Pathogenesis of Candida glabrata in the Urinary Tract

尿道光滑念珠菌的发病机制

• 批准号: 7868931
• 负责人: Brendan Cormack
• 金额: $ 2.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7868931
• 关键词: Accounting; Adherence; Amino Acids; Bacterial Adhesins; Binding; Biochemical; Blood; Candida; Candida albicans; Candida glabrata; Candidiasis; Cell surface; Cells; Clone Cells; Collaborations; DNA Binding; Disseminated candidiasis; Enzymes; Eosinophil-Derived Neurotoxin; Family; Family member; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Transcription; Grant; Growth; Haploidy; Histone Deacetylase; Histones; Human; Infection; Ligand Binding Domain; Ligands; Mediating; Mediator of activation protein; Modeling; Niacinamide; Nicotinic Acids; Oligonucleotide Microarrays; Organism; Pathogenesis; Process; Regulation; Reporter; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Saccharomycetales; Signal Transduction; Specificity; Stream; System; Testing; Therapeutic Intervention; United States; Urinary tract; Urine; Virulence; Virulence Factors; Vitamins; Work; Yeasts; activating transcription factor; asexual; base; derepression; genetic analysis; improved; insight; interest; mutant; novel; pathogen; programs; promoter; response; sugar; tool; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this application is a comprehensive analysis of virulence factors in pathogenic yeast required for colonization and persistence in the urinary tract. Candida glabrata and Candida albicans are the two major organisms responsible for funguria, as well as disseminated candidiasis. Little is known about the factors that allow Candida to colonize or persist in the urinary tract. Unlike C. albicans, C. glabrata is haploid making it an excellent model for genetic analysis of virulence using already established genetic tools. We have exploited this to identify and to begin to characterize the function and regulation of genes implicated in experimental UTI. We have previously identified an adhesin EPA6 that is specifically induced during UTI, and provided evidence that it is regulated by a novel mechanism in which limiting environmental levels of nicotinic acid, a precursor of NAD+, leads to derepression of EPA6 gene transcription. We propose to build on these results in several ways. First, we propose to analyze the importance of NA-limitation as a general signal for C. glabrata gene regulation in the urinary tract. As part of this, we will determine if other NA-regulated genes (regulated by two NAD* dependent histone deacetylases Sir2 and Hst1) are in fact induced during UTI. We also hypothesize that regulation by NA limitation acts with other transcription factors to control EPA6 transcription and propose to identify some of these factors. We have evidence that Hst1- and Sir2 regulated genes respond to different levels of NA, and hypothesize that different levels of NA limitation can signal to the cell by differential effects on Sir2 and Hst1, as a result of differences in the Km of the two enzymes for NAD*. Secondly, we propose that NA-regulated genes impact UTI virulence. We hypothesize that EPA6 and five other EPA adhesins are induced during UTI, and that these act in combination in colonization of the urinary tract. In addition, we hypothesize and will test whether three HSH1-regulated genes, which encode transporters of NAD* precursors, are critical in UTI virulence. These approaches will provide insight into significant aspects of the yeast-host interaction and an improved understanding of the processes contributing to fungal UTI, with the ultimate aim of enhancing therapeutic intervention.

描述（由申请人提供）：本申请的长期目标是对泌尿道中定植和持久存在所需的病原酵母菌的毒力因子进行全面分析。光滑念珠菌和白色念珠菌是导致真菌和播散性念珠菌病的两种主要微生物。对于念珠菌在泌尿道定植或持续存在的因素知之甚少。与白色念珠菌不同，光滑念珠菌是单倍体，使其成为使用已建立的遗传工具进行毒力遗传分析的绝佳模型。我们利用这一点来识别并开始表征与实验性尿路感染相关的基因的功能和调控。我们之前已经鉴定了一种在 UTI 期间特异性诱导的粘附素 EPA6，并提供了证据表明它受到一种新机制的调节，在该机制中限制烟酸（NAD+ 的前体）的环境水平会导致 EPA6 基因转录的去抑制。 我们建议以多种方式巩固这些成果。首先，我们建议分析 NA 限制作为泌尿道光滑念珠菌基因调节的一般信号的重要性。作为其中的一部分，我们将确定其他 NA 调节基因（由两个 NAD* 依赖性组蛋白脱乙酰酶 Sir2 和 Hst1 调节）实际上是否在 UTI 过程中被诱导。我们还假设 NA 限制的调节与其他转录因子一起作用来控制 EPA6 转录，并建议鉴定其中一些因子。我们有证据表明 Hst1 和 Sir2 调节基因对不同水平的 NA 作出反应，并假设由于两种酶对 NAD* 的 Km 差异，不同水平的 NA 限制可以通过对 Sir2 和 Hst1 的不同影响向细胞发出信号。其次，我们提出 NA 调控的基因影响 UTI 毒力。我们假设 EPA6 和其他五种 EPA 粘附素在 UTI 过程中被诱导，并且这些粘附素在尿路定植中联合作用。此外，我们假设并将测试编码 NAD* 前体转运蛋白的三个 HSH1 调节基因是否对 UTI 毒力至关重要。 这些方法将深入了解酵母与宿主相互作用的重要方面，并加深对真菌性尿路感染过程的理解，最终目的是加强治疗干预。