Translational Regulation of Candida glabrata Azole Resistance

光滑念珠菌唑耐药性的转化调控

基本信息

批准号：
10681915
负责人：
DAVID KADOSH
金额：
$ 19.38万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-20 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10681915
关键词：
5&apos Untranslated Regions Acquired Immunodeficiency Syndrome Anabolism Antifungal Agents Automobile Driving Azole resistance Azoles Bioinformatics Cancer Patient Candida Candida albicans Candida glabrata Candidiasis Cells Centers for Disease Control and Prevention (U.S.)Chromosomal Rearrangement Classification Clinical Data Development Drug Efflux Drug resistance Ergosterol Event Filament Fluconazole Fungal Drug Resistance Genes Genetic Genetic Transcription Goals Human Immunocompromised Host Individual Infection Laboratories Lanosterol Life Mediating Monitor Morbidity - disease rate Mucous Membrane Oxidative Stress Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Point Mutation Predisposition Process Property Protein Biosynthesis Proteins Proxy Public Health Resistance Role Saccharomyces cerevisiae Sepsis Testing Transcript Translational Regulation Translations Treatment Protocols Virulence Work Yeasts chemotherapy clinically significant effective therapy efflux pump genome-wide mortality mutant new therapeutic target novel novel therapeutics organ transplant recipient overexpression pathogenic fungus protein expression resistance frequency resistance mechanism response ribosome profiling therapeutically effective trait transcriptome sequencing treatment response whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Candida glabrata is an important human fungal pathogen capable of causing both systemic and mucosal infections in a wide variety of immunocompromised individuals, including organ transplant recipients, cancer patients on chemotherapy and AIDS patients. C. glabrata is the second most frequently isolated Candida species in invasive bloodstream infections, has a high crude mortality rate (~40-60%), and has been classified as a “serious” threat to public health by the Centers for Disease Control (CDC). While resistance of C. glabrata clinical isolates to multiple antifungals, particularly azoles, is on the rise only three major drug classes are available for treatment. Previous studies have shown that C. glabrata antifungal resistance can be attributed to a variety of genetic point mutations, chromosomal rearrangements as well as increased transcription of certain drug efflux pumps. In contrast to genetic and transcriptional mechanisms, very little is known about translational mechanisms that control antifungal resistance in C. glabrata or other human fungal pathogens. However, we and others have shown that long 5’ UTR-mediated translational efficiency mechanisms play an important role in controlling the expression of several key regulators of virulence-related processes in Candida albicans and, based on RNA-seq data, many C. glabrata genes specifically involved in azole resistance also possess long 5’ UTRs that could be involved in translational regulation. Using genome-wide ribosome profiling, we have recently demonstrated that the C. albicans yeast-filament transition is under widespread translational control and several genes associated with antifungal resistance also showed altered translational efficiency during this transition. A similar ribosome profiling analysis in Saccharomyces cerevisiae, which is more closely related to C. glabrata, also showed significant translational expression changes in response to oxidative stress. Many C. glabrata genes important for protein synthesis are significantly down-regulated in response to azole treatment. In addition, only a small fraction of C. glabrata genes showing altered protein expression in azole resistant vs. susceptible isolates also showed changes at the transcript level and evidence suggests that C. glabrata ERG11, encoding the azole target lanosterol 14-demethylase, could be under translational control. Based on these observations, we hypothesize that translational mechanisms play an important role in controlling azole resistance in C. glabrata. In order to test this hypothesis, we will: 1) determine the genome- wide translational profile of C. glabrata in response to treatment with fluconazole, the most commonly used azole drug, 2) identify and characterize translational mechanisms important for driving C. glabrata azole resistance. Ultimately, this study will provide a better understanding of global regulatory circuits and pathways that control C. glabrata azole resistance at the translational level. In addition, this study will identify and characterize several key translationally regulated factors important for C. glabrata drug resistance that could potentially serve as targets for the development of novel antifungal strategies.

项目概要/摘要光滑念珠菌是一种重要的人类真菌病原体，能够引起全身和粘膜感染多种免疫功能低下个体的感染，包括器官移植受者、癌症化疗患者和艾滋病患者是第二常见的念珠菌。侵袭性血流感染中的物种，具有较高的粗死亡率（~40-60%），已被分类为疾病控制中心 (CDC) 将其视为对公众健康的“严重”威胁，而光滑念珠菌具有抗药性。多种抗真菌药物（尤其是唑类药物）的临床分离株呈上升趋势，仅三种主要药物类别先前的研究表明光滑念珠菌抗真菌耐药性可归因于各种基因点突变、染色体重排以及某些基因的转录增加与遗传和转录机制相比，人们对药物流出泵知之甚少。控制光滑念珠菌或其他人类真菌病原体抗真菌耐药性的翻译机制。然而，我们和其他人已经证明，长 5’UTR 介导的翻译效率机制发挥着重要作用在控制念珠菌毒力相关过程的几个关键调节因子的表达中发挥重要作用白色念珠菌，根据 RNA-seq 数据，许多光滑念珠菌基因也专门参与唑类抗性拥有可能参与翻译调控的长5’UTR，使用全基因组核糖体分析，我们最近证明白色念珠菌酵母丝转变处于广泛的翻译过程中控制和与抗真菌耐药性相关的几个基因也显示出翻译效率在此转变过程中，对酿酒酵母进行了类似的核糖体分析，结果更接近。与 C. glabrata 相关的，也显示出响应氧化应激的显着翻译表达变化。许多对蛋白质合成很重要的光滑 C. glabrata 基因响应唑类而显着下调此外，只有一小部分光滑 C. glabrata 基因显示唑类蛋白表达发生改变。耐药菌株与敏感菌株在转录水平上也表现出变化，证据表明 C. glabrata ERG11 编码唑类靶点羊毛甾醇 14α-去甲基酶，可能处于翻译控制之下。基于这些观察，我们认为翻译机制在控制 C. glabrata 的唑类抗性为了检验这一假设，我们将： 1) 确定基因组。光滑念珠菌对氟康唑（最常用的药物）治疗的广泛翻译谱唑类药物，2) 识别和表征对于驱动光滑 C. glabrata 唑类重要的翻译机制最终，这项研究将提供对全球监管回路和途径的更好理解。在翻译水平上控制 C. glabrata 唑耐药性此外，本研究将鉴定和表征对光滑念珠菌耐药性很重要的几个关键翻译调节因子，这些因子可以可能作为开发新型抗真菌策略的目标。