Signals and switches for Candida albicans commensalism

描述（由申请人提供）：肠道微生物如何引起疾病？一般认为，由寄生生物引起的侵入性感染主要是由于宿主免疫力的破坏。然而，也有可能这些微生物在嗜热菌性和毒力程序之间积极转换。事实上，我们最近发现，暴露于人类真菌性脑膜炎病原体C。白色念珠菌进入哺乳动物肠道触发了一个重大的发育转变。这种开关需要经过充分研究的Wor1转录因子，该转录因子被认为仅在罕见的遗传背景下表达，在这种背景下，它促进了参与交配的表观遗传开关。相反，我们发现这种转录因子的表达可以在野生型细胞中发生，但只有当它们通过哺乳动物肠道时才能表达。我们已经证明，在宿主中的WOR1表达诱导一种新的开关，重新编程细胞和菌落形态，并赋予植物适应性。这些GUT（胃肠道诱导的转变）细胞缺乏有性能力的不透明细胞的功能标志，它们在形态上类似，真正的不透明细胞在生殖功能上是有缺陷的。相反，GUT细胞转录组似乎是针对哺乳动物远端消化道的环境而优化的。我们对GUT细胞类型转换的发现提供了对单个微生物如何在寄生虫病和侵入性组织发病机制之间转变的深入了解。我们建议利用这一进展，发展的概念，一个单一的生物体可以是一个寄生虫和病原体通过进化的适应性开关在细胞类型，是由宿主环境的变化触发。为了实现这一目标，我们将1）识别介导白色GUT开关的Wor1调节回路的节点，2）识别触发白色GUT开关的环境信号和调节途径，3）测试C需要开关的假设。白色念珠菌从病原体转变为病原体。我们预计，这些研究将定义一个新的监管网络所需的念珠菌，确定触发这个网络的信号，并发展其作用的能力，念珠菌切换到病原体的能力的理解。预计这些进展将为预防性策略打开大门，这些策略将在高风险患者（如早产儿和接受广谱抗生素治疗的住院成人）中消除念珠菌。

DESCRIPTION (provided by applicant): How do commensal microbes cause disease? It is generally assumed that invasive infections produced by commensal organisms result primarily from a breakdown of host immunity. However, it is also possible that these microbes actively transition between programs of commensalism and virulence. Indeed, we have recently discovered that exposure of the human fungal commensal-pathogen C. albicans to the mammalian gut triggers a major developmental switch. This switch requires the well-studied Wor1 transcription factor, which was thought to be expressed only in rare genetic backgrounds where it promotes an epigenetic switch involved in mating. In contrast, we discovered that expression of this transcription factor can occur in wild-type cells but only when they pass through the mammalian gut. We have demonstrated that WOR1 expression within the host induces a novel switch that reprograms cell and colony morphology and confers commensal fitness. These GUT (Gastrointestinally-IndUced Transition) cells lack the functional hallmarks of sexually-competent opaque cells, which they resemble morphologically, and bona fide opaque cells are defective for commensalism. Rather, the GUT cell transcriptome appears to be optimized for the environment of the distal mammalian digestive tract. Our discovery of the GUT cell type switch offers insight into how a single microbe can transition between commensalism and invasive tissue pathogenesis. We propose to capitalize on this advance to develop the concept that a single organism can be both a commensal and a pathogen via the evolution of an adaptive switch in cell type that is triggered by changes in the host environment. To accomplish this goal, we will 1) identify nodes of a Wor1 regulatory circuit that mediate the white-GUT switch, 2) Identify the environmental signals and regulatory pathways that trigger the white-GUT switch and 3) test the hypothesis that switching is required for C. albicans to transition from a commensal to a pathogen. We anticipate that these studies will define a novel regulatory network required for commensalism, identify the signals that trigger this network and develop an understanding of its role in the ability of Candida to switch from being a commensal to pathogen. These advances are anticipated to open the door to preventative strategies that eliminate Candida from its commensal niche in high-risk patients such as premature babies and hospitalized adults on broad-spectrum antibiotic therapies.