Regulation of Candida albicans gene expression in response to host environmental stresses

白色念珠菌基因表达响应宿主环境胁迫的调节

基本信息

批准号：
10867738
负责人：
DAVID KADOSH
金额：
$ 58.2万
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：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10867738
关键词：
5&apos Untranslated Regions Acquired Immunodeficiency Syndrome Address Affect Antibiotics Antifungal Agents Binding Binding Proteins Bioinformatics Biological Assay Cancer Patient Candida albicans Candidiasis Cell Wall Cell membrane Complex Cryptococcus neoformans Defect Development Disseminated candidiasis EIF-2alpha Environment Epitopes Eukaryotic Initiation Factor-4F Fungal Drug Resistance Gene Expression Genes Genetic Transcription Goals Growth HIV/AIDS Hospitals Human Immune Immunocompromised Host Individual Infection Link Macrophage Mediating Membrane Messenger RNA Morphology Mucous Membrane Mutation Orthologous Gene Osmosis Oxidative Stress Pathogenesis Pathogenicity Patients Phagocytes Phosphorylation Phosphotransferases Play Predisposition Process Proteins Public Health Regulation Ribosomes Role Saccharomyces cerevisiae Sepsis Signal Pathway Stress Structure Systemic infection Testing Transcript Translational Regulation Translations Virulence Yeasts biological adaptation to stress chemotherapy combat environmental stressor experimental study genome-wide helicase mRNA capping mouse model mutant neutrophil new therapeutic target novel novel therapeutic intervention organ transplant recipient pathogenic fungus prevent protein function response ribosome profiling translation factor treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Candida albicans is a major human fungal pathogen responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals, including organ transplant recipients, AIDS patients and cancer patients on chemotherapy are highly susceptible to infection. In the host environment C. albicans encounters a wide variety of environmental stresses, including acidic pH, osmotic/cationic, thermal, oxidative, nitrosative, cell wall and cell membrane stresses. While transcriptional and post-translational mechanisms that mediate C. albicans stress responses have been well-characterized, considerably less is known about the role of translational mechanisms; given that many effective classes of antibiotics target bacterial translation mechanisms, this remains an unexplored and unexploited avenue for antifungal development. The eIF4F translation initiation complex is important for binding to the 5' CAP of mRNAs and contains helicase activity that unwinds complex secondary structures in 5' untranslated regions (UTRs) to promote translation and ribosome accessibility. We have recently demonstrated that fungal-specific C. albicans orthologs of the yeast eIF4E-binding proteins Eap1 and Caf20, which function as negative regulators of the eIF4F complex, play an important role in controlling oxidative and cell wall/cell membrane stress responses. In addition, we have shown that both C. albicans proteins are down-regulated in response to membrane stress and orf19.7034 (the Eap1 ortholog) functions as a key negative regulator of P-body formation under multiple stress conditions (P- bodies are translationally inactive cellular compartments). Using ribosome profiling, we have also recently demonstrated that the C. albicans morphological transition, and most likely additional virulence processes, is under widespread global translational control. Based on this evidence, and additional studies, our hypothesis is that elucidating translational regulatory mechanisms which control the ability of C. albicans to respond to host environmental stresses will provide a new strategy to identify and characterize potential antifungal targets. To address this hypothesis, we plan to: 1) determine the global translational profile of C. albicans in response to a variety of host environmental stress conditions; we will also identify and characterize selected translationally controlled target genes important for C. albicans stress responses, 2) determine how eIF4E-binding proteins and components of the eIF4F complex control the ability of C. albicans to respond to host environmental stresses, 3) determine how translational stress response mechanisms control C. albicans virulence and pathogenicity using both a mouse model of systemic candidiasis and macrophage/neutrophil killing and survival assays. These studies will provide a better understanding of global regulatory circuits and individual factors that control the translational response of C. albicans to host environmental stress conditions. Ultimately, common fungal-specific translation factors and/or target genes important for stress responses, virulence and pathogenesis could serve as important targets for the development of novel and more effective antifungals.

项目概要/摘要白色念珠菌是一种主要的人类真菌病原体，可导致多种系统和粘膜疾病感染。免疫功能低下的个体，包括器官移植受者、艾滋病患者和癌症患者化疗患者极易受到感染。在宿主环境中，白色念珠菌遇到各种环境压力，包括酸性 pH、渗透/阳离子、热、氧化、亚硝化、细胞壁和细胞膜应力。而介导 C. 的转录和翻译后机制白色念珠菌的应激反应已被充分表征，但人们对它的作用知之甚少。翻译机制；鉴于许多有效的抗生素类别都针对细菌翻译机制，这仍然是抗真菌开发的一个未探索和未开发的途径。 eIF4F 翻译起始复合物对于结合 mRNA 的 5' CAP 很重要，并且含有解旋酶活性解开 5' 非翻译区 (UTR) 中的复杂二级结构，以促进翻译和核糖体可及性。我们最近证明了酵母的真菌特异性白色念珠菌直系同源物 eIF4E 结合蛋白 Eap1 和 Caf20 作为 eIF4F 复合物的负调节因子，发挥着在控制氧化和细胞壁/细胞膜应激反应中发挥重要作用。此外，我们还有结果表明，两种白色念珠菌蛋白都会因膜应激和 orf19.7034（ Eap1直系同源物）在多种应激条件下（P-body）作为P体形成的关键负调节因子发挥作用体是翻译不活跃的细胞区室）。使用核糖体分析，我们最近还证明白色念珠菌形态转变以及最有可能的额外毒力过程是受到广泛的全球翻译控制。基于这些证据和其他研究，我们的假设是阐明控制白色念珠菌响应宿主能力的翻译调控机制环境压力将提供一种新的策略来识别和表征潜在的抗真菌目标。到为了解决这个假设，我们计划：1）确定白色念珠菌的全球翻译概况，以响应各种宿主环境应激条件；我们还将通过翻译来识别和表征所选的对白色念珠菌应激反应很重要的受控靶基因，2) 确定 eIF4E 结合蛋白如何 eIF4F 复合物的组成部分控制白色念珠菌对宿主环境做出反应的能力应激，3) 确定转化应激反应机制如何控制白色念珠菌毒力和使用系统性念珠菌病和巨噬细胞/中性粒细胞杀灭小鼠模型进行致病性和生存分析。这些研究将有助于更好地了解全球监管回路和个人控制白色念珠菌对宿主环境应激条件的翻译反应的因素。最终，常见的真菌特异性翻译因子和/或对应激反应、毒力和发病机制可以作为开发新型且更有效的抗真菌药物的重要目标。