Signals and switches for Candida albicans commensalism

白色念珠菌共生的信号和开关

• 批准号: 9172234
• 负责人: SUZANNE M NOBLE
• 金额: $ 39.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172234
• 关键词: Acids; Adult; Alpha Cell; Animal Model; Antibiotic Therapy; Bacteria; Biological; Candida; Candida albicans; Carbon Dioxide; Cells; ChIP-seq; Competence; Development; Disease; Distal; Environment; Epigenetic Process; Evolution; Fatty Acids; Fungal Components; Gastrointestinal tract structure; Genetic; Genetic Transcription; Goals; Human; Human Microbiome; Immunity; In Vitro; Infection; Intravenous; Knock-out; Libraries; Life; Mediating; Microbe; Modeling; Monitor; Morphology; Mycoses; Nature; Nutritional; Organism; Partner in relationship; Pathogenesis; Pathway interactions; Patient risk; Phase; Phase Transition; Phenotype; Premature Infant; Prevention strategy; Preventive therapy; Property; Publications; Regulatory Pathway; Reporter; Role; Signal Pathway; Signal Transduction; Symbiosis; Testing; Tissues; Transitional Cell; Virulence; alkalinity; base; cell type; commensal microbes; experimental study; exposed human population; fitness; gastrointestinal; high risk; insight; microorganism; novel; oropharyngeal thrush; overexpression; pathogen; programs; promoter; public health relevance; response; small molecule; transcription factor; transcriptome

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.

描述（由申请人提供）：共生微生物如何引起疾病？一般认为，由共生生物产生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共生和毒力程序之间主动转换。事实上，我们最近发现，人类真菌共生病原体白色念珠菌暴露于哺乳动物肠道会触发一个主要的发育开关。这种开关需要经过充分研究的Wor1转录因子，该因子被认为仅在罕见的遗传背景下表达，在这种遗传背景下，它促进了与交配有关的表观遗传开关。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的肠道时才会发生。我们已经证明，WOR1在宿主体内的表达诱导了一种新的开关，这种开关可以重编程细胞和集落形态，并赋予共生适应性。这些GUT（胃肠道诱导转化）细胞缺乏具有性能力的不透明细胞的功能特征，它们在形态上与不透明细胞相似，真正的不透明细胞在共生方面存在缺陷。相反，肠道细胞转录组似乎针对哺乳动物远端消化道的环境进行了优化。我们发现的肠道细胞类型转换提供了对单个微生物如何在共生和侵入性组织发病机制之间转换的见解。我们建议利用这一进展来发展这样一个概念，即单个生物体既可以是共生体，也可以是病原体，这是通过宿主环境变化引发的细胞类型适应性开关的进化来实现的。为了实现这一目标，我们将1)确定介导白色肠道开关的Wor1调节回路的节点，2)确定触发白色肠道开关的环境信号和调节途径，3)验证白色念珠菌从共生菌转变为病原体所需的开关假设。我们预计这些研究将定义共生体所需的一个新的调控网络，确定触发该网络的信号，并了解其在念珠菌从共生体转变为病原体的能力中的作用。预计这些进展将为在高危患者（如早产儿和接受广谱抗生素治疗的住院成人）中消除念珠菌的共生生态位的预防策略打开大门。