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全面分析致病酵母中的毒力因素，这些因素是在尿路中定植和持续存在所需的。光滑念珠菌和白色念珠菌是引起真菌尿和播散性念珠菌病的两种主要微生物。人们对念珠菌在尿路中定植或存活的因素知之甚少。与白色念珠菌不同，光滑念珠菌是单倍体，这使其成为利用已建立的遗传工具进行毒力遗传分析的极佳模型。我们已经利用这一点来鉴定并开始表征与实验性尿路感染有关的基因的功能和调节。我们以前已经发现了一种粘附素EPA6，它是在UTI过程中特异性诱导的，并提供了证据表明，它受到一种新的机制的调节，在这种机制中，限制环境中NAD+的前体烟酸水平会导致EPA6基因转录的去抑制。 我们建议在这些结果的基础上采取几种方式。首先，我们建议分析NA限制作为尿路中光滑念珠菌基因调控的一般信号的重要性。作为这项工作的一部分，我们将确定其他NA调节的基因(由两个依赖于NAD*的组蛋白去乙酰基酶Sir2和Hst1调控)是否实际上在尿路感染期间被诱导。我们还假设NA限制的调节作用与其他转录因子一起控制EPA6的转录，并建议确定其中一些因子。我们有证据表明，Hst1和Sir2调控的基因对不同水平的NA做出反应，并假设不同水平的NA限制可以通过对Sir2和Hst1的不同影响向细胞发出信号，这是两种酶对NAD*的Km不同的结果。其次，我们提出NA调节基因影响UTI毒力。我们假设EPA6和其他五种EPA粘附素是在尿路感染期间诱导的，并且这些粘附素共同作用于尿路定植。此外，我们假设并将测试编码NAD*前体转运蛋白的三个HSH1调节基因是否在UTI毒力中起关键作用。 这些方法将提供对酵母-宿主相互作用的重要方面的洞察，并更好地理解导致真菌UTI的过程，最终目的是加强治疗干预。