毒力。,GENETICS

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锌簇转录因子改变白色念珠菌的毒力。
GENETICS ( IF 3.3 ) Pub Date : 2016-12-10 , DOI: 10.1534/genetics.116.195024
Luca Issi ₁ , Rhys A Farrer ₂ , Kelly Pastor ₁ , Benjamin Landry ₁ , Toni Delorey ₁ , George W Bell ₃ , Dawn A Thompson ₂ , Christina A Cuomo ₂ , Reeta P Rao ₄

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几乎所有人类都被白色念珠菌定殖。但是，在免疫功能低下的个体中，这种良性共生生物成为严重的威胁生命的病原体。在这里，我们描述并分析了调节宿主壁regulatory先天反应的调节网络。我们确定了Zcf15和Zcf29，两个白色念珠菌毒力所需的锌簇转录因子（ZCF）。从免疫功能低下的患者对白色念珠菌临床分离株的先前序列分析表明，两个ZCF基因在克隆进化过程中均发生了分化。使用体内动物模型，离体细胞培养方法和体外敏感性测定，我们证明ZCF15和ZCF29的敲除突变体对活性氧（ROS）高度敏感，表明它们有助于中和吞噬细胞产生的宿主源性ROS。，以及在体内建立持续感染的突变体在静止条件下，细胞未经历氧化应激的突变体的转录组学分析显示，一个大型网络可控制宏观和微量营养素稳态，这可能有助于宿主体内适当的病原体适应性。在氧化应激下，两个转录因子均调节涉及ROS解毒和下调核糖体生物发生的一组独立基因。ChIP-seq分析揭示了氧化应激前后每种转录因子（TF）的结合伴侣差异很大，进一步证实了这些结果。此外，不存在显性结合基序可能会促进它们的移动性，并支持它们代表病原性念珠菌属中ZCF家族最近扩展的观点。

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Zinc Cluster Transcription Factors Alter Virulence in Candida albicans.

Almost all humans are colonized with Candida albicans However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs.

更新日期：2019-11-01

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