Signals and switches for Candida albicans commensalism

描述(申请人提供)：共生微生物如何致病？通常认为，由共生生物产生的侵袭性感染主要是由于宿主免疫崩溃造成的。然而，这些微生物也有可能在共生和毒力计划之间积极过渡。事实上，我们最近发现，人类真菌共生病原体白念珠菌接触到哺乳动物的肠道会触发一个重大的发育开关。这种转换需要经过充分研究的Wor1转录因子，该转录因子被认为只在罕见的遗传背景下表达，在那里它促进了参与交配的表观遗传转换。相反，我们发现这种转录因子可以在野生型细胞中表达，但只有在它们通过哺乳动物的肠道时才能表达。我们已经证明，WOR1在宿主内的表达诱导了一种新的开关，这种开关重新编程了细胞和克隆的形态，并赋予了共生适合性。这些肠道(胃肠诱导转化)细胞缺乏具有性能力的不透明细胞的功能特征，它们在形态上与之相似，真正的不透明细胞在共生方面是有缺陷的。相反，肠道细胞转录组似乎对哺乳动物远端消化道的环境进行了优化。我们对肠道细胞类型转换的发现为单一微生物如何在共生和侵袭组织发病机制之间过渡提供了洞察力。我们建议利用这一进展来发展这样的概念，即通过宿主环境变化触发的细胞类型适应性切换的进化，单个有机体既可以是共生体，也可以是病原体。为了实现这一目标，我们将1)识别介导白肠开关的Wor1调节电路的节点，2)识别触发白肠开关的环境信号和调节通路，3)检验白念珠菌从共生菌向病原体转变需要开关的假设。我们预计，这些研究将定义共生所需的新的调控网络，识别触发该网络的信号，并了解其在念珠菌从共生转变为病原体的能力中所起的作用。这些进展预计将为预防战略打开大门，这些战略将消除念珠菌在早产儿和接受广谱抗生素治疗的住院成年人等高危患者中的共生利基地位。

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.