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: 10398003
• 负责人: DAVID KADOSH
• 金额: $ 37.8万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398003
• 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; 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; Vagina; Virulence; Virulence Factors; Yeasts; base; chemotherapy; design; experimental study; fungus; genome-wide; mouse model; mutant; neonate; novel; organ transplant recipient; 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.

项目总结/摘要 白色念珠菌是最常见的分离的人类真菌病原体，是导致多种疾病的原因。 全身和粘膜感染。免疫功能低下的人，包括癌症患者， 化疗，艾滋病患者，新生儿和器官移植受者，特别容易受到 感染C.白色念珠菌进行可逆的形态转变，从单一的芽殖酵母 细胞到细丝（细长的细胞首尾相连）对毒力以及几种毒力都很重要， 相关属性。而控制C.白色 形态转变已经得到很好的表征，相当少的是知道的作用， 翻译机制我们最近发现UME 6，它编码一个特定于细丝的关键 C.转录调节子白色念珠菌的形态和毒力，具有最长的5' 非翻译区（UTR）在真菌中鉴定的日期。UME 6 5' UTR抑制C.白色念珠菌感染 在各种诱导条件下，以及UME 6表达的能力，以确定C.白色 形态学5' UTR不影响UME 6转录水平或诱导动力学，而是特异性地影响UME 6转录水平或诱导动力学。 降低UME 6的翻译效率，如通过多核糖体谱分析所确定的。重要的是 由UME 6 5' UTR指导的翻译抑制水平通过不同的诱导表达调节。 条件最近的一项初步核糖体分析实验表明，存在两种不同的核糖体 UME 6 5' UTR中的停滞位点，两者都位于预测的复合物的上游 稳定的RNA二级结构。RNA-seq分析表明，除了UME 6， 大量的C。白念珠菌参与毒力形成的基因，以及其他多种毒力相关基因， 过程，包括生物膜的形成，粘附和分泌的降解酶的产生，也具有 长5'UTR。基于这一证据，我们假设5'UTR介导的翻译效率 机制在控制C.白色念珠菌形态、毒力和毒力相关 响应宿主环境线索的过程。为了解决这一假设，我们计划：1） 确定C.白色念珠菌丝状生长信号通路控制形态和Ume 6表达 通过5 ′ UTR调节UME 6的翻译效率，2）确定分子机制， UME 6 5' UTR抑制翻译效率，3）确定5' UTR介导的翻译效率的更广泛作用。 控制C.白念珠菌的毒力与多种毒力有关 特性.这些研究将为我们更好地理解5'UTR介导的翻译效率 在一个主要的人类真菌病原体中控制形态和毒力的机制。最终，共同 调节真菌致病性的翻译效率机制的真菌特异性组分可以 作为开发新的和更有效的抗真菌策略的潜在目标。