Translational Control of Morphology and Virulence in Candida albicans

白色念珠菌形态和毒力的转化控制

• 批准号: 9910361
• 负责人: DAVID KADOSH
• 金额: $ 39.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910361
• 关键词: 5' Untranslated Regions; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adhesions; Agar; Antifungal Agents; Antifungal Therapy; Cancer Patient; Candida albicans; Candidiasis; Cells; Complex; Cues; Cytotoxic Chemotherapy; Data; Development; Disseminated candidiasis; Enzymes; Filament; Gastrointestinal tract structure; Genes; Genetic Transcription; Goals; Growth; Human; Immunocompromised Host; In Vitro; Individual; Infection; Kinetics; Laboratories; Life; Measures; Mediating; Microbial Biofilms; Molecular; Morphology; Mucous Membrane; Oral; Oral candidiasis; Organ Transplantation; Pathogenesis; Pathogenicity; Patients; Play; Process; Production; Property; Public Health; RNA; Research; Ribosomes; Role; Saccharomycetales; Signal Pathway; Signal Transduction; Site; Structure; Systemic infection; Therapeutic immunosuppression; Transcript; Translational Repression; Translations; Transplant Recipients; Vagina; Virulence; Virulence Factors; Yeasts; base; chemotherapy; design; experimental study; fungus; genome-wide; mouse model; mutant; neonate; novel; pathogenic fungus; polysome profiling; response; ribosome profiling; transcriptome sequencing; yeast infection

PROJECT SUMMARY/ABSTRACT Candida albicans, the most commonly isolated human fungal pathogen, is responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals, including cancer patients on chemotherapy, AIDS patients, neonates, and organ transplant recipients, are particularly susceptible to infection. The ability of C. albicans to undergo a reversible morphological transition from single budding yeast cells to filaments (elongated cells attached end-to-end) is important for virulence as well as several virulence- related properties. While transcriptional and post-translational mechanisms that control the C. albicans morphological transition have been well-characterized, considerably less is known about the role of translational mechanisms. We have recently discovered that UME6, which encodes a key filament-specific transcriptional regulator of C. albicans morphology and virulence, possesses one of the longest 5’ untranslated regions (UTRs) identified in fungi to date. The UME6 5’ UTR inhibits C. albicans filamentation under a variety of inducing conditions as well as the ability of UME6 expression to determine C. albicans morphology. The 5’ UTR does not affect UME6 transcript levels or induction kinetics, but instead specifically reduces translational efficiency of UME6, as determined by a polysome profiling analysis. Importantly, the level of translational inhibition directed by the UME6 5’ UTR is modulated by different filament-inducing conditions. A recent preliminary ribosome profiling experiment indicates the presence of two distinct ribosome stalling sites in the UME6 5’ UTR, both of which are located immediately upstream of predicted complex stable RNA secondary structures. An RNA-seq analysis has demonstrated that in addition to UME6, a significant number of C. albicans genes involved in filamentation, and a variety of other virulence-related processes, including biofilm formation, adhesion, and secreted degradative enzyme production, also possess long 5’ UTRs. Based on this evidence, our hypothesis is that 5’ UTR-mediated translational efficiency mechanisms play an important role in controlling C. albicans morphology, virulence and virulence-related processes in response to host environmental cues. In order to address this hypothesis, we plan to: 1) determine how C. albicans filamentous growth signaling pathways control morphology and Ume6 expression by regulating UME6 translational efficiency via the 5’ UTR, 2) determine the molecular mechanism(s) by which the UME6 5’ UTR inhibits translational efficiency, 3) determine the broader role of 5’ UTR-mediated translational efficiency mechanisms in controlling C. albicans virulence and a variety of virulence-related properties. These studies will provide a better understanding of how 5’ UTR-mediated translational efficiency mechanisms control morphology and virulence in a major human fungal pathogen. Ultimately, common fungal-specific components of translational efficiency mechanisms that regulate fungal pathogenicity could serve as potential targets for the development of novel and more effective antifungal strategies.

项目摘要/摘要 白色念珠菌是最常见的人类真菌病原体，负责多种多样 系统性和粘膜感染。免疫功能低下的个体，包括癌症患者 化学疗法，艾滋病患者，新生儿和组织接受者，特别容易受到 感染。白色念珠菌经历单个萌芽酵母的可逆形态过渡的能力 细胞到细丝（端到端附着的细长细胞）对于病毒以及几种病毒至关重要 相关属性。而控制白色念珠菌的转录和翻译后机制 形态学转变已经得到充分的特征，仔细的少知识已知 翻译机制。我们最近发现，编码特定于密钥丝的UME6 白色念珠菌形态和病毒的转录调节剂具有最长的5' 迄今为止，在真菌中确定的未翻译区域（UTR）。 UME6 5'UTR抑制白色念珠菌细丝 在多种诱导条件下以及UME6表达确定白色念珠菌的能力 形态学。 5'UTR不会影响UME6的转录水平或归纳动力学，而是专门 通过多聚合体分析分析确定了UME6的翻译效率。重要的是， UME6 5'UTR指导的翻译抑制水平受不同的丝诱导调节 状况。最近的初步核糖体分析实验表明存在两个不同的核糖体 在UME6 5'UTR中存储站点，这两个位置都位于预测复合物的上游 稳定的RNA二级结构。 RNA-seq分析表明，除了UME6之外 大量参与细丝的白色念珠菌基因以及各种其他病毒有关的 过程，包括生物膜形成，粘合剂和分泌的降解酶产生，也具有 长5'utrs。基于此证据，我们的假设是5'UTR介导的翻译效率 机制在控制白色念珠菌的形态，病毒和病毒相关方面起着重要作用 响应主机环境提示的过程。为了解决这一假设，我们计划：1） 确定白色念珠菌丝状生长信号通路如何控制形态和UME6表达 通过5'UTR调节UME6的转化效率，2）通过 UME6 5'UTR抑制翻译效率，3）确定5'UTR介导的更广泛的作用 控制白色念珠菌病毒和多种与病毒有关的转化效率机制 特性。这些研究将更好地了解5'UTR介导的翻译效率 机制控制了主要人类真菌病原体中的形态和病毒。最终，常见 调节真菌致病性的转化效率机制的真菌特异性组成部分可以 作为开发新颖和更有效的抗真菌策略的潜在目标。