Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response
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DOI：
10.1128/mbio.0013-16
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发表时间：
2016-03-01
期刊：
影响因子：
6.4
通讯作者：
Doering, Tamara L.
中科院分区：
文献类型：
--
作者：
Gish, Stacey R.;Maier, Ezekiel J.;Doering, Tamara L.
新型隐球菌是一种普遍存在的机会性真菌病原体，每年导致超过60万人死亡。在这里，我们报告了隐球菌感染中转录调控的作用和机制的综合计算和实验研究。隐球菌的主要毒力特征包括黑色素的产生和宿主进入后大多糖荚膜的发展;脱落的荚膜多糖也会损害宿主的防御能力。我们发现，转录和翻译都需要胶囊的生长和Usv 101是一个主调节器的发病机制，调节黑色素的产生，胶囊的生长，和胶囊脱落。它通过直接调节编码糖活性酶的基因和编码其他三种对荚膜生长至关重要的转录因子的基因来实现这一点：GAT 201，RIM 101和SP1。鼠感染隐球菌缺乏Usv 101显着改变的动力学和发病机制的疾病，延长生存期，意外的是，死亡的肺炎，而不是脑膜炎我们的方法和发现将通知其他病原微生物的研究。重要性新型隐球菌导致致命的脑膜炎免疫功能低下的个人，主要是艾滋病毒阳性，每年杀死超过60万。这种酵母的一个独特的特征，使它特别有毒，是它的多糖胶囊;这种结构阻碍宿主对抗感染的努力。胶囊的大小和结构响应于环境条件，例如在受感染的宿主中遇到的环境条件。我们结合了计算和实验工具来阐明胶囊调节，我们表明主要发生在转录水平。我们还表明，一种新的转录因子的损失改变了毒力因子的表达和宿主细胞的相互作用，改变了致命的条件，从脑膜炎肺炎与加剧的主机响应。我们进一步展示了相关的目标的监管和动力学地图的关键监管和主机的相互作用。我们的工作阐明了胶囊调节的机制，为研究界提供了方法和资源，并证明了类似于某些人类条件的改变的致病结果。
Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. We found that both transcription and translation are required for capsule growth and that Usv101 is a master regulator of pathogenesis, regulating melanin production, capsule growth, and capsule shedding. It does this by directly regulating genes encoding glycoactive enzymes and genes encoding three other transcription factors that are essential for capsule growth: GAT201, RIM101, and SP1. Murine infection with cryptococci lacking Usv101 significantly alters the kinetics and pathogenesis of disease, with extended survival and, unexpectedly, death by pneumonia rather than meningitis Our approaches and findings will inform studies of other pathogenic microbes.IMPORTANCE Cryptococcus neoformans causes fatal meningitis in immunocompromised individuals, mainly HIV positive, killing over 600,000 each year. A unique feature of this yeast, which makes it particularly virulent, is its polysaccharide capsule; this structure impedes host efforts to combat infection. Capsule size and structure respond to environmental conditions, such as those encountered in an infected host. We have combined computational and experimental tools to elucidate capsule regulation, which we show primarily occurs at the transcriptional level. We also demonstrate that loss of a novel transcription factor alters virulence factor expression and host cell interactions, changing the lethal condition from meningitis to pneumonia with an exacerbated host response. We further demonstrate the relevant targets of regulation and kinetically map key regulatory and host interactions. Our work elucidates mechanisms of capsule regulation, provides methods and resources to the research community, and demonstrates an altered pathogenic outcome that resembles some human conditions.