Pathogenesis of Candida glabrata in the Urinary Tract

尿道光滑念珠菌的发病机制

• 批准号: 8062115
• 负责人: Brendan Cormack
• 金额: $ 31.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8062115
• 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; 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（由申请方提供）：本申请的长期目的是全面分析致病酵母菌在尿路中定植和持久存在所需的毒力因子。光滑念珠菌和白色念珠菌是导致真菌尿和播散性念珠菌病的两种主要微生物。关于念珠菌在泌尿道定植或持续存在的因素知之甚少。与C.白色念珠菌、C. glabrata是单倍体，使其成为使用已经建立的遗传工具进行毒力遗传分析的极好模型。我们已经利用这一点，以确定和开始的功能和实验性尿路感染的基因调控的特点。我们以前已经确定了一种粘附素EPA 6，它是在UTI过程中特异性诱导的，并提供了证据表明，它是由一种新的机制，其中限制环境水平的烟酸，NAD+的前体，导致EPA 6基因转录的去抑制。 我们建议以几种方式在这些结果的基础上再接再厉。首先，我们建议分析NA限制作为C的一般信号的重要性。glabrata基因在泌尿道的调控。作为这项研究的一部分，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Sir 2和Hst 1调节）是否在UTI期间被诱导。我们还假设，NA限制的调节作用与其他转录因子控制EPA 6转录，并提出确定这些因素中的一些。我们有证据表明，Hst 1和Sir 2调节基因对不同水平的NA作出反应，并假设不同水平的NA限制可以通过对Sir 2和Hst 1的差异效应向细胞发出信号，这是两种酶对NAD* 的Km差异的结果。其次，我们提出NA调控基因影响UTI毒力。我们假设EPA 6和其他五种EPA粘附素在UTI期间被诱导，并且这些粘附素在尿路的定植中联合起作用。此外，我们假设并将测试是否有三个HSH 1调控的基因，编码NAD* 前体转运蛋白，是UTI毒力的关键。 这些方法将提供深入了解酵母-宿主相互作用的重要方面，并提高对真菌UTI过程的理解，最终目的是加强治疗干预。