Regulation of Multidrug Resistance in the Emerging Human Fungal Pathogen Candida auris

新兴人类真菌病原体耳念珠菌的多药耐药性调控

基本信息

批准号：
10409832
负责人：
DAVID KADOSH
金额：
$ 23.25万
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：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10409832
关键词：
5&apos Untranslated Regions Acquired Immunodeficiency Syndrome Address Amphotericin B Antifungal Agents Azole resistance Azoles Bioinformatics Cancer Patient Candida Candida albicans Candida auris Candidiasis Centers for Disease Control and Prevention (U.S.)Development Disease Outbreaks Drug Efflux Drug resistance Event Filament Fluconazole Fluconazole resistance Fungal Drug Resistance Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Hospitals Human Immunocompromised Host Individual Infection Laboratories Lanosterol Mediating Microbial Biofilms Monitor Morphology Mucous Membrane Multi-Drug Resistance Mutation Open Reading Frames Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Point Mutation Polyenes Predisposition Process Property Protein Biosynthesis Proteins Proxy Public Health Regulation Resistance Ribosomes Role Site Skin Surface Testing Translational Regulation Translations Treatment Protocols Virulence Work Yeasts base chemotherapy effective therapy efflux pump genome-wide mortality mutant new therapeutic target novel novel therapeutics organ transplant recipient overexpression pathogen pathogenic fungus protein expression resistance frequency resistance mechanism response ribosome profiling therapeutically effective trait transcriptome transcriptome sequencing treatment response virtual whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Candida auris is a rapidly emerging 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. auris has emerged on multiple continents, is responsible for numerous hospital outbreaks and, with a high crude mortality rate (30-70%), has been classified as an “urgent” threat to public health by the Centers for Disease Control (CDC). Many C. auris isolates are highly resistant to multiple classes of antifungals, particularly azoles and polyenes, which is especially concerning given that only three major drug classes are available to treat patients with candidiasis. Previous studies have shown that C. auris antifungal resistance can be attributed to a variety of genetic point mutations (eg: mutations in ERG11, encoding lanosterol 14α-demethylase, the target of azoles) 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. auris or other human fungal pathogens. However, our laboratory and others, have shown that 5' UTR-mediated translational efficiency mechanisms play an important role in controlling the expression of several key transcriptional regulators of morphology, biofilm formation, white-opaque switching and virulence in the related major human fungal pathogen Candida albicans. In addition, RNA-seq analyses have shown that many genes involved in a variety of additional virulence processes, including antifungal resistance, in C. albicans and other Candida species possess long 5' UTR regions 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 that does not simply parallel transcriptional changes in gene expression. Several genes associated with antifungal resistance also showed altered translational efficiency during this transition. Importantly, recent transcriptional profiling of a multidrug resistant C. auris isolate has demonstrated that a significant number of genes involved in protein synthesis show altered expression in response to antifungal treatment. Based on these observations, we hypothesize that translational mechanisms play an important role in controlling multidrug resistance in C. auris. In order to address this hypothesis, we will: 1) determine the genome-wide translational profile of C. auris in response to treatment with fluconazole, a commonly used azole, and the polyene drug amphotericin B, 2) identify and characterize translational mechanisms important for promoting C. auris multidrug resistance. Ultimately, this study will provide a better understanding of global regulatory circuits and pathways that control C. auris multidrug resistance at the translational level. In addition, this study will identify and characterize several key translationally regulated factors important for C. auris multidrug resistance that could potentially serve as targets for the development of novel antifungal strategies.

项目概要/摘要耳念珠菌是一种迅速出现的人类真菌病原体，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、癌症接受化疗的患者和艾滋病患者中，耳念珠菌已在多个大洲出现，是造成这种疾病的原因。多起医院爆发疫情，粗死亡率很高（30-70%），已被列为“紧急”事件疾病控制中心 (CDC) 对公共卫生构成威胁许多耳念珠菌分离株具有高度耐药性。多类抗真菌剂，特别是唑类和多烯类，鉴于仅先前的研究表明，三种主要药物可用于治疗念珠菌病患者。耳念珠菌抗真菌耐药性可归因于多种基因点突变（例如：ERG11、编码羊毛甾醇 14α-去甲基酶（唑类的靶标）以及某些药物的转录增加与遗传和转录机制相比，我们对翻译知之甚少。控制耳念珠菌或其他人类真菌病原体抗真菌耐药性的机制。实验室和其他人已经表明，5'UTR介导的翻译效率机制发挥着重要作用在控制形态学、生物膜形成、相关主要人类真菌病原体白色念珠菌的白色不透明转换和毒力。此外，RNA-seq 分析表明，许多基因涉及多种额外的毒力白色念珠菌和其他念珠菌物种具有长 5' UTR 的过程，包括抗真菌耐药性使用全基因组核糖体分析，我们得到了可能参与翻译调控的区域。最近证明白色念珠菌酵母丝转变受到广泛的翻译控制这不仅仅是与基因表达相关的几个基因的转录变化平行。重要的是，最近抗真菌耐药性在这一转变过程中也表现出了转化效率。多重耐药耳念珠菌分离株的转录谱表明，大量参与蛋白质合成的基因在抗真菌治疗后表现出表达改变。这些观察结果表明，翻译机制在控制中发挥着重要作用。为了解决这个假设，我们将：1）确定全基因组。耳念珠菌对氟康唑（一种常用的唑类）治疗的反应的翻译概况，以及多烯药物两性霉素 B，2) 识别和表征对于促进 C. 重要的翻译机制。最终，这项研究将提供对全球调节回路的更好理解。此外，本研究还将研究在翻译水平上控制耳念珠菌多药耐药性的途径。识别和表征对耳念珠菌多药重要的几个关键翻译调节因子耐药性可能成为开发新型抗真菌策略的目标。