Pathogenesis of Candida glabrata in the Urinary Tract

描述（由申请人提供）：本申请的长期目标是对病原菌在泌尿道中定植和持续所需的毒力因子进行综合分析。光秃念珠菌和白色念珠菌是导致真菌病和播散性念珠菌病的两种主要微生物。对于允许念珠菌在泌尿道中定居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，这使得它成为利用已经建立的遗传工具进行毒力遗传分析的绝佳模型。我们已经利用这一点来识别并开始表征与实验性UTI相关的基因的功能和调控。我们之前已经发现了一种在UTI期间特异性诱导的粘附素EPA6，并提供了证据表明它受一种新机制的调节，在这种机制中，限制环境中烟酸（NAD+的前体）的水平会导致EPA6基因转录的抑制。

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.