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尿路定植和持续性所需的致病性酵母中毒力因子的全面分析。念珠菌glabrata和白色念珠菌是负责真菌的两个主要生物，以及传播的念珠菌病。关于使念珠菌在尿路中定殖或持续存在的因素知之甚少。与白色念珠菌不同，C. glabrata是单倍体的，它是使用已经建立的遗传工具对毒力进行遗传分析的绝佳模型。我们已经利用了这一点来识别并开始表征与实验UTI有关的基因的功能和调节。我们先前已经鉴定出在UTI期间特异性诱导的粘附素EPA6，并提供了证据表明它受一种新型机制的调节，在这种机制中限制了NAD+的前体的烟酸的环境水平，导致EPA6基因转录的压抑。 我们建议以几种方式以这些结果为基础。首先，我们建议分析Na限制作为尿路中glabrata基因调节的一般信号的重要性。为此，我们将确定在UTI期间诱导了其他NA调节的基因（受两个依赖性组蛋白脱乙酰基酶SIR2和HST1的调节）。我们还假设通过NA限制的调节与其他转录因子有关控制EPA6转录，并建议识别其中一些因素。我们有证据表明，HST1和SIR2调节基因对不同水平的Na响应，并假设不同水平的Na限制可以通过对SIR2和HST1的差异作用向细胞发出信号，这是由于NAD*的两个酶的KM差异。其次，我们提出NA调节的基因会影响UTI毒力。我们假设在UTI期间诱导了EPA6和其他五个EPA粘附素，并且这些粘附素是在尿路定植中的结合作用。此外，我们假设并将测试编码NAD*前体转运蛋白的三个HSH1调节的基因在UTI毒力中至关重要。 这些方法将提供有关酵母 - 宿主相互作用的重要方面的洞察力，以及对导致真菌UTI的过程的改进理解，最终是增强治疗干预措施的最终目的。